Palladium-Catalyzed Asymmetric Decarboxylative Addition of ß-Keto Acids to Heteroatom-Substituted Allenes.

The Pd-catalyzed asymmetric addition reaction of ß-keto acids to heteroatom-substituted allene is reported. This reaction generates ß-substituted ketones in an asymmetric manner through a branch-selective decarboxylative allylation pathway. The reaction accommodates various alkoxyallenes as well as amidoallenes.

Extracellular Vesicles: The Next Frontier in Regenerative Medicine and Drug Delivery.

Extracellular vesicles (EVs) are nanosized membrane particles secreted by cells to convey intercellular information. In recent years, EVs have enticed scientists owing to their prevalent distribution, enormous possibility as therapeutic aspirants, and probable roles as disease biomarkers. As natural transporters in the endogenous communication system, they play a role in protein, lipid, miRNA, mRNA, and DNA transport. In this chapter, we recapitulate the roles of EVs in the vast field of regenerative medicine. This summary mainly describes the potential roles of EVs in the regeneration of extensively studied organs or tissues, such as the heart, kidney, lung, liver, skin, and hair. Furthermore, EV can also transport drugs and corroborate their uptake by target cells through endocytosis; therefore, this chapter also highlights the use of EVs in the field of drug delivery.

Enhanced Solubility, In-Vitro Dissolution and Lipase Inhibition of a Self-Nanoemulsifying Drug Delivery System Containing Orlistat.

The aim of this work was to prepare and assess a self-nanoemulsifying drug delivery system (SNEDDS) containing water-insoluble orlistat that was used for the inhibition of lipase activity in gastrointestinal lumen. The pseudo-ternary phase diagram, composed of orlistat and medium chain triglycerides (MCT) as oil phase and Cremophor EL as surfactant, was made for the confirmation of giving SNEDDS preconcentrate. The physical state, particle size dispersed in water, dissolution and lipase inhibition of SNEDDS preconcentrates were investigated. The appointed SNEDDS preconcentrates in the pseudo-ternary phase diagram showed no endothermic peak of orlistat and a liquid state. The particle sizes of SNEDDS dispersed with water were uniform and in the range of <200 nm. In the dissolution test, the liquid SNEDDS preconcentrate and solid state mixture exhibited 90.89±2.03% versus 22.42±3.71% at 60 min., respectively, whereas the raw orlistat showed no significant dissolution rate. The SNEDDS preconcentrate showed a lipase inhibition of 92.42±1.58% until 60 min., with no significant inhibition activity of orlistat. Therefore, the SNEDDS preconcentrate presented in this work solubilized orlistat and increased its dissolution rate, and resulted in sufficient inhibitory action on lipase.

Preparation, Characterization, and In Vitro Release of Chitosan-Ecabet Electrolyte Complex for the Mucosal Delivery.

Ecabet has a mucosal protection and anti-Helicobacter pylori effect only by local action in the gastric mucous layer, due to an extremely poor absorption into the systemic blood circulation. The aim of the present work was to develop chitosan-ecabet electrolyte complex (ChE) for the enhanced mucosal drug delivery. ChEs were prepared with various ecabet-chitosan concentration ratios. Entrapment efficiency (%), sedimentation volume (%), transmission electron microscopy (TEM), FT-IR spectrum, and drug release were investigated. ChEs were prepared by the simple mixing method in a pH-adjusted solution based on the electrostatic interaction between the sulfonate (negatively charged) group from ecabet and the amine (positively charged) group from chitosan. Sedimentation volume and entrapment efficiency at the same concentration of ecabet sodium with that of chitosan resulted in 53.6% and 86.75%, respectively, suggesting a high degree of forming complex. In TEM images, the complex was approximately 200 nm in particle size and had loosely entangled particles. Forming complex of ChEs was supported by new bands appearance in the FT-IR spectrum. In the drug release study using dialysis membrane sac, ChEs showed a sustainable release up to 80% during 12 h as compared to ecabet sodium suspension at pH 1.2 medium. Based on the results of this work, ChE would be a promising drug delivery system for gastric mucosa.

