Effect of Equipment Parameters on Amount and Dispersion of Wetting Liquid in Planetary Centrifugal Granulation.

In planetary centrifugal wet granulation, the binder is often mixed into the formulation as a powder, followed by the addition of a wetting liquid, in a single step. Therefore, the amount and dispersion of the wetting liquid are important factors that determining granulation success and granules characteristics. In this study, granulation experiments, according to the Box-Behnken design, were performed. Further, the effects of equipment parameters, namely, processing speed, processing time, and vessel size, on the minimum amount of wetting liquid required to enable granulation and dispersion state in the vessel were statistically analyzed. Placebo granules were formulated with lactose hydrate and corn starch (7 : 3), using sodium carmellose as a binder. Results showed that the amount of wetting liquid decreased with increase in processing speed, processing time, and vessel size; however, the dispersion state of the wetting liquid was not significantly affected. Analysis of the effects of the equipment parameters on granule characteristics showed that a larger vessel size was proportional to a larger median diameter and smaller particle-size distribution width (span), and a faster processing speed was proportional to a smaller span. Furthermore, granules with the target properties could be prepared according to the parameters estimated from the model. In conclusion, the equipment parameters for controlling the amount of wetting liquid, which affected the granule properties, were clarified.

Small-Scale Spherical Granulation Using a Planetary Centrifugal Mixer.

A concise spherical granulation method is required to prepare extemporaneously granules remanufactured from oral dosage forms for administration to individuals who cannot swallow tablets or capsules. In this study, we determined the feasibility of spherical granulation using a planetary centrifugal mixer. A model formulation, 20% ibuprofen (IBP) granules, was prepared using a lactose/cornstarch (7 : 3, w/w) mixture or D-mannitol as diluents, and changes in granule characteristics (mean diameter (d50), distribution range of granule size (span), and yield) were evaluated according to the amount of water added and the granulation time. The amount of water was assessed using the plastic limit value as measured using a digital force gauge. We successfully produced granules, and larger amounts of water and longer granulation times resulted in larger d50 values and smaller span values. The optimal granulation time was 45 s and the optimal water contents were 70 and 67.5% of the plastic limit value for the lactose/cornstarch mixture and D-mannitol, respectively. When compared to commercial 20% IBP granules, powder X-ray diffraction and differential scanning calorimetry analyses showed that the granulation process did not alter the crystallinity of the drug. Thus, this novel granulation method using a planetary centrifugal mixer may be a promising technique for compounding in pharmacies and in pharmaceutical manufacturing.

Evaluation of Dantrolene Granules Extemporaneously Reformulated from Capsules in a Pharmacy.

Dantrolene capsule, an effective therapeutic agent for the treatment of spasticity, is administered to children who cannot swallow the capsule after reformulation into a powder. The powdered drug can alter the specified dosage and it is also difficult to dispense the powdered formulation because of its bulky and sticky nature. To resolve these problems, we reformulated dantrolene capsules into granules using a centrifugal planetary mixer in the pharmacy. The granules containing lactose-cornstarch, D-mannitol, or microcrystalline cellulose as a diluent were examined to determine particle size distribution, flowability, drug content uniformity, and disintegration time. The granules with microcrystalline cellulose were superior to the other forms, owing to their smaller size, good drug content uniformity, and rapid disintegration. We further investigated the usability of the granules in the dispensing procedure (dividing and packing) and in the dosing process (retrieval from package) using the powders as controls. The deviation of the divided amount and loss on dosing were reduced relative to the powders. In addition, drug dissolution properties and storage stability for 12 months were the same as those of the powders. Therefore, we concluded that dantrolene granules are excellent alternatives as an extemporaneous preparation in pharmacies.

Development of a Novel Simple Gel Formulation Containing an Ion-Pair Complex of Diclofenac and Phenylephrine.

