A Hollow Microneedle Equipped with a Micropillar for Improved Needle Insertion and Injection of Drug Solution.

PURPOSE: Hollow-type microneedles (hMNs) are a promising device for the effective administration of drugs into intradermal sites. Complete insertion of the needle into the skin and administration of the drug solution without leakage must be achieved to obtain bioavailability or a constant effect. In the present study, several types of hMN with or without a rounded blunt tip micropillar, which suppresses skin deformation, around a hollow needle, and the effect on successful needle insertion and administration of a drug solution was investigated. Six different types of hMNs with needle lengths of 1000, 1300, and 1500 µm with or without a micropillar were used. METHODS: Needle insertion and the disposition of a drug in rat skin were investigated. In addition, the displacement-force profile during application of hMNs was also investigated using a texture analyzer with an artificial membrane to examine needle factors affecting successful insertion and administration of a drug solution by comparing with in vivo results. RESULTS: According to the results with the drug distribution of iodine, hMN1300 with a micropillar was able to successfully inject drug solution into an intradermal site with a high success rate. In addition, the results of displacement-force profiles with an artificial membrane showed that a micropillar can be effective for depth control of the injected solution as well as the prevention of contact between the hMN pedestal and the deformed membrane. CONCLUSION: In the present study, hMN1300S showed effective solution delivery into an intradermal site. In particular, a micropillar can be effective for depth control of the injected solution as well as preventing contact between the hMN pedestal and the deformed membrane. The obtained results will help in the design and development of hMNs that ensure successful injection of an administered drug.

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.

Development of an Auraptene-Loaded Transdermal Formulation Using Non-ionic Sugar Ester Surfactants.

Auraptene (Aur) is a naturally occurring monoterpene coumarin ether that exhibits numerous therapeutic properties. Its high lipophilicity and low skin penetration, however, limit its potential application for local and transdermal delivery. Biocompatible non-ionic sugar esters (SEs) possess beneficial properties for the development of transdermal formulations in delivering pharmaceutically challenging molecules such as graphene and Aur. In the present study, we conducted a series of experiments to demonstrate the effect of several previously unstudied SEs on the skin permeation and distribution of Aur by preparing gel- and dispersion-type formulations. Skin permeation and deposition experiments were conducted using a Franz diffusion cell with rat skin as the membrane. The dispersion-type formulations prepared using SEs had higher entrapment efficiency, as well as better skin permeation and retention profiles. The dispersion-type formulation containing sucrose palmitate (sSP) exhibited the highest skin permeation over 8 h. Notably, the enhancement effects on Aur concentration in full-thickness skin after the application of the dispersion-type formulation was higher than those of the control formulation. These results indicated that the prepared formulation has potential for use in the transdermal delivery of Aur in pharmaceutical and cosmetic products.

Effects of Intradermal Administration Volume Using a Hollow Microneedle on the Pharmacokinetics of Fluorescein Isothiocyanate Dextran (M.W. 4,000).

PURPOSE: Hollow microneedles (hMNs) have been gaining attention as a tool to enable the intradermal (i.d.) administration of pharmaceutical products. However, few reports have examined the effect of administration volume on distribution in the skin and pharmacokinetics parameters after i.d. injection. In the present study, a model middle molecular weight compound, fluorescein isothiocyanate dextran (M.W. 4,000, FD-4), was selected, and blood concentration-time profiles after i.d. and subcutaneous (s.c.) injections with different administration volumes were compared. METHODS: FD-4 solution was injected i.d. using a hMN or injected s.c. with a 27 G needle. Pharmacokinetics and dermatokinetics of FD-4 were analyzed using a compartment model. The skin distribution of iodine, as an X ray tracer, was used to evaluate drug disposition. RESULTS: With the administered drug assumed to be absorbed from the broad injection site into blood vessels in the upper and lower dermis by rapid (krapid) and slow (kslow) first-order absorption rate constants, respectively, better agreement of observed and theoretical values was obtained. Furthermore, the fraction, F, of the administered dose absorbed with krapid decreased with the increase in injection volume after i.d. injection, although the pharmacokinetics parameters were almost the same regardless of administration volume after s.c. injection. CONCLUSION: The drug distribution in the skin may be related to the obtained pharmacokinetics parameters suggested that the number of needles in the MN system and the total administration volume should be considered in designing hMN systems. The present results provide useful information that may support effective drug delivery with hMNs.