Preparation and Characterization of Celecoxib Nanosuspension Using Bead Milling.

The aim of this study is to develop nanosuspension for improved dissolution of poorly water-soluble celecoxib. We first prepared coarse suspension of celecoxib with Tween 80 and hydroxypropyl methylcellulose as stabilizers, and then fabricated nanosuspension using the bead milling technique. Depending on milling time, the physical properties of nanosuspension were evaluated by photon correlation spectroscopy (e.g., particle size and distribution) and scanning electron microscopy (SEM) (e.g., morphology). As results, the mean size of crystalline celecoxib particles was highly reduced (368.1±14.5 nm) as milling process proceeded comparing to celecoxib powder (6.5±1.0 µm). Morphology of milled celecoxib particles has changed considerably from bar-shape or plate-shape to needle-shape due to a high energy caused by milling. In the dissolution test, the celecoxib nanosuspension showed an improved dissolution profile at pH 1.2 compared to celecoxib powder (less than 1%). In contrast, 53.4% of celecoxib in nanosuspension was dissolved up to 30 minutes, demonstrating improved dissolution of celecoxib. Taken together, bead-milled nanosuspension could be an effective strategy that can improve the dissolution and bioavailability.

Preparation of Silica Microparticles as Volatile Material Carrier and Their Sustained-Release Property.

The aim of this study is to develop an effective delivery system (silica microparticles) encapsulating volatile essential oil (EO) by multiple emulsification process and sol-gel method. Depending on critical materials (Pluronic P123 and HPC) and process parameter (drying temperature), silica microparticles were prepared and evaluated. As results, the amount of EO inside microparticles increased in polymer-dependent manners. On the other hand, the amount of EO was reduced as drying temperature increased. Based on these data, the condition fabricating silica microparticles was optimized: drying temperature (25 °C), Pluronic P123 (1.2%) and HPC (1.2%). The size and morphology of microparticles were observed by scanning electron microscopy. Also, the loadings and release profiles of EO in these particles were quantitatively analyzed by HPLC. Optimized silica microparticles showed the high encapsulation efficiency (32.7%) and sustained-release profiles of EO for 3 days. Taken together, silica microparticles are effective carrier for encapsulating volatile materials and providing sustained-release.

Comparative Assessment of Biological Activities of Mistletoes for Cosmetic Applications: Viscum Album Var. Coloratum (Kom.) Ohwi and Loranthus Tanakae Franch. & Sav.

Mistletoes, hemiparasites, contain many components with various biological activities and have been used in cosmetics industry. Loranthacease (1,000 species) and Viscaceae (550 species) have the most dominant species in mistletoes (nearly 1,600 species). It can be expected that the biological activities vary from species to species; therefore, we have tested Viscum album var. coloratum (Kom.) Ohwi (belonging to Santalaceae) and Loranthus tanakae Franch. & Sav. (belonging to Loranthacease) for a comparative study of their cosmetic properties, including antioxidant, antimelanogenic, and antiwrinkle activities. As results, the ethanol extract of L. tanakae had higher phenolic content and showed effective antioxidant activity and elastase inhibition. Meanwhile, the ethanol extract of V. album more effectively inhibited tyrosinase. Comparing with ethanol extracts, the water extracts of both mistletoes showed lower biological efficacy than the ethanol extracts or no significant effect. Thus, these results show that different extracts of mistletoe have different levels of biological activities, presumably because of the differences in their phytochemical profiles and because of the different extraction methods used.

Removing Control of Cyclodextrin-Drug Complexes Using High Affinity Molecule.

Nanostructured supramolecular assemblies with hydrophobic cavities are used for improving the solubility, bioavailability, and stability of poorly water soluble drugs. In particular, host-guest inclusion using 2-hydroxypropyl-beta-cyclodextrin (HP-ß-CD) is a typical approach in the pharmaceutical field. In this study, celecoxib (CXB), a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug (NSAID), was used as the model drug (guest material) and effectively incorporated into HP-ß-CD (host material). After forming a complete complex of HP-ß-CD and CXB, 1-adamantylamine (ADA) was used to allow CXB to be released from the HP-ß-CD in a concentration-dependent manner. This was revealed from Fourier-transform infrared spectroscopy and drug dissolution studies. Notably, the use of ADA, which is a high-affinity guest molecule, with cyclodextrin accelerated the removal of CXB from the host material through the exchange of guest molecules. Taken together, the host-guest based approach using a second guest molecule is useful for regulating on-demand drug release and could therefore be a potential tool for biomedical applications.