BACKGROUND AND AIM: Since the pharmacological effects of diclofenac (DF) are short-lived because of its short half-life, prolongation of the pharmacological effect in a topical formulation is needed for more appropriate clinical use. For the enhancement of dermal accumulation and prolongation of the pharmacological effect of drugs, the aim of this study was to develop a simple gel formulation containing an ion-pair complex of DF and phenylephrine (PHE), which induce constriction of the vascular smooth muscles. MATERIALS AND METHODS: The ion-pair complex was prepared by mixing sodium DF and an ethanolic solution of PHE. The formed complex was characterized by powder X-ray diffraction (PXRD) and Fourier-transform infrared (FT-IR) spectroscopy. The ion-pair complex for the gel formulation was prepared by mixing an equimolar concentration of 50% 1,3-butylene glycol and distilled aqueous solution of 2% xanthan gum, which was characterized by proton nuclear magnetic resonance (1H-NMR). Skin permeation and accumulation of DF and PHE were evaluated by in vitro and in vivo studies. RESULTS: From the results of PXRD and FT-IR, it was suggested that new crystalline peaks formed by the ion-pair complex and their complex interacted with the carboxyl group in DF and the amino group in PHE. In the gel formulation, the ion-pair complexes were detected by 1H-NMR. The ion-pair complex enhanced the accumulation of DF in the skin in the in vitro study. On the other hand, PHE accumulation in the dermis increased with the ion-pair complex, as exhibited by the in vivo study. CONCLUSION: A new gel formulation containing the ion-pair complex of DF and PHE was developed, which improved the accumulation of DF in skin.

Application of Response Surface Methodology to Estimate the Design Space of Pharmaceutical Diluents for Dispensing Powdered Formulations.

Scientific approaches for dispensation are important for the quality and efficacy of drug treatments. Therefore, for the dispensation of powdered medicines, we have developed a powder blending method using a planetary centrifugal mixer (PCM) to replace the empirical manual method involving a mortar and pestle. The aim of this study was to optimize the formulation of pharmaceutical diluents for dispensing powdered medicines, using PCM. The diluents, composed of powdered lactose, crystalline lactose, and corn starch were assigned to a {3,2}-Simplex Lattice design. Then, the designed diluents were blended with model powders, such as carbazochrome sodium sulfonate powder, rifampicin capsule contents, and crushed sulfasarazine tablets, at ratios of 1 : 4, 1 : 1, and 4 : 1 using PCM at 800 rpm for 60 s at a 20% filling rate. The mixtures were examined for content uniformity relative standard deviation (RSD) and flowability angle of repose (AOR). Response surface methodology was applied to optimize the formulation with the smallest RSD and AOR, and then the design space of desired diluents was estimated. On the basis of the design space, crystalline lactose, the mixture of lactose powder and crystalline lactose at a ratio of 1 : 4, and the mixture of corn starch and crystalline lactose at a ratio of 1 : 4, were suitable diluents for the powdered formulation, the content of the capsules, and the crushed tablets, respectively. The selected diluents were successfully applied to other model medicines showing a sufficient RSD and AOR. This technique could contribute to the development of scientific approaches for dispensation.

Dry Powder Coating using Planetary Centrifugal Mixer.

PURPOSE: Extemporaneous compounding is an important part of pharmacy practice, and should be standardized and sophisticated to ensure the quality of the compounded preparations. Recently, we applied a planetary centrifugal mixer (PCM) to powder blending, which has attracted interest for its small scale and lack of contamination. In this study, we aimed to reveal the feasibility of dry powder coating through ordered mixing of fine particles using PCM. METHODS: Cohesive lactose powders (Pharmatose450M) were dry coated with magnesium stearate (MgSt) using from 0.1 to 5%(w/w) content. The operational variables tested were operation time (1-30 min), operation speed (400-1000 rpm), vessel size (24-100 mL), and charging rate in the vessel (20-40%). The processed powders were evaluated for their surface morphology, flowability, and wettability. Furthermore, fine ibuprofen particles were coated with various lubricants, and then the dissolution profiles were examined. The crystallinity of ibuprofen was assessed using FT-IR and PXRD. RESULTS: Lactose powders were successfully coated with MgSt using PCM. When the level of MgSt was over 1%, the surface of the lactose powders was thoroughly covered. Angles of repose were 51° and 41° for unprocessed and processed powders with 1% MgSt, respectively. The contact angle of the water drop on the 1% MgSt sample leached to be 132°, changing to a hydrophobic surface. Investigations under various operational conditions revealed that higher improvement was observed upon higher speed and longer time, and a smaller charging rate in the vessel. Vessel size had no impact. Moreover, improved dissolution of ibuprofen coated with both hydrophilic and hydrophobic lubricants was observed owing to good dispersing behavior. Besides, no alteration of crystallinity was detected. CONCLUSIONS: PCM is an effective tool for dry powder coating with low impact stress. The presented method will contribute a great deal to making crushed tablets a functional powder.

