Permeation Of Caffeine Research Articles

Towards the understanding of the IVPT results variability—Development, verification and validation of the PBPK model of caffeine in vitro human skin permeation

In the context of evaluating the safety and efficacy of dermal products, pharmacokinetic (PK) studies face considerable challenges, particularly concerning topically applied formulations. This underscores the necessity for alternative methods, such as in vitro permeation tests (IVPT) and physiologically based pharmacokinetic (PBPK) modelling, to better understand the dermal pharmacokinetics of a product. The purpose of this study was to modify, verify, and validate the PBPK model of caffeine permeation through human skin previously developed by Patel et al. (2022), and compare simulation results with experimental data from IVPT studies. Moreover, the study aimed to analyse the IVPT data variability and explore the potential of using the PBPK model to understand the influence of biological and drug-related factors on the IVPT results. In total, eight manuscripts describing nine experiments were included. The overall shapes of the permeation curves were considered acceptable based on visual checks for all analysed experiments. Five out of nine experiments met the predefined standard 2-fold difference criterion for comparison of the cumulative amount of caffeine in the receptor solution.. Our investigation highlights challenges in validating PBPK models for IVPT experiments, as the quality and consistency of experimental results pose significant hurdles. Despite access to data on caffeine permeation in scientific literature, reliable model validation is currently infeasible. Inter-laboratory variation suggests that alternative validation methods may be needed. Further studies should focus on issues with other compounds, especially lipophilic ones.

Demonstrating the principal mechanism of action of medical devices intended for vaginal use on reconstructed human vaginal epithelium: the case of two hyaluronic acid-containing devices

Regulation (EU) 2017/745 on medical devices (MDR) has significantly modified the rules to be adopted for MD qualifications and classification. New requirements require robust evidence on mechanisms of action (MoAs) that cannot be produced by existing common EU or ISO standards. Therefore, on a “case-by-case basis,” a new evidence-based non-clinical approach to MD qualification must be defined. In this study, an in vitro experimental approach is described to assess the physicochemical and mechanical MoA of two hyaluronic acid (HA)-based medical devices: Mucogyne® Gel and Mucogyne® Ovule for vaginal use. They both act as moisturizers and lubricants as well as a healing adjuvant by promoting the continued moisture of the vulvovaginal area. The MoA of these two products has been demonstrated by using a 3D reconstructed human vaginal epithelium (HVE) model in a homeostatic physiological state and in stressed conditions. Film forming and persistency properties were assessed on intact HVE tissues by caffeine permeation assay and Lucifer Yellow (LY) localization on HVE vertical sections. Healing properties were assessed on injured HVE tissues by trans-electrical epithelial resistance (TEER) measurements associated with histo-morphological analysis (H&E), and moisturizing efficacy was evaluated on HVE tissues cultured in dry conditions by histomorphological analysis (H&E) and aquaporin 3 (AQP3) expression and localization by immunohistochemistry (IHC). Using the same “dry” HVE model, the non-pharmacological action of the two products was addressed by CD44 (hyaluronic acid receptor) expression and localization. The results suggest that in vitro evaluations can provide robust results on a human-relevant experimental model for the intended use of the products and supports clinical data with mechanistic information which may not be achieved with in vivo studies but are particularly important for product qualification. The results also underline the specific relative efficacy of the mechanisms investigated for Mucogyne® Gel and Mucogyne® Ovule in line with their different formulation types (respectively, hydrophilic and lipophilic) that influence the action of the active ingredient HA. The present in vitro non-clinical evaluation of HVE combined with clinical investigation data obtained in women explain why Mucogyne MDs provide significant benefits in various physiological or pathological situations, including vaginal dryness and healing.

A compact and low-frequency drive ultrasound transducer for facilitating cavitation-assisted drug permeation via skin.