Improved Dissolution and Oral Bioavailability of Celecoxib by a Dry Elixir System.

The purpose of this study was to develop and evaluate a dry elixir (DE) system for enhancing the dissolution rate and oral bioavailability of celecoxib. DE system has been used for improving solubility, oral bioavailability of poorly water-soluble drugs. The encapsulated drugs or solubilized drugs in the matrix are rapidly dissolved due to the co-solvent effect, resting in both an enhanced dissolution and bioavailability. DEs containing celecoxib were prepared by spray-drying method and characterized by morphology, drug/ethanol content, drug crystallinity, dissolution rate and oral bioavailability. The ethanol content and drug content in DE system could be easily altered by controlling the spraydrying conditions. The dissolution profile of celecoxib from DE proved to be much higher than that of celecoxib powder due to the nano-structured matrix, amorphous state and encapsulated ethanol. The bioavailability of celecoxib from DEs was compared with celecoxib powder alone and commercial product (Celebrex®) in rats. In particular, blood concentrations of celecoxib form DE formulation were much greater than those of native celecoxib and market product. The data demonstrate that the DE system could provide an useful solid dosage form to enhance the solubility, dissolution rate and oral bioavailability of celecoxib.

Intravenous Delivery of Xenon Incorporated in Thermosensitive Nano-Emulsions for Anesthesia.

Xenon anesthesia has several advantages over conventional anesthetics, however, it has not been widely used in clinical sites, since the cost and minimum alveolar concentration were higher than conventional inhalational anesthetics. The purpose of this study was to develop an optimum vehicle for stable intravenous delivery of xenon with sufficient concentration. Thermosensitive lipid based nano-emulsions (TS-LE) were prepared by blending medium chain triglyceride, polyethylene glycol-15-hydroxystearate, D-α tocopherol polyethylene glycol succinate and Poloxamer 188. Three folds higher xenon was loaded in TS-LE when it was prepared under 5.5 atm of xenon pressure compared to that under 1 atm of xenon pressure at 22 °C (11.4±0.7 vs. 3.82±0.34 mg/ml). Poloxamer 188 conferred thermosensitive viscosity and outer rigid structure on TS-LE, and the properties led to the enhanced stability of xenon compared to usual lipid emulsion. Induction of anesthesia was investigated by monitoring loss of forepaw righting reflex (LORR) in rats. The ED50 for LORR was 131.9 mg/kg and the anesthesia was maintained for 65.3±7.1 sec at a dose of 179 mg/kg in rats. When it is considered that TS-LE stably loads enough concentration of xenon for the induction of therapeutically sufficient anesthesia, TS-LE may be regarded as a promising candidate for intravenous xenon delivery.

Optimization of thermoreversible poloxamer gel system using QbD principle.

The objective of this study was to optimize thermoreversible gel formulations with respect to their gelation temperature and solubilizing capacity, using quality by design (QbD) principles based on design of experiment (DoE). Independent variables, X1, X2 and X3, represent the weight percentages of poloxamer 407 (P407), poloxamer 188 (P188) and the polyethylene glycol 400, respectively (these polymers are either thermoreversible gelling agents or solubilizers). Emodin, a poorly water-soluble compound, was used as a model drug. Fifteen gel formulations were prepared based on the compositions generated by an extreme vertices type of mixture design using a DoE software, in which their gelation temperatures (Y1) and emodin solubility (Y2) were measured. The gelation temperature and emodin solubility were each described adequately using a full cubic model and a quadratic model, respectively. Theoretical and experimental responses showed linearity with R2=0.9943 for the gelation temperature and R2=0.9629 for emodin solubility. The design space was established from the models describing the gelation temperature (test accuracy: 104.5%) and emodin solubility (test accuracy: 96.6%). This study demonstrates successful application of DoE for prediction of gelation temperature and solubility of emodin thermoreversible poloxamer gel (PG). In conclusion, the present DoE approach has led to the establishment of a design space and manufacturing control strategy for gel formulations.

