Permeation Of Caffeine Research Articles

Skin penetration enhancing properties of the plant N-alkylamide spilanthol

Ethnopharmacological relevancePlants are often used for skin diseases in different ethnopharmacological systems. Local and systemic effects of topically applied compounds can be significantly increased by plant constituents having skin penetration enhancers. Materials and methodsIn this study, we examined the proposed penetration enhancing properties of spilanthol, an N-alkylamide abundantly present in several Asteraceae plants like Spilanthes acmella L., on three model drugs (caffeine, testosterone and ibuprofen). Moreover, as plants are frequently contaminated with toxic environmental substances, the mutual influence on the transdermal behavior between spilanthol and six model mycotoxins (aflatoxin B1, ochratoxin A, fumonisin B1, citrinin, zearalenone, T-2 toxin) was investigated. ResultsSpilanthol exhibits component and concentration dependent penetration enhancing effects. No significant penetration enhancing effect for ibuprofen has been observed, but with increasing spilanthol concentration (from 0 up to 1w/V%), the permeability of caffeine increased, resulting in an enhancing ratio (ER) of 4.60. For testosterone, a maximal penetration enhancing concentration of 0.5% spilanthol was found (ER=4.13). Next to its beneficial applicability to increase local as well as systemic pharmacological effects of dermally co-administrated drug, this N-alkylamide negatively influences human health risk if spilanthol containing formulations are polluted with mycotoxins: the presence of spilanthol (0.3w/V%) induced a significant increase of permeability coefficient Kp of five investigated mycotoxins, with ER values ranging between 1.57 and 6.37. On the other hand, mycotoxins themselves do not significantly influence the transdermal behavior of spilanthol. ConclusionsThe existence of a significant mutual influence of compounds towards skin penetration should always be considered during the development or as part of the functional quality evaluation of topical products.

Assessing vehicle effects on skin absorption using artificial membrane assays

A vast number of variations in drug/vehicle combinations may come into contact with skin. Evaluating the effect of potential drug, vehicle and skin interactions for all possible combinations is a daunting task. A practical solution is a rapid screening technique amenable to high throughput approaches (e.g. 96-well plates). In this study, three artificial membranes (isopropyl myristate (IPM), certramides and Strat-M™) were evaluated for their ability to predict the skin permeability of caffeine, cortisone, diclofenac sodium, mannitol, salicylic acid and testosterone applied in propylene glycol, water and ethanol as unsaturated and saturated concentrations. Resultant absorption data was compared to porcine skin diffusion cell data. The correlations (r2) between membrane and diffusion cell data from saturated and unsaturated concentrations were 0.38, 0.47 and 0.56 for the Strat-M™, certramide and IPM membranes, respectively. This relationship improved when only saturated concentrations were evaluated (r2=0.60, 0.63 and 0.66 for the Strat-M™, certramide and IPM membranes, respectively). A correlation between membrane retention and the amount remaining in skin had r2 values of 0.73 (Strat-M™), 0.67 (certramides), and 0.67 (IPM). Quantitative structure-permeability relationship models for each membrane identified different physicochemical factors influencing the absorption process. Although further investigations exploring complex topical formulations are required, these results suggest potential use as an initial screening approach to assist in narrowing the selection of formulations to be evaluated with a more biologically intact model, thereby assisting in the development of new topical formulations.

Microfluidic passive permeability assay using nanoliter droplet interface lipid bilayers

Membrane permeability assays play an important role in assessing drug transport activities across biological membranes. However, in conventional parallel artificial membrane permeability assays (PAMPA), the membrane model used is dissimilar to biological membranes physically and chemically. Here, we describe a microfluidic passive permeability assay using droplet interface bilayers (DIBs). In a microfluidic network, nanoliter-sized donor and acceptor aqueous droplets are alternately formed in cross-flowing oil containing phospholipids. Subsequently, selective removal of oil through hydrophobic pseudo-porous sidewalls induces the contact of the lipid monolayers, creating arrayed planar DIBs between the donor and acceptor droplets. Permeation of fluorescein from the donor to the acceptor droplets was fluorometrically measured. From the measured data and a simple diffusion model we calculated the effective permeabilities of 5.1 × 10(-6) cm s(-1), 60.0 × 10(-6) cm s(-1), and 87.6 × 10(-6) cm s(-1) with donor droplets at pH values of 7.5, 6.4 and 5.4, respectively. The intrinsic permeabilities of specific monoanionic and neutral fluorescein species were obtained similarly. We also measured the permeation of caffeine in 10 min using UV microspectroscopy, obtaining a permeability of 20.8 × 10(-6) cm s(-1). With the small solution volumes, short measurement time, and ability to measure a wide range of compounds, this device has considerable potential as a platform for high-throughput drug permeability assays.