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.

Prediction of Critical Quality Attributes Based on the Numerical Simulation of Stress and Strain Distributions in Pharmaceutical Tablets.

Various stresses and strains are generated on the surface and inside of pharmaceutical tablets when an external force is applied. In addition, stresses in various directions can remain on the surface and inside the tablets because they are generally prepared by compaction of pharmaceutical powders using dies and punches. As it is difficult to measure the stress and strain generation in the tablets experimentally, a numerical simulation was applied by employing a finite element method (FEM). An elastic model is often used to represent stress and strain generation after loading an external force to tablets, and the Drucker-Prager cap (DPC) model has been widely recognized for representing the remaining stress distributions during the compaction of powder to tablet form. Firstly, this article describes an FEM simulation of the stress generation on the surface of the scored tablets after loading the bending force from the back side of the tablets. Next, the FEM simulation was introduced to determine the effect of diametrical compression on the stress and strain generation in the tablets by comparing the results measured experimentally. Furthermore, the residual stresses remaining inside the tablets were simulated using FEM, in which powder compaction was represented as the DPC model. A clear difference was observed in the residual stress distributions between the flat and convex tablets. This indicates that FEM simulation is useful for achieving a science-based understanding of critical quality attributes in various types of tablets.

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.

The Effect of Iontophoresis with and without Electroporation on the Penetration of High Molecular Compounds into the Stratum Corneum.

Both iontophoresis (IP) and electroporation (EP) can be utilized to increase the penetration of relatively high molecular pharmaceutical and/or cosmeceutical compounds into the stratum corneum (SC), the uppermost layer of the skin. However, few reports exist on which molecular weights are capable of penetrating the SC, although low molecular compounds of less than 500 Da have been found to readily permeate the skin barrier. In our investigation, we applied fluorescein amine-labeled sodium hyaluronate to porcine aural skin after treatment by IP alone or EP + IP. Each layer of the SC was then tape stripped several times. The stripped SC sheets were observed using a confocal laser scanning microscope to determine the relative amounts of sodium hyaluronate present. The results confirmed that the molecular weight of sodium hyaluronate that penetrated the SC was higher with EP + IP than with IP alone. A high correlation was also established between the quantity of sodium hyaluronate that penetrated and its molecular weight following combined EP + IP treatment.

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.

Self-Assembled Structure of α-Isostearyl Glyceryl Ether Affects Skin Permeability-a Lamellar with 70-nm Spaces and L3 Phase Enhanced the Transdermal Delivery of a Hydrophilic Model Drug.

Self-assembled surfactant structures, such as liquid crystals, have the potential to enhance transdermal drug delivery. In the present study, the pseudo-ternary system of GET (composed of α-Isostearyl glyceryl ether (GEIS) and polysorbate 60)/1,3 butanediol (BG)/water) was shown to exhibit a complex phase diagram. Small- and wide-angle X-ray scattering (SWAXS) and freeze-fracture transmission electron microscopy (FF-TEM) revealed that GET6BG60 (6%GET/60%BG/34%Water) formed a lamellar phase with a repeated distance of approximately 72 nm. Such a long-repeated distance of the lamellar phase was unique in the surfactant system. Moreover, the various structures, such as multilamellar vesicles and branched-like layers, were observed, which suggested that they might be deformable. On the other hand, only core-shell particles were observed in GET6BG20, the core of which was an L3 phase. GET6BG20 and GET6BG60 significantly enhanced the skin permeation of the hydrophilic model drug, antipyrine (ANP) (log Ko/w, - 1.51). However, their permeation profiles were distinct. Liquid chromatography-tandem mass spectrometry revealed that epidermal accumulation of GEIS was significantly higher with GET6BG60 than GET6BG20 after 1.5 h of permeation, which might be attributed to differences in their deformable properties. Furthermore, GEIS was reported to affect intercellular lipids. Accumulated GEIS in the epidermis may have interacted with intercellular lipids and enhanced the transdermal delivery of ANP. The difference in the permeation profiles of ANP may be attributed to the penetration process of GEIS in the epidermis. This study suggests that GET6BG20 and GET6BG60 are unique carriers to enhance the permeation of hydrophilic drugs, such as ANP.