Glyceryl monooleyl ether-based liquid crystalline nanoparticles as a transdermal delivery system of flurbiprofen: characterization and in vitro transport.

Liquid crystalline nanoparticles (LCNs) were prepared using glyceryl monooleyl ether (GME) by the modified film rehydration method. Hydrogenated lecithin (HL), 1,3-butylene glycol (1,3-BG), and Poloxamer 407 were used as additives. The prepared LCN formulations were evaluated based on particle size, small-angle X-ray diffraction (SAXS) analysis, (1)H- and (19)F-NMR spectra, and in vitro skin permeation across Yucatan micropig skin. The composition (weight percent) of the LCN formulations were GME-HL-1,3-BG (4 : 1 : 15), 4% GME-based LCN and GME-HL-1,3-BG (8 : 1 : 15), 8% GME-based LCN and their mean particle sizes were 130-175 nm. Flurbiprofen 5 and 10 mg was loaded into 4% GME-based LCN and 8% GME-based LCN systems, respectively. The results of SAXS and NMR suggested that both flurbiprofen-loaded formulations consist of particles with reverse type hexagonal phase (formation of hexosome) and flurbiprofen molecules were localized in the lipid domain through interaction of flurbiprofen with the lipid components. Flurbiprofen transport from the LCN systems across the Yucatan micropig skin was increased compared to flurbiprofen in citric buffer (pH=3.0). The 8% GME-based LCN systems was superior to the 4% GME-based LCN for flurbiprofen transport. Since the internal hexagonal phase in the 8% GME-based LCN systems had a higher degree of order compared to the 4% GME-based LCN in SAXS patterns, the 8% GME-based LCN system had a larger surface area, which might influence flurbiprofen permeation. These results indicated that the GME-based LCN system is effective in improving the skin permeation of flurbiprofen across the skin.

Reconstitution of L-Asparaginase in Siliconized Syringes with Shaking and Headspace Air Induces Protein Aggregation.

The aim of this study was to characterize protein aggregation during reconstitution of a highly concentrated solution of lyophilized L-asparaginase (L-ASP). The effect of the preparation method on L-ASP aggregation using siliconized or non-siliconized syringes and the effect of storage after preparation were evaluated by far-UV circular dichroism spectroscopy, Raman microscopy, flow cytometry, and flow particle image analysis. To investigate the effect of syringe type in combination with shaking and headspace air on L-ASP aggregation, four kinds of L-ASP in 5% glucose solutions were prepared (in the presence or absence of silicon oil and headspace air). Slight differences in L-ASP secondary structure were observed between the siliconized and non-siliconized syringe systems before shaking. Large numbers of sub-visible (0.1-100 µm) and submicron (0.1-1 µm) particles were formed by preparation with siliconized syringes and the combination of shaking and headspace air. The number of aggregated particles was not decreased with increased storage time. The Raman microscopy, flow cytometry and flow particle image results suggested that L-ASP interacted with silicone oil, which induced aggregation. Nevertheless, sub-visible and submicron particles were also formed with non-siliconized syringes. However, using non-siliconized syringes, the number of aggregated particles decreased with storage. No changes in particle character were observed before or after shaking with headspace air in non-siliconized syringes, indicating that soluble aggregates formed and dissolved with storage. Silicone oil in syringes, in combination with shaking and headspace air, strongly affected the aggregation of lyophilized L-ASP formulations during preparation.

Preparation of goreisan suppository and pharmacokinetics of trans-cinnamic acid after administration to rabbits.