Microfluidic Passive Permeability Assay using Nanoliter Droplet Interface Lipid Bilayers

Membrane permeability assays play an important role in assessing drug transport activities across biological membranes. However, in conventional parallel artificial membrane permeability assays (PAMPA), the membrane model used is dissimilar to biological membranes physically and chemically. Here, we describe a microfluidic passive permeability assay using droplet interface bilayers (DIBs). In a microfluidic network, nanoliter-sized donor and acceptor aqueous droplets are alternately formed in cross-flowing oil containing phospholipids. Subsequently, selective removal of oil through hydrophobic pseudo-porous sidewalls induces the contact of the lipid monolayers, creating arrayed planar DIBs between the donor and acceptor droplets. Permeation of fluorescein from the donor to the acceptor droplets was fluorometrically measured. From the measured data and a simple diffusion model we calculated the effective permeabilities of 5.1 × 10−6 cm s−1, 60.0 × 10−6 cm s−1, and 87.6 × 10−6 cm s−1 with donor droplets at pH values of 7.5, 6.4 and 5.4, respectively. The intrinsic permeabilities of specific monoanionic and neutral fluorescein species were obtained similarly. We also measured the permeation of caffeine in 10 min using UV microspectroscopy, obtaining a permeability of 20.8 × 10−6 cm s−1. Furthermore, DIBs of brain lipids were used to measure permeability coefficients of several pharmaceutical compounds. With the small solution volumes, short measurement time, and ability to measure a wide range of compounds, this device has considerable potential as a platform for high-throughput drug permeability assays.

Development of light-responsive porous polycarbonate membranes for controlled caffeine delivery

For controlled caffeine release, light-responsive membranes were developed. It was possible to produce membranes that reduced their caffeine permeability resistance by about 97% when irradiated with UV-light compared to measurements at daylight. This was achieved by grafting polymers possessing photochromic units onto track-edged polycarbonate membranes. Covalently linked coatings on porous polycarbonate membranes were obtained by plasma activation of the membrane surface followed by plasma-induced graft polymerization. Copolymerization of spiro-compounds during the coating process as well as postmodification of preformed coatings with spiropyran resulted in photochromic membranes. For the copolymerization process, the synthesis of five photochromic methacrylic and acrylic spiropyrans and spirooxazines was successfully performed. Additionally, a spiropyran with carboxylic acid functionality was synthesized for the postmodification process. This enabled us to postmodify polymeric materials containing alcohol or amine groups to obtain photochromic materials. UV-irradiation of these light-responsive membranes resulted in a strong colouration of the membrane, in a reduction of surface tension, which resulted in a decreased caffeine permeability resistance. The membranes were characterized using XPS for the elemental composition of the coating, contact angle measurements for the surface tension, solid-state UV/VIS measurements for the determination of the kinetic and stability properties, and two-photon microscopy for the localisation of the photochromic substance in the porous membrane.

Influence of the application area on finite dose permeation in relation to drug type applied

For finite dose skin absorption experiments, a homogeneous donor distribution over the skin surface is usually assumed. However, the influence of the surface distribution on skin absorption is still unknown. The aim of this study was to evaluate the influence of the application area on the permeation of drugs during finite dose skin absorption experiments in static Franz diffusion cells. Permeation experiments with stained aqueous drug formulations were conducted, and the application area was determined by a suitable, objective, automated computational approach. The permeation of caffeine is strongly dependent on the application area. The variability between single experiments decreased when including the application area. For the lipophilic flufenamic acid, this was not the case. The variability highly increased after inclusion of the application area. Thus, a correction of the area is misleading. In summary, depending on the drug's physicochemical characteristics, the application area may influence skin absorption.