Inferring new drug indications using the complementarity between clinical disease signatures and drug effects.

BACKGROUND: Drug repositioning is the process of finding new indications for existing drugs. Its importance has been dramatically increasing recently due to the enormous increase in new drug discovery cost. However, most of the previous molecular-centered drug repositioning work is not able to reflect the end-point physiological activities of drugs because of the inherent complexity of human physiological systems. METHODS: Here, we suggest a novel computational framework to make inferences for alternative indications of marketed drugs by using electronic clinical information which reflects the end-point physiological results of drug's effects on the biological activities of humans. In this work, we use the concept of complementarity between clinical disease signatures and clinical drug effects. With this framework, we establish disease-related clinical variable vectors (clinical disease signature vectors) and drug-related clinical variable vectors (clinical drug effect vectors) by applying two methodologies (i.e., statistical analysis and literature mining). Finally, we assign a repositioning possibility score to each disease-drug pair by the calculation of complementarity (anti-correlation) and association between clinical states ("up" or "down") of disease signatures and clinical effects ("up", "down" or "association") of drugs. A total of 717 clinical variables in the electronic clinical dataset (NHANES), are considered in this study. RESULTS: The statistical significance of our prediction results is supported through two benchmark datasets (Comparative Toxicogenomics Database and Clinical Trials). We discovered not only lots of known relationships between diseases and drugs, but also many hidden disease-drug relationships. For example, glutathione and edetic-acid may be investigated as candidate drugs for asthma treatment. We examined prediction results by using statistical experiments (enrichment verification, hyper-geometric and permutation test P<0.009 in Comparative Toxicogenomics Database and Clinical Trials) and presented evidences for those with already published literature. CONCLUSION: The results show that electronic clinical information is a feasible data resource and utilizing the complementarity (anti-correlated relationships) between clinical signatures of disease and clinical effects of drugs is a potentially predictive concept in drug repositioning research. It makes the proposed approach useful to identity novel relationships between diseases and drugs that have a high probability of being biologically valid.

Context-based resolution of semantic conflicts in biological pathways.

BACKGROUND: Interactions between biological entities such as genes, proteins and metabolites, so called pathways, are key features to understand molecular mechanisms of life. As pathway information is being accumulated rapidly through various knowledge resources, there are growing interests in maintaining the integrity of the heterogeneous databases. METHODS: Here, we defined conflict as a status where two contradictory pieces of evidence (i.e. 'A increases B' and 'A decreases B') coexist in a same pathway. This conflict damages unity so that inference of simulation on the integrated pathway network might be unreliable. We defined rule and rule group. A rule consists of interaction of two entities, meta-relation (increase or decrease), and contexts terms about tissue specificity or environmental conditions. The rules, which have the same interaction, are grouped into a rule group. If the rules don't have a unanimous meta-relation, the rule group and the rules are judged as being conflicting. RESULTS: This analysis revealed that almost 20% of known interactions suffer from conflicting information and conflicting information occurred much more frequently in the literature than the public database. CONCLUSIONS: By identifying and resolving the conflicts, we expect that pathway databases can be cleaned and used for better secondary analyses such as gene/protein annotation, network dynamics and qualitative/quantitative simulation.

Formal Synthesis of (+)-Sinefungin by Way of Sequential Asymmetric Metal Catalysis.

Here, we report a de novo approach toward (+)-sinefungin, a potent inhibitor of the physiological methyl transfer process. A key feature is represented by the sequential metal catalysis combining Pd-catalyzed hydroalkoxylation and ring-rearrangement metathesis. The unique advantage of the method is highlighted by the unprecedented complete control of the C6 stereocenter.

