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As direct-acting oral anticoagulants (DOACs) have short half-lives of around 12 h, even a short gap in DOAC therapy may diminish anticoagulation effects, increasing risks of adverse clinical outcomes. We aimed to evaluate clinical consequences of a gap in DOAC therapy with atrial fibrillation (AF) and to identify its potential predictors. In this retrospective cohort study, we included DOAC users aged over 65 years with AF from the 2018 Korean nationwide claims database. We defined a gap in DOAC therapy as no claim for a DOAC one or more days after the due date of a refill prescription. We used a time-varying-analysis method. The primary outcome was a composite of death and thrombotic events including ischemic stroke/transient ischemic attack or systemic embolism. Potential predictors of a gap included sociodemographic and clinical factors. Among 11,042 DOAC users, 4857 (44.0 %) patients had at least one gap. Standard national health insurance, non-metropolitan locations of medical institutions, history of liver disease, chronic obstructive pulmonary disease, cancer, or dementia, and use of diuretics or non-oral agents were associated with increased risks of a gap. In contrast, history of hypertension, ischemic heart disease, or dyslipidemia were associated with a decreased risk of a gap. A short gap in DOAC therapy was significantly associated with a higher risk of the primary outcome compared to no gap (hazard ratio 4.04, 95 % confidence interval 2.95–5.52). The predictors could be utilized to identify at-risk patients to provide additional support to prevent a gap. [Display omitted] • Approximately half of elderly DOAC users had at least one gap in DOAC therapy. • This gap was significantly associated with a higher risk of death or thrombosis. • The predictors could be utilized to provide additional support to prevent a gap. [ABSTRACT FROM AUTHOR]

Quetiapine myristate (QM), an ester‐bonded lipophilic prodrug of quetiapine (QTP), is synthesized and converted into an amphiphilic structure in acidic pH to trigger a novel self‐assembled QM nanosuspension (QMN). Following injection, this QMN rearranges within physiological pH to form nanoaggregates in structure, resulting in enhanced physicochemical properties and in vivo therapeutic performance without an initial burst release. The 200‐nm‐sized QMN exhibits less invasive injection, higher drug content, and better storage stability profile than conventional poly(lactide‐co‐glycolide) (PLGA) nanosuspensions containing QTP or QM. Following a single intramuscular injection to beagle dogs (35 mg kg−1 QTP), QMN undergoes pH‐responsive nanoaggregation to form the lipophilic prodrug, providing esterase‐oriented sustained release for five weeks compared with the two‐week period of PLGA nanosuspensions. Notably, QMN exhibits improved in vivo pharmacokinetic performance with long‐acting delivery while minimizing issues associated with polymeric PLGA formulations, including the initial massive burst release, cellular toxicity, and adverse side effects. These results support the further development of QMN as a novel long‐acting injectable to improve patient compliance and dosing frequency. [ABSTRACT FROM AUTHOR]

[Display omitted] Industrial-scale pharmaceutical applications still face many challenges in overcoming the low absorption and bioavailability of poorly water-soluble drugs. Hot-melt extrusion has emerged as a promising approach with continuous processing on an industrial scale for the preparation of drug delivery systems. Many reviews have mentioned the potential applications, processes, principles and advantages and disadvantages of hot-melt extrusion in the pharmaceutical industry. However, a focus on the recent progress of hot-melt extrusion, which investigates the impacts of processes and formulations of solid dispersions of poorly water-soluble drugs, is missing. In this review, various factors, including polymers, drug properties, additives and surfactants, in solid dispersion SD formulations by hot-melt extrusion will be discussed. Moreover, the effects of the hot-melt extrusion process on the physicochemical properties of solid dispersions will be mentioned. The utilization of molecular interactions in hot-melt extrusion to improve drug stability will also be described. Overall, this summary of recent studies on solid dispersion by hot-melt extrusion will provide perspectives and effectiveness for the development of formulations containing poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to improve the bioavailability of biochanin A, a poorly soluble bioflavonoid, via the preparation of solid dispersion (SD) using Solutol® HS15 and HPMC 2910. Solubility of biochanin A was enhanced by 8–60 folds as the drug-carrier ratio was increased in SDs. Furthermore, compared to pure biochanin A or physical mixture (PM), SDs significantly improved the dissolution rate and the extent of drug release. Particularly, SDs (Drug:Solutol® HS15:HPMC 2910=1:5:5 or 1:10:10) achieved the rapid and complete drug release (approximately 100% within 1h) at pH 6.8. The XRD patterns indicated that SDs might enhance the solubility of biochanin A by changing the drug crystallinity to amorphous state in addition to the solubilizing effect of hydrophilic carriers. The improved dissolution of biochanin A via SD formulation appeared to be well correlated with the enhanced oral exposure of biochanin A in rats. After an oral administration of SD (Drug:Solutol® HS15:HPMC 2910=1:10:10), C max and AUC of biochanin A were increased by approximately 13 and 5 folds, respectively, implying that SDs could be effective to improve the bioavailability of biochanin A. In conclusion, solid dispersion with Solutol® HS15 and HPMC 2910 appeared to be promising to improve the dissolution and oral exposure of biochanin A. [Copyright &y& Elsevier]