Drug silica nanocomposite: preparation, characterization and skin permeation studies

The aim of this work was to evaluate silica nanocomposites as topical drug delivery systems for the model drug, caffeine. Preparation, characterization, and skin permeation properties of caffeine-silica nanocomposites are described. Caffeine was loaded into the nanocomposites by grinding the drug with mesoporous silica in a ball mill up to 10 h and the efficiency of the process was studied by XRPD. Formulations were characterized by several methods that include FTIR, XRPD, SEM and TEM. The successful loading of caffeine was demonstrated by XRPD and FTIR. Morphology was studied by SEM that showed particle size reduction while TEM demonstrated formation of both core-shell and multilayered caffeine-silica structures. Solid-state NMR spectra excluded chemical interactions between caffeine and silica matrix, thus confirming that no solid state reactions occurred during the grinding process. Influence of drug inclusion in silica nanocomposite on the in vitro caffeine diffusion into and through the skin was investigated in comparison with a caffeine gel formulation (reference), using newborn pig skin and vertical Franz diffusion cells. Results from the in vitro skin permeation experiments showed that inclusion into the nanocomposite reduced and delayed caffeine permeation from the silica nanocomposite in comparison with the reference, independently from the amount of the tested formulation.

Synthetic polymer membranes as a proxy of skins in permeation studies of biologically active compounds

This study provides a practical approach that can afford evaluation of drug compound permeability through the skin in which synthetic polymer membranes are used as a proxy. For this, permeation behaviors of a variety of drug molecules through the synthetic membranes were characterized under the iontophoresis condition as well as passive delivery. As a proof of concept, the permeability of caffeine and Triamiondil™, both of which are model drug compounds, through the membranes correlated with conventional use of porcine skin. The synthetic polymer membranes showed similar drug permeation patterns to that of the porcine skin, which allowed us to apply them to an alternate to the animal skin. Moreover, the application of iontophoresis to the device system enabled the drug molecules to pass through both the polymer membranes and porcine skin. Our study also verified that drug permeation is substantially influenced by the current direction that likely drives either electrorepulsion or electroosmosis under iontophoretic conditions. Open image in new window

Effect of concentration on skin permeation of caffeine from gel formulations

Various studies have considered the impact of different physico-chemical drug characteristics, skin thickness, or formulation on the absorption from the skin surface to underlying tissues or to the systemic circulation, but they rarely discuss the influence of drug concentration on the permeation flux of molecules. This research therefore aimed at studying the influence of drug concentration in a caffeine formulation. For this study, three same base gels were used at 1, 3 and 5% of caffeine to evaluate the effect of concentration on in vitro release through synthetic membrane and on ex vivo permeation of caffeine through human skin. No correlation was found between transfer through synthetic membrane and that observed through the skin. This shows that the diffusion flux of caffeine permeation does not depend on the concentration of the formulation but rather on the quantity of formulation applied. This is evidenced by the fact that the lowest lag time (Tlag) and higher absorption rates were obtained with gel at 1% of caffeine applied at 1mg/cm2.Keywords: Absorption rate; Bioavailability; Caffeine; Diffusion flux; Lag time.

Storage Conditions of Skin Affect Tissue Structure and Subsequent in vitro Percutaneous Penetration

Storage of skin at low temperatures may affect its structure. There is no report in the literature on the correlation between spatially resolved skin structure and percutaneous penetration after different storage conditions. The present study applies imaging techniques (multiphoton excitation fluorescence microscopy) and in vitro percutaneous penetration of caffeine under four different storage conditions using skin samples from the same donors: fresh skin, skin kept at –20°C for 3 weeks (with or without the use of polyethylene glycol) and at –80°C. Our results show a correlation between increasing permeation of caffeine and tissue structural damage caused by the storage conditions, most so after skin storage at –80°C. The presented approach, which combines imaging techniques with studies on percutaneous penetration, enables the link between tissue damage at selected depths and penetration into the upper layers of the epidermis to be investigated.