Low-frequency sonophoresis has emerged as a promising minimally invasive transdermal drug delivery method. However, effectively inducing cavitation on the skin surface with a compact, low-frequency ultrasound transducer poses a significant challenge. This paper presents a modified design of a low-frequency ultrasound transducer capable of generating ultrasound cavitation on the skin surfaces. The transducer comprises a piezoelectric ceramic disk and a bowl-shaped acoustic resonator. A conical slit structure was incorporated into the modified transducer design to amplify vibration displacement and enhance the maximum sound pressure. The FEM-based simulation results confirmed that the maximum sound pressure at the resonance frequency of 78 kHz was increased by 1.9 times that of the previous design. Ultrasound cavitation could be experimentally observed on the gel surface. Moreover, 3 min of ultrasound treatment significantly improved the caffeine permeability across an artificial membrane. These results demonstrated that this transducer holds promise for enhancing drug permeation by generating ultrasound cavitation on the skin surface.

Physiologically-based pharmacokinetic model of in vitro porcine ear skin permeation for drug delivery research.

In silico techniques, such as physiologically based pharmacokinetic modeling (PBKP), are recently gaining importance. Computational methods in drug discovery and development and the generic drugs industry enhance research effectiveness by saving time and money and avoiding ethical issues. One key advantage is the ability to conduct toxicology studies without risking harm to living beings. This study aimed to repurpose the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) PBPK model for simulation permeation through porcine ear skin under in vitro conditions. The work was divided into four steps: (1) the development of a pig ear skin model based on a previously collected dataset; (2) testing the model's ability to discriminate permeation between pig ear, human abdomen, and human back skin; (3) development of a caffeine permeation model; and (4) testing the caffeine model's performance against in vitro generated data sourced from the scientific literature. Data from 31 manuscripts were used for the development of the pig skin model. Based on these data, values specific to pig skin were found for 22 parameters of the MPML MechDermA model. The model was able to discriminate permeation between pig and human skin. A caffeine model was developed and used to simulate seven experiments identified in the literature. The model's performance was assessed by comparing simulated to observed results. Based on a visual check, all simulations were considered acceptable, whereas three out of seven experiments met the twofold difference criterion. The variability of the experimental data was considered the biggest challenge for reliable model assessment.

Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1G93A mouse model of amyotrophic lateral sclerosis following oral administration

Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114–120 male and female SOD1G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration–time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1G93A and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1G93A compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1G93A compared to WT mice, suggesting reduced gastric emptying in SOD1G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.

Biophysical and permeability characterization of lyophilized (freeze-dried) human cadaver skin

The in vitro permeation testing (IVPT) of topical products is performed across the human cadaver skin, which is stored frozen for a prolonged duration. The cryo-preservation technique is not economical and is a cumbersome process. Moreover, prolonged skin preservation in a frozen state and frequent freeze-thawing are known to affect the integrity of the skin barrier. Therefore, lyophilization was explored as an alternative to protect the skin tissue from microbial contamination and degeneration. Notably, the project's objective was to investigate the impact of the freeze-drying process on the skin's barrier properties. The morphometrics of the lyophilized skin were measured. Histological studies did not reveal any notable changes in the organization and intactness of the layers due to the freeze-drying process. The biophysical attributes of the skin, such as transepidermal water evaporation rate and transepidermal electrical resistivity (TEER), were not significantly different between the control skin (not subjected to the freeze-drying process) and the freeze-dried skin (FDS). The permeability of caffeine, a hydrophilic model permeant, and nicotine, a lipophilic model permeant, were consistent across the control and the FDS. It is evident from the studies that the lyophilization process did not significantly impact the barrier properties and permeability of the skin.

Culture insert device with perfusable microchannels enhances in vitro skin model development and barrier function assessment

The ever-stricter regulations on animal experiments in the field of cosmetic testing have prompted a surge in skin-related research with a special focus on recapitulation of the in vivo skin structure in vitro. In vitro human skin models are seen as an important tool for skin research, which in recent years attracted a lot of attention and effort, with researchers moving from the simplest 2-layered models (dermis with epidermis) to models that incorporate other vital skin structures such as hypodermis, vascular structures, and skin appendages. In this study, we designed a microfluidic device with a reverse flange-shaped anchor that allows culturing of an in vitro skin model in a conventional 6-well plate and assessing its barrier function without transferring the skin model to another device or using additional contraptions. Perfusion of the skin model through vascular-like channels improved the morphogenesis of the epidermis compared with skin models cultured under static conditions. This also allowed us to assess the percutaneous penetration of the tested caffeine permeation and vascular absorption, which is one of the key metrics for systemic drug exposure evaluation.

