Enhanced Physical Stability of L-Ascorbic Acid in an Ionic Liquid.

Ionic liquid (IL) technology was used to enhance the stability of L-ascorbic acid (AA). Pyridoxine was selected as the counter cation for anionic AA in IL. After AA was dissolved in water at 40 °C, its ratio decreased to 3.2% after 7 d. In contrast, the IL formulation showed negligible degradation, with almost no loss of AA even after 28 d. These results suggest that the use of IL enhances the stability of AA.

Design of Ionic Liquid Formulations with Azone-Mimic Structures for Enhanced Drug Skin Permeation.

Although laurocapram (Azone) significantly enhances the skin permeation of drugs, its development was hindered by its skin irritation. We then developed an Azone-mimic ionic liquid (IL-Azone), composed of less irritating cationic ε-caprolactam and anionic myristic acid. IL-Azone dissociates to the original cation and anion in the presence of water in the formulation. We tried to select a formulation suitable for IL-Azone in the present study. Each formulation contained 5 % of either Azone or IL-Azone along with the model drug antipyrine, and skin permeation experiments of the drug were conducted. The results revealed that IL-Azone did not enhance skin permeation when combined with most formulations tested. However, a notable and rapid enhancement in skin permeation was observed when combined with white petrolatum. This effect could be attributed to the minimal water content in white petrolatum, which prevented IL-Azone degradation. Furthermore, its permeation-enhancing effects from IL-Azone in white petrolatum were more pronounced and rapid than Azone. The rapid onset observed with IL-Azone can be attributed to its degradation into its original components at the interface between the stratum corneum and the living epidermis, which results in a shorter lag time before achieving a steady-state concentration in the SC compared to Azone.

Design of an Ante-enhancer with an Azone-Mimic Structure using Ionic Liquid.

PURPOSE: Laurocapram (Azone) was broadly examined as a representative enhancer of skin penetration in the 1980s. However, it was not approved for treatment because it caused skin irritation following its penetration into the epidermis through the stratum corneum. In the present study, a so-called ante-enhancer with an Azone-mimic structure was designed based on an ante-drug with negligible systemic toxic effects following its permeation through the skin. METHODS: The ante-enhancer was designed using ionic liquid technology: an ionic liquid-type ante-enhancer (IL-Azone) with an Azone-mimic structure was prepared from ε-caprolactam and myristic acid as cationic and anionic substances, respectively. The enhancing effects of IL-Azone on the permeation by the following model drugs through pig skin were examined: isosorbide 5-mononitrate (ISMN), antipyrine (ANP), and fluorescein isothiocyanate dextran (FD-4). Skin irritation by IL-Azone was assessed using the Draize method. RESULTS: The primary irritation index (P.I.I.) of IL-Azone by the Draize method was markedly lower than that of Azone (6.9). Although the ability of IL-Azone to enhance skin penetration was not as high as Azone, IL-Azone moderately increased skin permeation by the model compounds tested (ISMN: 4.7 fold, ANP: 4.5 fold, FD-4: 4.0 fold). CONCLUSIONS: These results suggest the usefulness of designing a skin penetration enhancer using ionic liquid technology. Further trials on the ionic liquid design with an Azone-mimic structure using other cations and anions may lead to the development of better ante-enhancers.

Remote-controllable dosage management through a wearable iontophoretic patch utilizing a cell phone.

With regard to medical treatment through operations, remote control is possible, however, the area of remote-controllable drug treatment is yet to be established. In this study, a prototyped remote-controllable dosage management system that allows patients and caregivers to administer therapeutic drugs via an internet line without touching the dosage device or formulation was developed. This system consists of a transmitter (System A) located away from the patient, and a dosage device (System B) equipped with a receiver (B1), dosage management unit (B2), and a drug treatment unit (B3) that can be installed on the patient. Additionally, Bluetooth® is adopted to communicate from System A to System B. In the present study, System A was incorporated into a cell phone, and System B was a constant-current iontophoresis (IP) device, which was applied on excised pig skin. Sodium salt of betamethasone phosphate (BP-Na+) was selected as a model drug, and the in vitro skin permeation of BP- was evaluated. As a result, by transmitting the administration information incorporated in System A through B1 to B2, the optimal current was passed between the IP electrodes in B3, and the skin permeation of BP- was obtained by remote control. That is, the skin permeation of BP- was obtained by the current flowing from the IP device. The permeation amount decreased when the voltage load was stopped. These results suggested that remote control from System A enables dosing management of bioactive substances from dosage devices applied on the skin, intracutaneously, or subcutaneously without being near the patient. Although various trials are still required to complete the remote-controlled system, the patient does not have to go to the hospital except to take injections. Such drug administrations would lead to decreased medical expenses and increased quality of life for patients.