Caffeine microspheres - an attractive carrier for optimum skin penetration

IFSCC Magazine, 12 (4) 359–363 (2009) Synopsis Caffeine is an effective slimming agent used for topical administration or in cosmetic products. The formulation must be such that caffeine reaches the adipocytes in the hypodermis. Biodegradable caffeine-loaded microspheres were evaluated for the transport of caffeine to its site of action for 24 h and upto 72 h. The mean diameter of the microspheres was 2.8 μm and their caffeine loading was 2.3 mg g-1 of particles. The permeation of caffeine from microspheres applied in aqueous suspension or from solution was evaluated through in vitro diffusion measurements with static Franz cells (n = 6) over 24 h or 72 h. The first experiments carried out on full-thickness skin without hypodermis showed that after 24 h the total amount of caffeine was twice as high from microspheres as from aqueous solution (22.6% vs. 9.99%). The results suggested that microspheres could easily penetrate through the skin and accumulate in the receptor compartment, ensuring continuous caffeine release. When the hypodermis was retained, microsphere penetration was only slightly decreased. After 72 hours of exposure the receptor fluid contained 15.3% free caffeine and 27.8% encapsulated fraction. The hypodermis hindered solution permeation, and therefore the free caffeine content was lower. Permeation of microspheres was not stopped by the presence of hypodermis.

A Novel Flow through Diffusion Cell for Assessing Drug Transport across the Buccal Mucosa In Vitro

A novel flow through (FT) diffusion cell for assessing the permeability of compounds across the buccal mucosa was designed. Porcine buccal mucosa was mounted between two chambers with flow through capacity in both the donor and receptor chambers. The permeability of caffeine (CAF), triamcinolone acetonide (TAC), and estradiol (E2) was determined over 4 h and flux values were compared to those obtained using a modified Ussing chamber (MUC). No significant differences in the flux of each probe compound were observed using either the MUC or the novel FT cell. The design of the FT cell allowed for monitoring appearance of receptor solution within the donor chamber during the initial equilibration period, allowing for visual inspection of tissue integrity. These permeability studies demonstrate that this FT cell is a suitable alternative model for assessing drug permeability across the buccal mucosa, without the limitations associated with the static MUC. This novel model was then utilized to determine whether salmeterol xinafoate (SX) could permeate the buccal mucosa at concentrations expected in the oral cavity following inhalation. Concentration-dependent studies demonstrated that SX permeates the buccal mucosa via passive diffusion and that oral mucosal absorption may contribute significantly to the overall systemic exposure of inhaled SX. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4577–4588, 2009

COMBINED EFFECT OF CHEMICAL ENHANCERS AND ULTRASOUND ON THE SKIN PERMEATION OF CAFFEINE

The combined effect of 800 kHz ultrasound with 2W/cm2 intensity and chemical enhancers on the skin permeation of caffeine was investigated using excised ear rabbit skin. Menthol, laurocapram (Azone®), isopropyl myristate and ethanol were selected as enhancers. Caffeine permeation was increased upon incorporation of all enhancers. The steady state fluxes were 05.69, 10.13, 22.42 and 25.06 µg/cm2 per h with enhancement factor equals 1.38, 2.458, 5.441 and 6.083 for 40% EtOH, 10% IPM, 3% AZ and 5% M, respectively. Combined application of ultrasound and enhancers increased the skin permeation rate (flux) of caffeine compared with ultrasound or enhancers alone. The enhancement factor equals 1.485, 4.514, 18.572, and 48.610 for 40% EOH, 10% IPM, 3% AZ and 5% M respectively. Better effects were obtained by the combination with 5%M. The influence of detailed conditions of ultrasound and enhancer applications on the caffeine flux was further investigated using 5% M. Caffeine fluxes were, 95.254, 115.368 and 200.06 µg/cm2 per h upon application of ultrasound for 10, 30, and 60 min respectively.The enhancement effect by this combination was increased with an increase in ultrasonic application duration, suggesting that these conditions might be used to achieve the controlled drug delivery. A pretreatment experiment with ultrasound or 5% M was carried out, and the drug content was measured to understand the role of ultrasound in the combined effect. Pretreatment of the skin with ultrasound increased the caffeine flux, while the effect of pretreatment with 5% M on the skin was similar to that of untreated skin. The results obtained suggested that simultaneous application of ultrasound and enhancers is essential to obtain the pronounced effect for transdermal as well as for topical delivery of caffeine though the skin.