Formulation and optimization of spray-dried amlodipine solid dispersion for enhanced oral absorption.

OBJECTIVE: To enhance the oral absorption of photosensitive amlodipine free base, which exhibits a slow dissolution rate and low permeability characteristics, an amorphous solid dispersion system was formulated and characterized. MATERIAL AND METHODS: The solid dispersion was prepared by dispersing the amlodipine free base in excess dextrin (1:10 by weight) using a spray-drying technique in the presence of a minimum amount (0.9% w/w) of SLS as an absorption enhancer. The dextrin-based solid dispersion of amlodipine (Amlo-SD) was evaluated in term of formulation, characterization and in vivo absorption study, as well as the spray-drying process was also optimized. RESULTS AND DISCUSSION: The Amlo-SD particles were spherical with a smooth surface and an average particle size of 12.9 µm. Amlodipine was dispersed in an amorphous state and its content remained uniform in the Amlo-SD. The physicochemical stability of the Amlo-SD was maintained at room temperature for 6 months and the photostability was considerably improved. The dissolution of the Amlo-SD was much faster than that of amlodipine at pH 1.2 and 6.8. Amlo-SD produced significantly higher plasma concentrations of amlodipine in rats than amlodipine alone. Amlo-SD with and without SLS provided 2.8- and 2.0-fold increase in AUC, respectively: the difference seems to be attributed to a permeability enhancement effect by SLS. CONCLUSION: The Amlo-SD with SLS system is a potential formulation option for amlodipine.

Paliperidone-Cation Exchange Resin Complexes of Different Particle Sizes for Controlled Release.

This study aimed to develop electrolyte complexes of paliperidone (PPD) with various particle sizes using cation-exchange resins (CERs) to enable controlled release (both immediate and sustained release). CERs of specific particle size ranges were obtained by sieving commercial products. PPD-CER complexes (PCCs) were prepared in an acidic solution of pH 1.2 and demonstrated a high binding efficiency (>99.0%). PCCs were prepared with CERs of various particle sizes (on average, 100, 150, and 400 µm) at the weight ratio of PPD to CER (1:2 and 1:4). Physicochemical characterization studies such as Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy between PCCs (1:4) and physical mixtures confirmed PCC formation. In the drug release test, PPD alone experienced a complete drug release from PCC of >85% within 60 min and 120 min in pH 1.2 and pH 6.8 buffer solutions, respectively. Alternatively, PCC (1:4) prepared with CER (150 µm) formed spherical particles and showed an almost negligible release of PPD in pH 1.2 buffer (<10%, 2 h) while controlling the release in pH 6.8 buffer (>75%, 24 h). The release rate of PPD from PCCs was reduced with the increase in CER particle size and CER ratio. The PCCs explored in this study could be a promising technology for controlling the release of PPD in a variety of methods.

The Development of Super-Saturated Rebamipide Eye Drops for Enhanced Solubility, Stability, Patient Compliance, and Bioavailability.

The present study aimed to develop clear aqueous rebamipide (REB) eye drops to enhance solubility, stability, patient compliance, and bioavailability. For the preparation of a super-saturated 1.5% REB solution, the pH-modification method using NaOH and a hydrophilic polymer was employed. Low-viscosity hydroxypropyl methylcellulose (HPMC 4.5cp) was selected and worked efficiently to suppress REB precipitation at 40 °C for 16 days. The additionally optimized eye drops formulation (F18 and F19) using aminocaproic acid and D-sorbitol as a buffering agent and an osmotic agent, respectively, demonstrated long-term physicochemical stability at 25 °C and 40 °C for 6 months. The hypotonicity (<230 mOsm) for F18 and F19 noticeably extended the stable period, since the pressure causing the REB precipitation was relieved compared to the isotonic. In the rat study, the optimized REB eye drops showed significantly long-lasting pharmacokinetic results, suggesting the possibility of reducing daily administration times and increasing patient compliance (0.50- and 0.83-times lower Cmax and 2.60- and 3.64-times higher exposure in the cornea and aqueous humor). In conclusion, the formulations suggested in the present study are promising candidates and offer enhanced solubility, stability, patient compliance, and bioavailability.