A Lipid-Based Depot Formulation with a Novel Non-lamellar Liquid Crystal Forming Lipid.

PURPOSE: Non-lamellar liquid crystal (NLLC)-forming lipids have gained attention as a novel component because of their ability to self-assemble upon contact with body fluids. In this study, a novel NLLC-forming lipid, mono-O-(5, 9, 13-trimethyl-4-tetradecenyl) glycerol ester (C17MGE), and a model drug with a middle molecule weight, leuprolide acetate (LA), were used to confirm the usefulness of C17MGE as an excipient for depot formulations with sustained release properties. METHODS: A self-constructed depot formulation was prepared by mixing C17MGE and different types of phospholipids. The constructed NLLC structure was evaluated using small angle X-ray analysis and cryo-transmission electron microscopy. In vitro release and blood concentration profiles of LA were investigated. RESULTS: The NLLC structure was confirmed by small angle X-ray analysis. LA release was able to be modified by adding different ratios of various phospholipids to C17MGE. Formulations containing 1, 2-dioleoyl-sn-glycero-3-phosphoglycerol sodium salt with a mixing ratio of 12% or 24% (MDOPG12 or MDOPG24, respectively) exhibited sustained release profiles of LA. In addition, the blood concentration of LA was detected over 21 days or more after administration of MDOPG12, and the absolute bioavailability was calculated to be about 100%. CONCLUSIONS: A depot formulation using C17MGE was useful to achieve sustained release of LA.

Enhancement of Skin Permeation of a Hydrophilic Drug from Acryl-Based Pressure-Sensitive Adhesive Tape.

PURPOSE: Penetration enhancers are necessary to overcome a formidable barrier function of the stratum corneum in the development of topical formulations. Recently, non-lamella liquid crystal (NLLC)-forming lipids such as glycerol monooleate and phytantriol (PHY) are gaining increasing attention as a novel skin permeation enhancer. In the present study, fluorescein sodium (FL-Na) was used as a model hydrophilic drug, and acryl-base pressure-sensitive adhesive (PSA) tape containing NLLC forming lipids, mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE) or PHY, was prepared to enhance drug permeation through the skin. METHODS: A PSA patch containing FL-Na was prepared by mixing FL-Na entrapped in NLLC and acrylic polymer. FL permeation through excised hairless rat skin, and also human skin, was investigated. Changes in lipid structure, folding/unfolding state of keratin in the stratum corneum, and penetration of MGE into the stratum corneum were investigated using confocal Raman microscopy. RESULTS: Enhanced FL permeation was observed by the application of a PSA patch containing MGE and PHY. Especially, dramatically enhancement effect was confirmed by 15% of MGE contained formulation. Penetration of MGE provided diminished orthorhombic crystal structure and a peak shift of the aliphatic CH3 vibration of keratin chains toward lower wavenumbers. CONCLUSION: The present results suggested that the formulation development by adding MGE may be useful for improving the skin permeation of mal-permeable drugs such as hydrophilic drugs.

Influence of Polyunsaturated Fatty Acid Intake on Kidney Functions of Rats with Chronic Renal Failure.

Arachidonic acid (ARA), an omega-6 (ω-6) polyunsaturated fatty acid (PUFA), is involved in the development and maintenance of renal functions, whereas docosahexaenoic acid (DHA) is an omega-3 (ω-3) PUFA that has anti-inflammatory effects and attenuates nephropathy. However, their effects on the progression of chronic kidney disease (CKD) remain unknown. The aim of this study was to assess the effects of feeding ARA, DHA, and ARA and DHA-containing diets on rats with 5/6 nephrectomized kidneys. Urine and feces were collected every 4 weeks, and the kidneys were collected at 16 weeks after surgery. Urinary albumin (U-ALB) excretion increased gradually with nephrectomy, but the U-ALB excretion was attenuated by feeding the rats with an ARA + DHA-containing diet. Reactive oxygen species (ROS) levels in the kidneys were lower in the ARA + DHA group than in the other groups. At 4 weeks after surgery, the lipid peroxide (LPO) levels in the plasma of the ARA + DHA groups decreased significantly after surgery compared to the control CKD group, but this did not happen at 16 weeks post-surgery. There was a significant negative correlation between LPO levels in the plasma at 4 weeks and creatinine clearance, and a positive correlation with urinary albumin levels. These results suggest that the combination of ARA and DHA inhibit the progress of early stage CKD.