Goreisan suppository is prepared as a hospital preparation, and successfully used for the treatment of diarrhea and vomiting in young children with common cold. While clinical efficacy of the suppository has been reported, few studies have been carried out to clarify the preparation procedure and pharmacokinetics of the suppository. In this study, trans-cinnamic acid (CA) was used as a representative substance of goreisan constituents, and assayed by HPLC-UV. We investigated the properties of goreisan suppositories prepared using various sizes of pulverized goreisan extract granules, in vitro dissolution profiles using the reciprocating dialysis tube method, and pharmacokinetics in rabbits compared with those for goreisan enema. Mass and content uniformity tests on the suppositories of three size fractions, 0-75, 75-150, and 150-300 µm, showed good acceptance for all kinds of suppository. Storage stability at 4°C was maintained until 4 months. In vitro dissolution of CA from the suppository was proportional to time until 45 min, and slower than that from the enema. Finally, 80% of CA had dissolved at 60 min. Pharmacokinetic study in rabbits revealed that the area under the plasma concentration-time curve from 0 to 120 min (AUC0-120 min) of the suppository was twice that of the enema. Moreover, from a study in rabbits using CA injection and CA suppository, we revealed that CA was rapidly and well absorbed from the rectum, showing 84% absolute bioavailability. Thus, we illustrated the defined preparation procedure of the suppository and the superiority of the suppository over the enema. This study will support evidence that the suppository is fast-acting and efficacious in clinical use.

Evaluation of degree of blending colored diluents using color difference signal method.

We developed a color difference signal method to evaluate the degree of blending powdered medicines in pharmacies. In the method, the degree of blending is expressed as the relative standard deviation of the color difference signal value (Cb or Cr) of the YCbCr color space after digital photos of the blended medicines are analyzed by image processing. While the method is effective to determine the degree of blending colored medicines, it remains unknown whether it can be applied to uncolored or white-colored medicines. To investigate this, we examined colored diluents to identify an indicator of the degree mixtures are blended. In this study, we applied this method to Pontal® and Prednisolone® powders, which were used as uncolored and white-colored medicines, respectively. Each of these medicines was blended with the colored lactose using a pestle and mortar, and then the uniformity of blending was evaluated. The degree of blending was well-monitored in both mixtures with various blending ratios (1 : 9-9 : 1), showing a sufficient uniformity at 60 rotations of the pestle. Moreover, the Cr values of the mixtures with various blending ratios were correlated with the concentration of active pharmaceutical ingredients in these medicines, which was determined using HPLC. This indicated the usefulness of the color difference signal method for the quantitative determination of medicines. Thus, we demonstrated the applicability and effectiveness of this method to check dispensing powders.

A novel blending method for dispensing powdered medicine.

We introduced the application of a planetary centrifugal mixer to dispensing powdered medicines to prevent from individual variation in the skills of pharmacists with a manual blending. The blending performance of the mixer was explored in terms of four operational variables, namely, operation speed (400-1000 rpm), operation time (10-60 s), charging rate in vessel (20-50%), and size of vessel (35, 58, 125, 550 mL), using colored lactose and crystalline lactose as the principle model medicine and diluent, respectively. The blending degree was assessed by image analysis, so the extent of uniformity was expressed as the relative standard deviation of the color difference signal Cb value of YCrCb color space. Application of the mixer to blending three commercial medicines with diluents was carried out. Sufficient blending was achieved at 10 s using a 20% charging rate and 35 mL vessel irrespective of operation speed. As the charging rate was increased, a higher operation speed was needed to obtain uniform blending. A larger sized vessel also required a higher operation speed. Uniform blending was achieved in all of the mixtures of colored lactose and crystalline lactose at the weight ratio of 1 : 9-9 : 1. In the application studies using Adona®, Anginal® and Neophylline® powder, the blending performance of the mixer was equivalent to that of the manual blending method, showing relative standard deviations of 2.2-3.3% and 1.8-3.8%, respectively. These results revealed that the planetary centrifugal mixer was suitable for blending powdered medicine.

Assessment of blending ratio of powdered medicine mixtures by image analysis.

In the dispensing process, powdered medicines are often blended with diluents or different kinds of powder. With blending, the mass percent of the medicine in the mixture is unknown until the active pharmaceutical ingredient is determined with techniques such as spectroscopy and chromatography. However, pharmacists need to confirm the exact blending ratio of the dispensing mixture in pharmacies. We aimed to develop a precise and concise method to measure the mass percent of powdered medicine mixtures without an expensive analytical apparatus. Digital photographs of three kinds of mixture of lactose powder, as diluents, with Adona®, Anginal®, or Asverin® powder were taken with a microscope at a 30× magnification. Thereafter, the mass percent was calculated from digital images of the mixture using calibrated color information in the YCbCr color space. A linear regression, between the mass percent and color difference signal, Cb, value was obtained from 10 to 90% of the medicines (r(2)=0.9806-9993) in all systems. The intra-day accuracy and precision were 0.67-12% (relative error) and <5% (relative standard deviation), respectively. Moreover, the mass percent measured using image analysis was consistent with the concentration of the active pharmaceutical ingredient determined spectrophotometrically. This effective image analysis method enables pharmacists to nondestructively ensure the exact mass percent of the medicine in the dispensing mixture in pharmacies.