The effect of topical caffeine on the morphology of swine hypodermis as measured by ultrasound

Cellulite or lipodystrophy involves the modification of the subcutaneous adipose tissue. A wide variety of topical products is available to combat cellulite, but these have difficulties in being absorbed through the skin. One option is the therapeutic use of the ultrasound to enhance the trans-dermic transport of these drugs. The objective of this study was the analysis of the effect of caffeine on the morphology of the swine hypodermis, both when applied topically and in combination with ultrasound treatment. The following treatments were applied to the dorsal areas of five pigs (Landrace x Large White, 35 days old, weighing 15 kg each): gel, gel + ultrasound, gel + caffeine (5%, w/w), and gel + caffeine + ultrasound, daily for 15 days. A fifth area received no topical application and was used as a control. Continuous ultrasound of 3 MHz with an intensity of 0.2 W/cm(2) was applied at a rate of 1 min/cm(2). After histological processing (hematoxylin and eosin), morphometric analyses were conducted to determine the thickness and numerical profile of the hypodermis. A one-way analysis variance using a Kolmogorov-Smirnov test was conducted, with a Tukey test used to identify significant differences. A confidence level of P < or = 0.05 was adopted. Caffeine treatment was effective only when associated with ultrasound therapy; the combination resulted in a significant reduction in the thickness of the subcutaneous adipose tissue, as well as damage to the adipocytes, consequently decreasing the number of cells. Ultrasound treatment was effective in increasing the cutaneous permeation of caffeine, as evidenced by the reduction in thickness of the hypodermis and number of adipocytes.

In vitro evaluation of the effect of electrotreatment on skin permeability

Stratum corneum composition and structure limit cutaneous bioavailability of pharmaceutical and cosmetical agents. Electrically assisted transport can increase the rate and extent of delivery; moreover, it also enables the administration of polar and charged molecules into the skin. The objective of this study was to investigate the effect of electrotreatment on skin permeability by measuring the cumulative delivery of caffeine and sodium ascorbyl phosphate. Furthermore, confocal microscopy was used to visualize the effect of electrotreatment on the penetration of calcein. Porcine ear skin was used for the in vitro permeation studies, which involved application of either the caffeine or sodium ascorbyl phosphate (NAP) containing gels using the roll-on supplied with the electrotreatment device. Electrotreatment increased the amount of caffeine and NAP in the skin. Enhancement factors (EF) for NAP of 7.2 and 14.9 were observed following 20 min of electrotreatment and either immediate sampling or a further 60 min of passive diffusion compared with passive diffusion for either 20 or 80 min. The effect on caffeine permeation was less significant (EF = 2.1 for 20 min electrotreatment compared with passive diffusion for 20 min). The confocal microscopy images showed that electrotreatment significantly increased calcein permeation; fluorescence was observed deep into the viable epidermis-reaching depths of up to 60 to 80 microns. We have shown that electrotreatment increases skin permeability and the cumulative delivery of cosmeticals into the skin.

Qualitative and quantitative comparison of heat separated epidermis and dermatomed skin in percutaneous absorption studies

Transepidermal water loss (TEWL), mainly regulated by the stratum corneum, was quantitatively correlated to percutaneous absorption of compounds in human and suggested for the ex vivo assessment of skin integrity. The present study investigated qualitatively and quantitatively the relevance of 100-microm heat separated epidermis (HSE) in percutaneous absorption studies as compared to 500-microm dermatomed skin by dual complementary approaches. Percutaneous absorption of caffeine delivered from aqueous solution through dermatomed skin or HSE specimens (n = 9) was measured using vertical static diffusion cells coupled with an unventilated evaporimeter enabling the assessment of TEWL and skin integrity for 21 h. Permeation of caffeine exhibited different finite dose-like profiles ranged according to the thickness of skin specimens (cumulative dose absorbed up to 21 h: 11.5 +/- 11.5 microg/cm(2) and 29.4 +/- 36.2 microg/cm(2) through dermatomed skin and HSE, respectively). Normalized TEWL and caffeine fluxes were similar through dermatomed skin and HSE suggesting that the intrinsic permeability properties of both models were undifferentiated over time. Interestingly, a significant relationship was shown between TEWL and caffeine fluxes, suggesting the usefulness of TEWL measurement as an element in the estimation of percutaneous drug absorption. In conclusion, the present showed that percutaneous absorption through HSE was qualitatively and quantitatively similar to dermatomed skin when TEWL as endogenous standard and skin thickness were considered in permeability data comparisons.