A Synthetic Model of the Mucosa for Oral Penetration Studies.

The main objective of this study is the evaluation of the use of a synthetic membrane, Nuclepore, as a model for permeation studies through sublingual mucosa. The permeability of two types of membranes, porcine sublingual oral mucosa and a synthetic Nuclepore membrane, to water was compared. Moreover, the water permeability of membranes modified with waterproofing formulations was measured to study their ability to protect against the penetration of viruses, toxins, etc. A relatively high correlation (R2 0.88) was obtained between the transmucosal water loss (TMWL) values of the artificial membrane and the mucosa. These results support the possible use of this synthetic membrane in the screening of the water permeability of formulations. In addition, studies of the permeation of different actives, drugs, and biocides through the two membranes were carried out, and these results were compared with their skin permeation data. The synthetic membrane does not seem to discern between compounds in terms of permeability. However, the permeation of caffeine through intact or modified membranes incorporating waterproofing formulations presents similar permeation profiles through the synthetic membrane and mucosa. The results from these assays should lend support to the use of this synthetic membrane when screening formulations to be applied in oral penetration studies.

Effect of Pretreatment Time with Enhancers on Caffeine Skin Permeability in Rats

Background: Caffeine is an edible chemical compound obtained from various plants, such as tea and coffee. Caffeine is an alkaloid that is highly hydrophilic and has limited skin permeability. The lipophilic nature of the stratum corneum is a major barrier to the passage of this substance through the skin. Topical drug delivery systems can effectively transfer caffeine to the skin. Objectives: This study investigated the effect of pretreatment time with chemical enhancers on caffeine's skin permeation. Methods: The skin was subjected to additives such as sodium lauryl sulfate, sodium lauryl ethyl sulfate, tynoline, nanoxinol, and lecithin for 5, 15, and 30 minutes. Then, the parameters of caffeine permeability and structural changes in the skin due to additive adsorption were studied using Fourier Transform Infrared (FT-IR) spectrometry. Results: The enhancers increased the permeation of caffeine through the skin. There are different mechanisms for penetration enhancers, including lipid liquefaction, disruption of lipid bilayers, and irreversible denaturation of intracellular keratin. Conclusions: Sodium lauryl sulfate can affect the skin permeability of caffeine.

Parallel evaluation of alternative skin barrier models and excised human skin for dermal absorption studies in vitro

Skin permeation is a primary consideration in the safety assessment of cosmetic ingredients, topical drugs, and human users handling veterinary medicinal products. While excised human skin (EHS) remains the ‘gold standard’ for in vitro permeation testing (IVPT) studies, unreliable supply and high cost motivate the search for alternative skin barrier models. In this study, a standardized dermal absorption testing protocol was developed to evaluate the suitability of alternative skin barrier models to predict skin absorption in humans. Under this protocol, side-by-side assessments of a commercially available reconstructed human epidermis (RhE) model (EpiDerm-200-X, MatTek), a synthetic barrier membrane (Strat-M, Sigma-Aldrich), and EHS were performed. The skin barrier models were mounted on Franz diffusion cells and the permeation of caffeine, salicylic acid, and testosterone was quantified. Transepidermal water loss (TEWL) and histology of the biological models were also compared. EpiDerm-200-X exhibited native human epidermis-like morphology, including a characteristic stratum corneum, but had an elevated TEWL as compared to EHS. The mean 6 h cumulative permeation of a finite dose (6 nmol/cm2) of caffeine and testosterone was highest in EpiDerm-200-X, followed by EHS and Strat-M. Salicylic acid permeated most in EHS, followed by EpiDerm-200-X and Strat-M. Overall, evaluating novel alternative skin barrier models in the manner outlined herein has the potential to reduce the time from basic science discovery to regulatory impact.