Evaluation of the pharmaceutical characteristics of various enteric-coated aspirin tablets under different storage conditions.

The formulation characteristics of 6 brands of enteric-coated aspirin tablets under unpackaged conditions at 40°C and 60°C for 4 weeks were analyzed. Appearance, salicylic acid content, dissolution rates, and surface properties (by Raman microscopy) were evaluated to determine stability data, taking into account the clinical use of generic drugs. No change in appearance, decomposition, or dissolution rates was observed in unpackaged aspirin tablets stored at 40°C for 4 weeks. However, when stored at 60°C, tablets of 5 of the 6 brands showed whiskers on their surfaces along with an increase in salicylic acid content and a decrease in dissolution rate. Results of Raman mapping on the surface and cross sectional surface of the tablets with whiskers showed a salicylic acid peak associated with storage at 60°C for 4 weeks. However, for tablets from 1 of the 6 brands, no salicylic acid peaks were observed. For this tablet, Raman microscopy revealed 2 layers of film coating, and talc, which greatly affected the stability of the acetylsalicylic acid, was found only in the outer layer film. These results indicated that the protection of compatibility with talc is one of the important factors in enhancement of aspirin tablet stability in this tablet. We concluded that certification of the characteristics associated with stability and formulation is essential for generic drugs, which are not required to undergo stability testing under extreme storage conditions.

Particle condition change in emulsion admixture evaluated by in situ flow particle imaging analysis.

We evaluated the particle state change in emulsion admixtures using in situ flow particle imaging analysis (FPIA). Ropion® intravenous (flurbiprofen axetil: Ropion®) served as the model emulsion formulation. A binary mixture of Ropion® and normal saline (NS), and a ternary admixture of Ropion®, NS, and Gaster® injection (famotidine: Gaster®) or Primperan® injection (metoclopramide hydrochloride: Primperan®) were prepared and the change in emulsion particle state was analyzed using FPIA under in situ condition. The effect of storage on pH change and the chemical stability of flurbiprofen axetil were also investigated. In Ropion®, various particle images (mean diameter: 2.4 µm) were obtained. From our analysis of changes in scattergrams and particle images, changing behaviors of emulsion particles as a function of storage time depended on the systems of admixture samples. In Ropion®/NS and Ropion®/Gaster®/NS systems, mean particle size and particle number increased with lengthening storage time; however, these values were dramatically increased beyond 6 h in the Ropion®/Primperan®/NS system, corresponding to a decrease in measured pH. The decomposition of flurbiprofen axetil due to incompatibility was not observed in all systems. Detailed information on the change in emulsion particle state was obtained using FPIA, indicating that this method is useful to evaluate state changes in emulsion admixtures under in situ condition.

Extemporaneous preparation of rifampicin granules from capsules to improve usability.

OBJECTIVES: Manipulation of tablets or capsules is frequently carried out in pharmacies to regulate doses for personalised therapy. We proposed the use of reconstructed granules as a suitable, flexible dosage form and developed an on-site granulation method using a compounding mixer. The aim of this study was to demonstrate the feasibility of small-scale preparation of granules in a pharmacy setting. Rifampicin capsules were used as a model medicine because of the associated need for drug desensitisation therapy. METHODS: The contents of a rifampicin capsule were granulated using a compounding mixer, and small ointment containers (12 mL) with filling rates of 4%, 8%, 12%, and 16% were used as granulation vessels. The obtained granules were examined for particle size distribution, yield, crystal transition, drug dissolution profile, storage stability, and weight loss during dosing. RESULTS: The yields increased by >95%, and the span of the particle size distribution decreased to 1.0, as the filling rate increased. The smallest batch size was found to be 0.8 g in a 12 mL vessel. Examination of the resultant granules revealed that granulation did not affect the crystal polymorphism, dissolution profile, or storage stability of rifampicin. Furthermore, the weight loss of the granules during the dosing process was significantly lower than that of the capsule powder content. CONCLUSIONS: We demonstrated that granules with sufficient quality for clinical use could be extemporaneously prepared using a compounding mixer in pharmacies. This improved the usability of the medicine, preventing weight loss, and making it a suitable alternative formulation for precise personalised pharmacotherapy.