Development and Evaluation of Self-Microemulsifying Drug Delivery System for Improving Oral Absorption of Poorly Water-Soluble Olaparib.

The purpose of this study is to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) to improve the oral absorption of poorly water-soluble olaparib. Through the solubility test of olaparib in various oils, surfactants and co-surfactants, pharmaceutical excipients were selected. Self-emulsifying regions were identified by mixing the selected materials at various ratios, and a pseudoternary phase diagram was constructed by synthesizing these results. The various physicochemical properties of microemulsion incorporating olaparib were confirmed by investigating the morphology, particle size, zeta potential, drug content and stability. In addition, the improved dissolution and absorption of olaparib were also confirmed through a dissolution test and a pharmacokinetic study. An optimal microemulsion was generated in the formulation of Capmul® MCM 10%, Labrasol® 80% and PEG 400 10%. The fabricated microemulsions were well-dispersed in aqueous solutions, and it was also confirmed that they were maintained well without any problems of physical or chemical stability. The dissolution profiles of olaparib were significantly improved compared to the value of powder. Associated with the high dissolutions of olaparib, the pharmacokinetic parameters were also greatly improved. Taken together with the results mentioned above, the microemulsion could be an effective tool as a formulation for olaparib and other similar drugs.

Polyhydroxyalkanoate Decelerates the Release of Paclitaxel from Poly(lactic-co-glycolic acid) Nanoparticles.

Biodegradable nanoparticles (NPs) are preferred as drug carriers because of their effectiveness in encapsulating drugs, ability to control drug release, and low cytotoxicity. Although poly(lactide co-glycolide) (PLGA)-based NPs have been used for controlled release strategies, they have some disadvantages. This study describes an approach using biodegradable polyhydroxyalkanoate (PHA) to overcome these challenges. By varying the amount of PHA, NPs were successfully fabricated by a solvent evaporation method. The size range of the NPS ranged from 137.60 to 186.93 nm, and showed zero-order release kinetics of paclitaxel (PTX) for 7 h, and more sustained release profiles compared with NPs composed of PLGA alone. Increasing the amount of PHA improved the PTX loading efficiency of NPs. Overall, these findings suggest that PHA can be used for designing polymeric nanocarriers, which offer a potential strategy for the development of improved drug delivery systems for sustained and controlled release.

Preparation and Characterization of Pazopanib Hydrochloride-Loaded Four-Component Self-Nanoemulsifying Drug Delivery Systems Preconcentrate for Enhanced Solubility and Dissolution.

The aim of this study was to develop a four-component self-nanoemulsifying drug delivery system (FCS) to enhance the solubility and dissolution of pazopanib hydrochloride (PZH). In the solubility test, PZH showed a highly pH-dependent solubility (pH 1.2 > water >> pH 4.0 and pH 6.8) and was solubilized at 70 °C in the order Kollisolv PG (5.38%, w/w) > Kolliphor RH40 (0.49%) > Capmul MCM C10 (0.21%) and Capmul MCM C8 (0.19%), selected as the solubilizer, the surfactant, and the oils, respectively. In the characterization of the three-component SNEDDS (TCS) containing Kolliphor RH40/Capmul MCM C10, the particle size of dispersion was very small (<50 nm) and the PZH loading was 0.5% at the weight ratio of 9/1. In the characterization of FCS containing additional Kollisolv PG to TCS, PZH loading was increased to 5.30% without any PZH precipitation, which was 10-fold higher compared to the TCS. The optimized FCS prepared with the selected formulation (Kolliphor RH40/Capmul MCM C10/Kollisolv PG) showed a consistently complete and high dissolution rate (>95% at 120 min) at four different pHs with 1% polysorbate 80, whereas the raw PZH and Kollisolv PG solution showed a pH-dependent poor dissolution rate (about 40% at 120 min), specifically at pH 6.8 with 1% polysorbate 80. In conclusion, PZH-loaded FCS in this work demonstrated enhanced solubility and a consistent dissolution rate regardless of medium pH.