Efficiency of emulsifier-free emulsions in delivering caffeine and α-tocopherol to human skin.

Increasing consumer demand for natural and environmentally friendly products is driving the cosmetic industry to seek greener and safer processes. High-frequency ultrasound technology (HFUT) stabilizes emulsions without adding emulsifying surfactants (ES). In this work, the formulation characteristics of an HFUT-treated emulsion and a Reference emulsion were compared for both caffeine and α-tocopherol. A comparison was made between ES-free emulsions and the Reference emulsions based on droplet size, viscosity, pH and rheology behaviour for both active cosmetic ingredients. The permeation of caffeine and the skin retention of α -tocopherol were studied in vitro using Franz diffusion cells on human skin biopsies, considered the gold standard for permeation assays. The formulations developed were stable and showed suitable droplet size distribution. In the case of ES-free emulsions, the average droplet size was inferior to 1.5μm regardless of the polarity of the active. All formulations presented a shear-thinning pseudoplastic behaviour, an attribute usually desired for cosmetic products. The skin permeation studies showed that in the case of caffeine (model hydrophilic molecule), the ES-free emulsion presented a delivery capacity similar to that of the Reference emulsion. However, for α-tocopherol (highly lipophilic model molecule), differences were observed in the distribution of the active in the stratum corneum with an advantage for the Reference emulsion, probably due to the impact of surfactants on the SC lipids. This work demonstrates that HFUT is a reliable tool that is able to prepare stable ES-free emulsions loaded with hydrophilic or lipophilic active ingredients. Skin permeation studies confirm that the emulsions produced by HFUT promote the delivery of the actives to the human skin. In the case of α-tocopherol, the delivery efficiency was lower than with the Reference emulsion, especially in the SC layers, due to the absence of surfactants. Nevertheless, the ES-free emulsion still represents a good compromise between efficacy and the need for green cosmetics in the market.

Assessment of penetration and permeation of caffeine by confocal Raman spectroscopy in vivo and ex vivo by tape stripping.

Tape stripping is an often-used non-invasive destructive method to investigate the skin penetration of a substance. In recent years, however, the suitability of confocal Raman spectroscopy (CRS) as a non-invasive method of non-destructive examination of the skin has become increasingly apparent. In this study, we compared invasion and depletion penetration and permeation kinetics of a 2% caffeine solution with and without 1,2-pentanediol as a penetration enhancer measured with CRS and tape stripping. Porcine skin was used for tape stripping and human skin for CRS. 2% caffeine solution was applied to the skin for different incubation times. Human skin was then examined by CRS while caffeine was extracted from porcine skin and quantified via reverse-phase HPLC. Fluxes were also measured and calculated by sum of the total amounts of caffeine penetrated into the skin. Without penetration enhancers, there is hardly any difference between the penetration profiles of the two measurement methods for invasion, but the curves for depletion are different. Furthermore, the calculated flux values for the invasion are almost identical, but for the depletion the tape stripping values are about twice as high as the CRS values. The relevance of conducting invasion and depletion studies became clear and was able to show the still existing problems in the comparability of CRS and tape stripping.

Protective Mechanisms of Liquid Formulations for Gastro-Oesophageal Reflux Disease in a Human Reconstructed Oesophageal Epithelium Model.