Influence of membrane–solvent–solute interactions on solute permeation in skin

The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. Previously, we have studied the effect of different vehicles on the permeation of caffeine, benzoic acid (BA) and salicylic acid (SA) through silicone membranes. The present paper investigates diffusion of the selected permeants from different saturated solutions through human epidermis. The permeation of caffeine was strongly affected by the vehicle chosen and the maximum enhancement observed for the permeation of caffeine was 288-fold. A maximum of 12-fold enhancement in the flux was observed for the permeation of SA and a maximum of 10-fold enhancement was observed for the permeation of BA. The diffusion profiles obtained for SA in the different solvents were very similar when compared with those obtained for BA but the permeation rates were higher for BA than for SA. This similarity results from the similar chemical structure and lipophilicity.

Caffeine-Loaded Niosomes: Characterization and in Vitro Release Studies

We prepared different neutral and positively charged niosomal formulations containing sorbitan esters for entrapment of caffeine. Drug entrapment reduced following the incorporation of positively charged molecule. Furthermore, the span 60-containing niosomes showed the highest drug encapsulation efficiency due to solid-state nature of this surfactant's bilayers. There was a regular relationship between lipophilicity (HLB values) of surfactants and mean particle sizes; increasing the HLB value resulted in larger niosomes. By means of diffusion experiments with Franz diffusion cells, the effects of different vesicular components and that of the positive charge on the release of caffeine from various vesicle formulations were studied. Obtained results indicate that a combined erosion-diffusion mechanism regulates the permeation of caffeine through cellulose acetate membranes. High encapsulation efficiency, appropriate size distribution, and good vesicular stability, especially in solid state niosomes, make this type of vesicular systems a good alternative to liposomes for topical delivery of caffeine.

Influence of membrane–solvent–solute interactions on solute permeation in model membranes

The interaction of the components of topical formulations with the skin is an important consideration for effective drug delivery and efficacy. The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. In this paper, the effect of different vehicles on the permeation of caffeine, salicylic acid and benzoic acid through silicone membranes was evaluated. Polydimethylsiloxane membranes were used as model membranes for comparing the release characteristics of saturated solutions of model permeants because of their homogeneity and uniformity. Log P (octanol–water partition coefficient) and solubility parameter values were calculated for the compounds under study. In vitro diffusion studies indicated that the permeation profiles of all solutes showed a similar pattern. The permeation rates of benzoic acid and salicylic acid through silicone membrane from saturated solutions were higher than those for caffeine reflecting the more lipophilic nature of these compounds in comparison with caffeine. Solvent uptake studies confirmed that the vehicles that were highly sorbed by the membrane altered its properties and hence the flux. Vehicles that were not sorbed by the membrane showed similar steady-state fluxes for the model drugs. This suggests that the diffusion process is mainly influenced by the interactions between the vehicles and the membrane. Solubility parameter alone cannot explain the interactions between the membrane and the vehicles in all cases. Rather, it is likely that membrane flux reflects a combination of different solvent and solute characteristics, such as size, shape and charge distribution.

Release and permeation kinetics of caffeine from bioadhesive transdermal films

The aim of this work was to investigate, in vitro, the kinetics of release and permeation of caffeine, chosen as model drug, from bioadhesive transdermal films. These films are not self-adhesive but become adhesive when applied to wet skin. Permeation experiments were performed from films with different drug loadings using rabbit ear skin as barrier. In order to characterize the release kinetics of caffeine from the film, a polyethylene membrane, impregnated with isopropyl myristate was employed. The data obtained in the present work suggest that caffeine release from transdermal bioadhesive films was controlled either by the permeability characteristics of the skin or by the film itself, depending on drug loading. When drug loading is low (ie, caffeine is dissolved in the polymers constituting the film), the control resides in the skin. When caffeine loading exceeds its solubility in the film, the permeation profile is not linear, but shows a sort of burst effect in the early times of permeation, probably owing to the presence of solid drug and/or to a certain degree of "conserved supersaturation" in the solid phase.