Chitosan-coated PLGA nanoparticles for transcutaneous immunization: Skin distribution in lysozyme-sensitized mice.

The effect of transcutaneous immunization was studied using a combined system of poly(DL-lactide-co-glycolide) (PLGA) nanoparticles and iontophoresis (IP). Both hen egg-white lysozyme (HEL)-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride and their fluorescent nanoparticles were prepared using an antisolvent diffusion method. Their mean volume diameters were 87.6 ± 38.9 nm and 84.9 ± 27.6 nm, respectively. It was suggested from the results of the ex vivo skin accumulation study using fluorescent nanoparticles that the HEL released from the nanoparticles to the skin surface was efficiently delivered to antigen-presenting cells. HEL-specific IgG1 and IgG2a titers were determined in an in vivo percutaneous immunoreactivity study using lysozyme-sensitized mice. As results, the group using nanoparticles and IP showed 1.33 times higher HEL-specific IgG1 titer than a sham treatment group. The HEL-specific IgG2a titer was 1.36 times higher in the nanoparticles and IP group than in the HEL solution and IP group. It was suggested from the quantification results of total IgE in serum that the combined use of PLGA nanoparticles and IP reduced the total IgE concentration. The level of cytokines may have decreased due to Th1 cell activation and relative suppression of Th2 cells. The cytokine level is presumed to be reduced by activation of Th1 cells and relative suppression of Th2 cells. The histamine amount in plasma and rectal temperature after the induction of anaphylactic shock using lysozyme-sensitized mice were also studied, which indicates that the combined use of PLGA nanoparticles and IP may provide the same therapeutic effect as an injection.

Effects of Physicochemical Properties of Constituent Ions of Ionic Liquid on Its Permeation through a Silicone Membrane.

Ionic liquids (ILs), defined as liquid salts composed of anions and cations, have the advantage of allowing constituent ions to be stably absorbed through biological membranes, such as skin. However, limited information is currently available on the effects of the physicochemical properties of constituent ions on the membrane permeation of ILs. Therefore, we herein investigated the effects of the polarity of constituent cations on the membrane permeation of each constituent ion from IL. Various ILs were prepared by selecting lidocaine (LID) as a cation and a series of p-alkylbenzoic acids with different n-octanol/water partition coefficients (Ko/w) as anions. These ILs were applied to a skin model, a silicone membrane, and membrane permeability was investigated. The membrane permeabilities of p-alkylbenzoic acids from their single aqueous suspensions were also measured for comparison. The membrane permeability of p-alkylbenzoic acid from the aqueous suspension increased at higher Ko/w. However, the membrane permeability of ILs was similar regardless of the Ko/w of the constituent p-alkylbenzoic acid. Furthermore, the membrane permeability of the counterion LID remained unchanged regardless of the constituent p-alkylbenzoic acid. These results suggest that even when the Ko/w of IL constituents markedly differs, the resulting IL does not affect membrane permeability.

Magnetic Field-Responsive Pulsatile Drug Release Using A Magnetic Fluid.

Ferrofluids are colloidal liquids with fine magnetic particles. They change shape and fluidity depending on the magnitude and direction of the external magnetic field. The magnetic field-responsive pulsatile release of a model drug, lidocaine hydrochloride (LID·HCl), was determined using a depot-type injection containing white petrolatum and/or hydrophilic cream with a magnetic fluid in various proportions. Drug release was confirmed using a self-made diffusion cell and the application of a moving magnet at the bottom of the preparation. Magnetic field-responsive LID release was observed only when using the white petrolatum preparation and depended on the concentration of the magnetic fluid. Magnetic field responsiveness was not observed in the preparation with only the hydrophilic cream. A greater magnetic field-responsive release was observed with a combination of white petrolatum and hydrophilic cream than with white petrolatum alone. These results may lead to the development of an injectable formulation that enables pulsatile administration of macromolecular drugs.