PurposeA novel experimental design based on a human-reconstructed oesophageal epithelium (HO2E) model has been applied to quantitively assess the properties of a set of liquid formulations, Device A (Gerdoff® Protection), Device B (Esoxx® One), and Device C (Marial® gel) developed to form a temporary physical barrier on the oesophageal epithelium and modify epithelial permeability so to protect the oesophageal mucosa from refluxate components.MethodsThe formulations were applied to a prewetted HO2E model for 15 min. Then, a 0.5% caffeine solution was applied, and its penetration kinetics was assessed at 1 h and 2 h in acidic environments (pH= 3.3) to mirror exposure of the oesophageal mucosa to acidic reflux in GORD patients. Caffeine permeated into the basolateral compartment (evaluated by HPLC-UV) and Lucifer yellow (LY) permeability were quantified 15 min after application of the caffeine in acidic environments.ResultsAt the 15 min timepoint, Device A reduced caffeine permeation by 77.2% and LY flux by 30.4% compared to the untreated control and with a faster mode of action than that of the other liquid formulations. Transepithelial caffeine flux was reduced, albeit with different timing and efficiency, by all three compounds up to the end of the 2 hour experiment. At 1 h, Device A reduced the caffeine flux by 79.2%; Device B, by 67.2%; and Device C, by 37%.ConclusionThese results confirm the ability of the medical devices tested to interact with the oesophageal epithelium and create a temporary physical protective film for up to 2 hours after their application. The results underline differences in the mechanism of action of the three medical devices, with Device A performing faster than the other formulations. The overall results support the relevance of the reconstructed mucosal model to investigate oesophageal epithelium–product interactions and precisely differentiate liquid formulation performance.

Highlighting the efficiency of ultrasound-based emulsifier-free emulsions to penetrate reconstructed human skin.

The cosmetic industry endeavours to strengthen the greener and safer claims of processes to respond to the high demand from customers for natural and environmentally friendly products. High-frequency ultrasonication technology (HFUT) is a physical process enabling the stabilization of emulsions without requiring additional ingredients, such as emulsifying surfactants (ES) to be introduced into the formulations. In this study, key formulation characteristics of an emulsion synthesized by HFUT and a reference emulsion (RE) were compared, as well as the permeation kinetics of caffeine, used as a model active cosmetic ingredient, from both types of emulsions. The pH, droplet size and viscosity of emulsions prepared by the HFUT and the RE were determined and compared. The permeation of caffeine from the HFUT emulsion and the RE applied to the surface of reconstructed human epidermis (RHE) models was compared. The ES-free formulations prepared by HFUT displayed a nearly 2-fold lower average droplet size and over 3-fold greater viscosity, compared to the RE. Despite these differences, the absence of ES in the HFUT emulsion did not significantly alter the permeation kinetics of caffeine through RHE. The caffeine steady-state flux, lag time and permeability coefficients differed by 20%-30% only. This study demonstrates the potential of the HFUT to yield topical cosmetic products with lower requirements ingredients-wise, without losing efficacy, supporting the possible implementation of the technology in the cosmetic industry.

Improvement of Skin Permeation of Caffeine, a Hydrophilic Drug, by the Application of Water Droplets Provided by a Novel Humidifier Device.

Recently, a novel humidifier that sprays water fine droplets equipped with a copolymer, poly(3,4-ethylene dioxythiophene)-poly(styrene sulfonate) (PEDOT/PSS) was developed. PEDOT/PSS in the humidifier absorbs water from the environment and releases fine water droplets by heating. In the present study, the effect of hydration on the skin barrier, stratum corneum, was first determined by the application of fine water droplets using the humidifier. The skin-penetration enhancement effect of a model hydrophilic drug, caffeine, was also investigated using the humidifier and compared with a conventional water-evaporative humidifier. More prolonged skin hydration effect was observed after application of the fine water droplet release humidifier using PEDOT/PSS than that using a conventional humidifier. In addition, markedly higher skin permeation of caffeine was observed in both infinite and finite dose conditions. Furthermore, higher skin permeation of caffeine from oil/water emulsion containing caffeine was observed in finite dose conditions by pretreatment with the humidifier using PEDOT/PSS. This device can provide water droplets without replenishing water, so it is more convenient for enhancing the skin permeation of chemical compounds from topical drugs and cosmetic formulations.