Latent Structure Analysis of Wet-Granulation Tableting Process Based on Structural Equation Modeling.

Quality by design (QbD) is an essential concept for modern manufacturing processes of pharmaceutical products. Understanding the science behind manufacturing processes is crucial; however, the complexity of the manufacturing processes makes implementing QbD challenging. In this study, structural equation modeling (SEM) was applied to understand the causal relationships between variables such as process parameters, material attributes, and quality attributes. Based on SEM analysis, we identified a model composed of the above-mentioned variables and their latent factors without including observational data. Difficulties in fitting the observed data to the proposed model are often encountered in SEM analysis. To address this issue, we adopted Bayesian estimation with Markov chain Monte Carlo simulation. The tableting process involving the wet-granulation process for acetaminophen was employed as a model case for the manufacturing process. The results indicate that SEM analysis could be useful for implementing QbD for the manufacturing processes of pharmaceutical products.

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.

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.

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.

Design and Optimization of Scored Tablets with Concave Surface and Application of Bayesian Estimation for Solving Scaleup Problem.

From the viewpoint of self-medication, it is valuable to develop patient-friendly scored tablets that possess dividing uniformity. In this context, we attempted to optimize the preparation conditions for a tablet with a unique shape, such as a concavely curved scored tablet (CCST). Employing a design of experiment and a response surface method incorporating a thin-plate spline interpolation, and a bootstrap resampling technique, the optimal preparation conditions for CCST were successfully developed. To make it possible to scaleup the optimal solution estimated on a trial-scale, a Bayesian estimation was applied. Credible ranges of critical responses in large-scale manufacturing were estimated as a posterior probability from the trial-scale experiment as a prior probability. In terms of the large-scale manufacturing, the possibility of solving the scaleup problem was suggested using Bayesian estimation. Furthermore, a simulation study using a finite element method revealed that strong tensile stresses generated along the tip of the score line in CCST when an outer force was applied to the back surface of CCST. An advantage in dividing uniformity is indicated by the unique shape of CCST.

Effect of Rubbing Application on the Skin Permeation of Active Ingredients from Lotion and Cream.

Effect of rubbing application on the skin permeation of a hydrophilic drug caffeine (CAF) and lipophilic drug rhododendrol (RD) from lotion and cream were investigated. Skin permeation of CAF was markedly increased by rubbing action independent of the formulation type. In addition, the skin penetration-enhancement effect was affected by the rubbing direction: rubbing application against the direction of hair growth showed the highest permeation compared with rubbing applications along the direction of hair growth and in a circular pattern on the skin. On the other hand, no enhancement effect was observed by the rubbing actions on the skin permeation of RD, regardless of formulation type. Change in the infundibula orifice size of hair follicles by the rubbing and following skin stretching may be related to the higher skin permeation for CAF. In contrast, high RD distribution into the stratum corneum may be a reason why no enhancement effect was observed by the rubbing action. These results can be helpful to predict safety and effectiveness of topically applied formulations.

Prolonged Distribution of Tranilast in the Eyes after Topical Application onto Eyelid Skin.

Tranilast, a lipophilic drug with various ophthalmic applications, was used as a model drug to establish the possibility of delivering lipophilic drugs through the eyelid skin. Pharmacokinetics and tissue distribution studies were conducted employing three application methods (topical application onto eyelid skin, eye drops, and intravenous injection in rats) to broaden the significance of delivering drugs through the eyelids. A two-compartment open model analysis was used for intravenous route while a non-compartmental evaluation was used for topical applications to estimate the pharmacokinetic parameters. Eyelid skin application, eye drops, and intravenous administration had mean residence times (MRTs) of 8.07, 1.79, and 3.25 h in the eyeball and 10.8, 1.29, and 2.97 h in the conjunctiva, correspondingly. In the eyeball, topical application of tranilast onto the eyelids corresponded to a 4.5- and 2.5-fold higher MRT compared with eye drops and intravenous administration, respectively. An 8.4- or 3.6-fold higher MRT was observed in the conjunctiva after topical application compared with eye drops or intravenous administration, respectively. This indicated a gradual penetration of tranilast into the eyeball and conjunctiva, subsequently a slow elimination from these target tissues.