Effect of Iontophoresis on the Intradermal Migration Rate of Medium Molecular Weight Drugs.

The purpose of the present study was to evaluate whether iontophoresis (IP) accelerates the intradermal migration rate of medium molecular weight drugs. Sodium polystyrene sulfonate (PSA) and fluorescein isothiocyanate-dextran (FD) were used as model medium molecular weight acidic and non-electrolyte drugs, respectively. Low molecular weight acid and non-electrolyte drugs were also used for comparison. Drug-loaded excised split-layered skin (SL skin) was used in the experiment. SL skin was prepared using (i) whole skin was split once, (ii) the drug solution was applied on the lower skin, and (iii) the upper skin was layered onto the lower skin containing the drug solution as in the original skin. The effect of constant-current cathodal or anodal IP was applied to the SL skin, and the time course of the cumulative amount of drug migration from the SL skin through the dermis to the receiver was followed. In cases without IP and with anodal IP, the intradermal migration rates of medium molecular weight drugs were much lower than those of small molecules. The driving force for drug migration was thought to be simple diffusion through the skin layer. In contrast, cathodal IP significantly increased the intradermal migration rate of PSA not but of FD or low molecular weight drugs. This IP-facilitated migration of PSA was probably due to electrorepulsion. These results suggest that IP can be used to increase the intradermal migration of medium molecular weight charged drugs.

Use of Silicone Membrane Permeation to Assess Thermodynamic Activities of Ionic Liquids and Their Component Cation and Anion.

Ionic liquid (IL) was prepared by mixing lidocaine and ibuprofen as a cation and anion, respectively, at various ratios. We determined the permeation of both compounds from the IL through a silicone membrane selected as a model biological membrane, and mathematically analyzed the permeation data from the viewpoint of the thermodynamic activities of lidocaine, ibuprofen, and the IL. As a result, IL and ibuprofen diffusely permeated through the membrane in the case of applying IL preparations with a molar fraction of ibuprofen of 0.5 or higher. The IL was thought to separate into lidocaine and ibuprofen in the receiver. On the other hand, when applying IL preparations with a molar fraction of lidocaine of 0.5 or higher, IL and lidocaine permeated. The permeation rate of IL itself was maximized when the applied IL was prepared using equimolar amounts of lidocaine and ibuprofen, and it decreased when the fraction of lidocaine or ibuprofen increased by more than 0.5. Their membrane permeation rates increased with an increase in their activity, and no more increase was found when the drugs were saturated in the IL. These membrane permeation profiles reflected well the mathematically calculated ones according to the concept of activity.

Prediction of skin permeation and concentration of rhododendrol applied as finite dose from complex cosmetic vehicles.

Finite dose experiments represent clinical use wherein depletion of dose, evaporation of excipients, and gradual change in vehicle composition may occur. In the present study, we attempted a mathematical approach for predicting skin permeation and concentration of a cosmetic active, rhododendrol (RD), from complex vehicle-based formulations applied in finite dose. In vitro skin permeation and concentration studies of RD were conducted from formulations containing water and polyols with concentrations ranging from 10 to 100% under infinite and finite dose conditions using vertical Franz diffusion cells. Observed data for skin permeation and the viable epidermis and dermis (VED) concentration of RD were estimated by the differential equations under Fick's second law of diffusion together with water evaporation kinetics and changes in the partition coefficient from vehicles to the stratum corneum. As a result, a goodness-of-fit was observed allowing accurate estimation of skin permeation and VED concentration of RD. This mathematical approach could become a useful tool to estimate the skin permeation and concentration of actives from topical formulation applied in finite dose conditions likened in actual use.

Usefulness of liquid-crystal oral formulations to enhance the bioavailability and skin tissue targeting of p-amino benzoic acid as a model compound.