Polysaccharide-based skin scaffolds with enhanced mechanical compatibility with native human skin

We report a custom-made technique to synthesize process-convenient skin scaffolds by tuning the mechanical properties of hydrogels based on a few naturally occurring polysaccharides to match the rheological properties of previously established benchmarks, i.e., the ex vivo native human skins. We studied the mechanical parameters using oscillatory shear rheology. At small strain amplitudes, the intrinsic elastic modulus showed an almost linear dependence in the middle and a changing rate profile at the two ends with concentration of the principal hydrogel component variant, i.e., kappa (κ)-carrageenan. At large strain amplitudes, the hydrogels demonstrated intercycle strain-softening behavior, the onset of which was directly proportional to the κ-carrageenan concentration. We observed a concentration match for the intrinsic elastic modulus of the benchmark within this sigmoidal curve fit. Contextually, we need to explore other potent polymeric hydrogel systems to achieve mechanical affinity in terms of multiple rheological parameters derived from both strain amplitude and angular frequency sweeps. Additionally, we carried out diffusion experiments to study caffeine permeation attributes. The hydrogels show improved barrier features with increasing κ-carrageenan concentration. In terms of the penetration flux and total cumulative amount of permeated caffeine, this enhanced mechanical adherence demonstrates comparable penetration features with the commercial 3D skin model.

Rheological Behavior of a New Mucoadhesive Oral Formulation Based on Sodium Chondroitin Sulfate, Xyloglucan and Glycerol.

Background: The study aimed at assessing the mucoadhesive properties and the barrier effect of a formulation, labelled as AL2106, containing sodium chondroitin sulfate (ChS), xyloglucan from tamarind seed extract, and glycerol, by evaluating the capacity to adhere to a layer of mucin, the rheological synergism and the barrier effect in comparison to the marketed Esoxx One medical device. AL2106 is a medical device distributed by Alfasigma SpA, Italy with REF FTP57 (Manufacturer: Labomar SpA); it is analogous to Esoxx One medical device: the two products are drinkable solutions that, after swallowing, adhere to the esophageal mucosa, protecting it from the corrosive effect of the gastric acid reflux. AL2106 has been conceived to be better performing in terms of duration of the barrier effect compared to Esoxx One. Methods: The mucoadhesive properties, rheological behavior, buffering capacity against acidity, and film-forming ability with the resultant protecting effect on esophagus mucosa (caffeine permeation test) was compared between the two products. Results: The mucoadhesivity of the formulations was shown in vitro: both remained adherent to a mucin layer, also when the support was rotated by 90°, and when the film layer was washed with water, intended to simulate the washout due to swallowing. AL2106 showed a good buffering efficacy, being able to absorb at least 50% of its weight of 0.03 M HCl while maintaining the pH above 4. The film-forming effect and barrier properties of AL2106 and Esoxx One were confirmed by an in vitro study on reconstructed human esophageal epithelium. A greater film-forming efficacy of AL2106, lasting for at least 5 h, than Esoxx One was observed. Noteworthy, the barrier function of esophageal tissues was shown to be preserved after the application of both formulations. Conclusions: The combination of ChS with the mucoadhesive glycerol−xyloglucan complex and other excipients, which contribute to the barrier effect and to mucoadhesion, contained in AL2106, allowed a longer-lasting protective effect than Esoxx One, proving its effectivity and safety for oral use.

Transdermal Permeation of Caffeine Aided by Ionic Liquids: Potential for Enhanced Treatment of Cellulitis.

Ginoid hydrolipodystrophy (HDLG) or "cellulite" involves alteration of the cutaneous relief and occurs in 80-90% of the female population. Several topical treatments are available with the use of substances capable of stimulating lipolysis, such as caffeine. However, the effectiveness of topical therapy is related to the processes of release and permeation of the active in skin cells. In this sense, ionic liquids, such as choline geranate, are considered to facilitate topical permeation agents. In this way, the aim of this research was to develop and evaluation of the effectiveness of a cosmetic product for topical treatment of cellulite with caffeine in association with choline geranate. The choline geranate was synthesized by the reaction between geranic acid and choline hydroxide [1: 2]. The gel was prepared using 2% Carpobol 940®, 5% caffeine, and 1% choline geranate. Preliminary and accelerated stability tests were performed by checking pH, spreadability, and organoleptic characteristics. The transdermal permeation capacity of caffeine in vitro was evaluated by the Franz cell permeation assay, and the gel cytotoxicity by the MTS method. To prove the efficacy in the treatment of cellulite, a pilot type 1 clinical trial was carried out. The formulation was considered stable and the product maintained your characteristics during 180 days of storage. The product showed moderate cytotoxicity and high skin permeation capacity. In the clinical trial, it showed results superior to the caffeine gel without ionic liquid. The developed gel favored the cutaneous permeation of caffeine, showing a promising product in the treatment of cellulite.