Comparative analysis of intercellular lipid organization and composition between psoriatic and healthy stratum corneum.

The lipid composition and organization of the stratum corneum (SC) in patients with psoriasis and healthy subjects were compared using X-ray diffraction, Fourier-transform infrared spectroscopy (FT-IR), and ultraperformance liquid chromatography, combined with time-of-flight mass spectrometry (UPLC-TOFMS). In healthy SC (HSC), SC lipids formed two lamellar phases (long and short periodicity phases). Hexagonal and orthorhombic hydrocarbon-chain packing were observed in the lateral lipid organization at 30 °C via X-ray diffraction. In HSC, the lamellar phases and the hydrocarbon-chain packing organizations changed with elevated temperatures and finally disappeared. In these behaviors, the high-temperature hexagonal hydrocarbon-chain packing organization, which appeared above the orthorhombic hydrocarbon-chain packing organization, transformed to the liquid phase at about 90 °C in HSC. In psoriatic SC (PSC), hexagonal hydrocarbon-chain packing organization disappeared at about 65 °C with elevated temperatures. No high-temperature hexagonal hydrocarbon-chain packing organization were observed in PSC during heating process. Disorder of the hydrocarbon-chain packing of SC lipids was observed in PSC via FT-IR. In UPLC-TOFMS, free fatty acid (FFA) and ceramide (CER) compositions differed between patients with PSC and HSC. Specifically, the levels of ultra-long chain fatty acids containing CER and phytosphingosine-containing CER were decreased, while those of sphingosine and dihydrosphingosine-containing CER and unsaturated FFA were increased in PSC. Furthermore, FFA and CER carbon chain lengths decreased in patients with PSC. These results suggest that the alteration of SC lipid composition and the reduction of carbon chain lengths in PSC lowered the structural transformation temperature, thereby reducing barrier function.

Release profiles of dexamethasone dipropionate from admixtures of steroid and heparinoid ointments prepared by different mixing methods.

Characterization and release profiles of commercial dexamethasone dipropionate (DDP) from an innovator and 2 generic ointments (Methaderm (IM), Promethasone (GP), and Mainvate (GM)) and their admixtures with heparinoid ointment (Hirudoid Soft) were investigated. The admixtures were prepared using 2 mixing methods (slab or rotation/revolution mixer). Microscopic and FT-Raman spectrometric analyses revealed that the ointments, except for IM, contained DDP crystals. A silicone membrane was used for the evaluation of the DDP permeation. The permeated DDP amounts from GP and GM were lower than that from IM, indicating that DDP solubility in the ointment vehicle affected the release of DDP from the ointment. No significant differences were observed in DDP release between IM alone and its admixture prepared using a slab; however, DDP release from the admixture prepared using a rotation/revolution mixer was significantly lower than those from IM alone and its admixture by slab. In the GP system, DDP release from the admixtures by the 2 mixing methods was higher than that from GP alone, whereas no significant difference in DDP release between the 2 mixing methods was observed. No significant differences were observed between the GM and admixtures. The apparent solubility of DDP in the admixtures as determined by the ultracentrifugal separation method indicated that the DDP amount in the liquid phase of admixtures with GP was 6 times higher than that of admixtures with IM or GM. Therefore, the apparent solubility of DDP in the liquid phase in the GP system might influence the DDP release in admixtures.

Stratum Corneum Function: A Structural Study with Dynamic Synchrotron X-ray Diffraction Experiments.