Topical formulations are not always suitable to deliver active ingredients to large areas of skin. Thus, in this study, we aimed to develop an oral formulation for skin tissue targeting with a high bioavailability using liquid crystal (LC) dispersions comprising cubosomes of a mal-absorptive model compound, p-amino benzoic acid (PABA), which is an active element in cosmeceuticals, dietary supplements and skin disorder medicines. The bioavailability and skin concentration of PABA were investigated after oral administration in rats. The effect of the remaining amount of the LC formulation in the stomach on the pharmacokinetic profiles of orally administered PABA was evaluated. The skin permeation and concentration of PABA were also investigated using an in vitro permeation experiment. As a result, the bioavailability of PABA was significantly improved by administration of PABA-LC formulations compared with PABA solution alone, although the effect was greatly influenced by the type of LC-forming lipids. The in vitro skin permeation study showed that the PABA concentration in the skin when applied from the dermis side was higher than when applied from the epidermis side. These findings suggested that oral administration advantageously supports skin targeting, and oral LC formulations could be a promising material in cosmeceutical, dietary and clinical fields.

Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-M™.

PURPOSE: The usefulness of the synthetic membrane, Strat-M™ as an alternative to human and animal skins was evaluated by estimating the skin permeabilities of chemical compounds. METHOD: Thirteen chemical compounds with molecular weights (M.W.) of 152-289 and lipophilicities (log Ko/w) of -0.9 to 3.5 were selected. Strat-M™, excised human skin, or hairless rat skin was set in a Franz-type diffusion cell and a saturated solution of each chemical compound was applied to determine membrane permeation profiles. The obtained permeability coefficients (log P) were compared among these membranes. RESULTS AND DISCUSSION: Elevations were observed in log P for Strat-M™ with an increase in the log Ko/w of the applied compounds, and similar results were observed with the human and hairless rat skins. A correlation was obtained in log P values between Strat-M™ and human or hairless rat skin. Furthermore, the diffusion and partition parameters of chemicals in Strat-M™ were similar to those in the excised human and rat skins. These results suggest that Strat-M™ could be used as an alternative to animal or human skin in permeation studies.

Estimation of skin concentrations of topically applied lidocaine at each depth profile.

Skin concentrations of topically administered compounds need to be considered in order to evaluate their efficacies and toxicities. This study investigated the relationship between the skin permeation and concentrations of compounds, and also predicted the skin concentrations of these compounds using their permeation parameters. Full-thickness skin or stripped skin from pig ears was set on a vertical-type diffusion cell, and lidocaine (LID) solution was applied to the stratum corneum (SC) in order to determine in vitro skin permeability. Permeation parameters were obtained based on Fick's second law of diffusion. LID concentrations at each depth of the SC were measured using tape-stripping. Concentration-depth profiles were obtained from viable epidermis and dermis (VED) by analyzing horizontal sections. The corresponding skin concentration at each depth was calculated based on Fick's law using permeation parameters and then compared with the observed value. The steady state LID concentrations decreased linearly as the site became deeper in SC or VED. The calculated concentration-depth profiles of the SC and VED were almost identical to the observed profiles. The compound concentration at each depth could be easily predicted in the skin using diffusion equations and skin permeation data. Thus, this method was considered to be useful for promoting the efficient preparation of topically applied drugs and cosmetics.

Mathematical model to predict skin concentration after topical application of drugs.

Skin permeation experiments have been broadly done since 1970s to 1980s as an evaluation method for transdermal drug delivery systems. In topically applied drug and cosmetic formulations, skin concentration of chemical compounds is more important than their skin permeations, because primary target site of the chemical compounds is skin surface or skin tissues. Furthermore, the direct pharmacological reaction of a metabolically stable drug that binds with specific receptors of known expression levels in an organ can be determined by Hill's equation. Nevertheless, little investigation was carried out on the test method of skin concentration after topically application of chemical compounds. Recently we investigated an estimating method of skin concentration of the chemical compounds from their skin permeation profiles. In the study, we took care of "3Rs" issues for animal experiments. We have proposed an equation which was capable to estimate animal skin concentration from permeation profile through the artificial membrane (silicone membrane) and animal skin. This new approach may allow the skin concentration of a drug to be predicted using Fick's second law of diffusion. The silicone membrane was found to be useful as an alternative membrane to animal skin for predicting skin concentration of chemical compounds, because an extremely excellent extrapolation to animal skin concentration was attained by calculation using the silicone membrane permeation data. In this chapter, we aimed to establish an accurate and convenient method for predicting the concentration profiles of drugs in the skin based on the skin permeation parameters of topically active drugs derived from steady-state skin permeation experiments.