The Influence of Oily Vehicle Composition and Vehicle-Membrane Interactions on the Diffusion of Model Permeants across Barrier Membranes.

In many instances, one or more components of a pharmaceutical or cosmetic formulation is an oil. The aims of this study were two-fold. First, to examine the potential of preferential uptake of one oily vehicle component over another into a model barrier membrane (silicone) from blended vehicles (comprising two from the common excipients isohexadecane (IHD), hexadecane (HD), isopropyl myristate (IPM), oleic acid (OA) and liquid paraffin). Second, to study the effect of membrane-vehicle interactions on the diffusion of model permeants (caffeine (CF), methyl paraben (MP) and butyl paraben (BP)) from blended vehicles. Selective sorption and partition of some oils (especially IHD and IPM) at the expense of other oils (such as OA) was demonstrated to take place. For example, the membrane composition of IHD was enriched compared to a donor solution of IHD-OA: 41%, 63% and 82% IHD, compared to donor solution composition of 25%, 50% and 75% IHD, respectively. Pre-soaking the membrane in IHD, HD or LP, rather than phosphate buffer, enhanced the flux of MP through the membrane by 2.6, 1.7 and 1.3 times, respectively. The preferential sorption of individual oil components from mixtures altered the barrier properties of silicone membrane, and enhanced the permeation of CF, MP and BP, which are typically co-formulated in topical products.

Deformable liposomes as enhancer of caffeine penetration through human skin in a Franz diffusion cell test.

The permeation of hydrophilic molecules through the skin is still a challenge due to the barrier posed by stratum corneum, the outermost layer of the skin. Liposomes have frequently been used as carriers for different types of drugs and may also function as permeation enhancers. Propylene glycol has also been used as an edge activator in liposomes to increase the permeation. The aim of this work was to prepare liposomes containing an edge activator and loaded with caffeine to evaluate the potential of caffeine reaching the deeper layers in the skin. The formulations were prepared by a top-down process using high-pressure homogenization at 20000 psi for 10min. They were characterized by size, polydispersity index (PI), zeta potential (ZP), pH, caffeine content and encapsulation efficiency (EE%) on preparation (time zero) and after 30days. Cytotoxicity of blank and loaded liposomes was assessed by MTT proliferation assay with a normal keratinocyte cell line (HaCaT). In vitro permeation tests were performed with human skin in Franz cells over 24h, and caffeine concentration was determined in the skin surface, stratum corneum, dermo-epidermal fraction and receptor medium by HPLC. The caffeine liposomes with (DL-Caf) or without propylene glycol (CL-Caf) showed, respectively, mean size 94.5 and 95.4nm, PI 0.48 and 0.42, ZP+1.3 and+18.1mV and caffeine content of 78.57 and 80.13%. IC50 values of caffeine in DL-Caf (3.59 v/v %) and CL-Caf (3.65 v/v %) were not significantly different from conventional blank liposome (3.27 v/v %). The DL-Caf formulation presented the best capability to enhance the caffeine permeation through the skin, resulting 1.94-folds higher than caffeine solution. Furthermore, the caffeine flux from DL-Caf was 1.56- and 3.05-folds higher than caffeine solution and CL-Caf, respectively. On the other hand, CL-Caf showed the lowest caffeine penetration revealing the importance of edge activator to aid hydrophilic drug penetration to all skin layers. The DL-Caf formulation tested was able to improve the permeation of caffeine through the stratum corneum and dermo-epidermal layers, suggesting that this delivery system may be effective for deep skin delivery of hydrophilic drugs.