Studies on the effectiveness of substances such as drugs and cosmetics that act on the skin require structural evidence at the molecular level in the stratum corneum to clarify their interaction with intercellular lipid and soft keratin. For this purpose, when applying the substances to the stratum corneum X-ray diffraction experiment is one of the powerful tools. To detect minute structural changes in a stratum corneum sample, using a "solution cell", dynamic synchrotron X-ray diffraction measurements were performed when applying aqueous solution of the substances to the stratum corneum: (1) It was found that a surfactant, sodium dodecyl sulfate, significantly disrupted the long-period lamellar structure. (2) To study the effects of water, structural modifications of the short-period lamellar structure and the soft keratin in corneocytes were measured as a function of time. At the initial water content of 15 wt%, the spacings of the short-period lamellar structure and the soft keratin increased toward those at the water content of 25 wt%, that is a key water content in the stratum corneum. (3) Nanoparticles composed of assembly of amphiphilic molecules are one of the leading pharmaceutical formulations. When the nanoparticles were applied, a new assembly of amphiphilic molecules originated from the nanoparticle appeared. This phenomenon suggests that the formation of the new assembly at the surface of skin is concerned with the release of the drug from the nanoparticles. (4) When ethanol was applied to the stratum corneum, only the liquid state in the intercellular lipid matrix was dissolved. After the removal of ethanol from this stratum corneum, the ordered hydrocarbon-chain packing structures appeared. From this fact we would propose that the liquid state region is the main pathway for hydrophobic drugs with a small molecular weight in connection with the so-called 500 Da rule. Here, not only the technique but also the background to these studies and the characteristic results obtained from these studies are explained.

Development of novel polyglycerol fatty acid ester-based nanoparticles for the dermal delivery of tocopherol acetate.

The aim of this study was to develop and evaluate novel polyglycerol fatty acid ester (PGFE)-based nanoparticles (NPs) for the dermal delivery of tocopherol acetate (TA). TA-loaded PGFE-based NPs (PGFE-NPs) were prepared by mixing PGFE, soya phosphatidylcholine, dimyristoylphosphatidylglycerol, and TA with film using the film rehydration and extrusion method. The prepared formulations were analyzed by dynamic light scattering, small-angle X-ray diffraction and polarization microscopy. An in vitro skin accumulation test was performed with TA under occlusive and non-occlusive applications, using Yucatan micropig skin. The size range of the TA-loaded liposome and PGFE-NPs was 107-128 nm, and they were encapsulated in 1.6-2.3 mg/mL TA. All PGFE-NP formulations were negatively charged and stable for 2 weeks. Under occlusive applications, all formulations induced small amounts of TA accumulation in the epidermis but not in the dermis. However, under non-occlusive applications, some of PGFE-NP formulations enhanced TA accumulation in the epidermis. Furthermore, only the polyglycerol 4-laurate (PG4L)-based formulation induced dermal TA accumulation with the change in the formulation from a vesicular to bilayer stacked structure following water evaporation under non-occlusive applications. These results indicated that the novel TA-loaded PG4L formulation enabled the dermal delivery of TA in non-occlusive applications.

Association of dry skin with intercellular lipid composition of stratum corneum after erlotinib administration.

PURPOSE: Erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, causes skin disorders such as dry skin, which impairs the skin barrier function. Stratum corneum (SC) lipids play an important role in skin barrier function; therefore, this study aimed to investigate the relationship between erlotinib-related dry skin and changes in the intercellular lipid composition and structure of the SC. METHODS: Overall, 21 patients with non-small lung cancer were enrolled in this study. All patients received 150 mg/day erlotinib orally. A SC sample of each patient was collected from the inner forearm using the tape stripping method on days 0, 7, 14, 28, and 56 after erlotinib administration. The intercellular lipid components of ceramide (CER), free fatty acid (FFA), and cholesterol sulfate (CS) in samples extracted from the tape were analyzed using liquid chromatography/time-of-flight/mass spectrometry. SC samples from six healthy subjects were collected as controls on days 0, 28 and 56 and analyzed similarly. RESULTS: Although total CER and FFA levels were not changed after erlotinib administration, the levels of CER subclasses [AP] and [AH] and hydroxy FFA, which are structural components of CER subclass [A], decreased. In contrast, the CS levels increased after erlotinib administration. Moreover, higher CS levels in the SC correlated with the clinical condition of dry skin. No changes were observed in the SC lipid composition in healthy subjects. CONCLUSION: Erlotinib-related dry skin was associated with a higher CS level in the SC.