[Evaluation of efficacy and safety of drugs absorbed through skin using their physicochemical parameters].

Skin has been paid attention as a site of application of prescription drugs, over-the-counter drugs (non-prescription drugs) and cosmetics. Skin permeation and skin concentration of the compounds should be considered after topical administration, as well as their blood concentration to evaluate efficacy and safety. Since the evaluation of the amount of drugs permeated through skin is important for topically applied drugs, studies on the skin permeation has been greatly advanced. In addition, many reports proved that skin permeabilities of drugs could be predicted from physicochemical parameters of drugs. On the other hand, few reports have been found on the prediction of skin concentration of drugs. Furthermore, many experimented problems are left to determine the skin concentration of drugs: severe consume of human or animal skins, difficult removal of applied drugs from the skin surface, low drug extraction ratio from skin and low sensitivity to determine skin concentration of drugs, and requirement of long time measurement. Thus, fast and accurate measurement of skin concentration of applied drugs are urgently required. This report describes the relationship between skin permeation and skin concentration, and the prediction of skin concentration of drugs using skin permeation parameters of drugs.

Effect of direction (epidermis-to-dermis and dermis-to-epidermis) on the permeation of several chemical compounds through full-thickness skin and stripped skin.

PURPOSE: Compound permeation through stratum corneum-stripped skin is generally greater than that through full-thickness skin. In addition, epidermis-to-dermis permeation profile should be the same as dermis-to-epidermis permeation profile. However, stripped skin permeability of some compounds was lower than full-thickness skin permeability and different permeabilities were found for some compounds between the two directions of skin permeation. The reasons for these findings were investigated in this study. METHODS: Full-thickness or stripped hairless rat skin was set in a Franz-type diffusion cell, and a solution of compound was applied on the epidermis or dermis side to determine the in vitro skin permeability. RESULTS: Although the stripped skin permeability of pentyl paraben (PeP) with extremely high logK(o/w) was lower than full-thickness skin permeabilities, the addition of 3% ethanol resulted in the expected permeation order. Epidermis-to-dermis permeation of PeP through full-thickness skin was higher than dermis-to-epidermis permeation. Epidermis-to-dermis permeations of fluorescein isothiocyanate dextran (FD-4) and isosorbide 5-mononitrate with negative logK(o/w) were also higher than those in the opposite direction. CONCLUSIONS: Morphological observation of skin after FD-4 permeation suggested that a conically shaped trans-follicular permeation pathway model could be advocated to explain the difference between the epidermis-to-dermis permeation and that in the opposite direction.

Mathematical model to predict skin concentration of drugs: toward utilization of silicone membrane to predict skin concentration of drugs as an animal testing alternative.

PURPOSE: To calculate the skin concentration of active ingredients in cosmetics and topical pharmaceuticals using silicone membrane permeation. METHODS: A series of parabens were used as model ingredients. Skin concentration of parabens was calculated using silicone membrane permeability. Their partition coefficient from formulations to the silicone membrane was determined by the membrane permeation profiles, and used to calculate their silicone membrane concentration, under an assumption that the membrane is one homogenous diffusion layer. The same procedure was applied for hairless rat skin. RESULTS: The calculated concentration of parabens in silicone membrane was very close to their observed values. However, the skin concentration calculated by skin permeability was not similar to the observed concentration. Re-calculation was performed under the assumption that the skin consists of two diffusion layers. This modification using permeation data through full-thickness and stripped skin enabled precise prediction of the skin concentration of parabens. In addition, the partition coefficient to the silicone membrane was useful to estimate their skin concentration. CONCLUSIONS: Ingredient concentration in skin can be precisely predicted using diffusion equations and partition coefficients through permeation experiments using a silicone membrane. The calculated in-skin concentration is useful for formulation studies of cosmetics and topical pharmaceuticals.