Abstract: This study investigated the effect of macelignan on the P-glycoprotein-mediated drug efflux as well as CYP3A4-mediated drug metabolism and subsequently its in vivo implication on the bioavailability of paclitaxel. The inhibition effect of macelignan on the CYP3A4-mediated metabolism was negligible over the concentration range of 0.01–100μM in rat liver microsome while approximately 33% inhibition was observed at 100μM in human liver microsome, implying that the interaction of macelignan with CYP3A4 might be insignificant at the physiologically achievable concentrations. In contrast, macelignan (20μM) increased the cellular accumulation of paclitaxel by approximately 1.7-fold in NCI/ADR-RES cells overexpressing P-gp, while it did not alter the cellular accumulation of paclitaxel in OVCAR-8 cells lacking P-gp. The effect of macelignan on the systemic exposure of paclitaxel was also examined in rats after the intravenous and oral administration of paclitaxel in the presence and the absence of macelignan. The concurrent use of macelignan significantly (p <0.05) enhanced the oral exposure of paclitaxel in rats while it did not affect the intravenous pharmacokinetics of paclitaxel, implying that macelignan might be more effective to improve the intestinal absorption rather than reducing hepatic elimination. In conclusion, macelignan appeared to be effective to improve the cellular accumulation as well as oral exposure of paclitaxel mainly via the inhibition of P-gp-mediated cellular efflux, suggesting that the concomitant use of macelignan may provide a therapeutic benefit in improving the anticancer efficacy of paclitaxel. [ABSTRACT FROM AUTHOR]

Abstract: The main objective of this study was to prepare a solid form of lipid-based self-emulsifying drug delivery system (SEDDS) by spray drying liquid SEDDS with an inert solid carrier Aerosil 200 to improve the oral bioavailability of poorly water-soluble drug dexibuprofen. The liquid SEDDS was a system that consisted of dexibuprofen, Labrasol, Capryol 90 and Labrafil M 1944 CS. The particle size analysis revealed no difference in the z-average particle diameter of the reconstituted emulsion between liquid and solid SEDDS. The solid SEDDS was characterized by SEM, DSC and XRD studies. In vivo results of solid SEDDS and dexibuprofen powder in rats at the dose of 10mg/kg showed that the initial plasma concentrations of drug in solid SEDDS were significantly higher than those of dexibuprofen powder (P <0.05). The solid SEDDS gave significantly higher AUC and Cmax than did dexibuprofen powder (P <0.05). In particular, the AUC of solid SEDDS was about twofold higher than that of dexibuprofen powder. Our results suggested that this solid SEDDS could be used as an effective oral solid dosage form to improve the bioavailability of poorly water-soluble drug dexibuprofen. [Copyright &y& Elsevier]

Abstract: This study aimed to examine the transporter-mediated drug interaction between fexofenadine and fluvastatin in rats. Compared to the control group given fluvastatin alone, the concurrent use of fexofenadine (10 or 20mg/kg) prior to the oral administration of fluvastatin (5mg/kg) decreased the systemic exposure of fluvastatin by 17–51% in rats. Consequently, the bioavailability of oral fluvastatin was significantly lower (p <0.05) in the presence of fexofenadine compared to that from the control group. Furthermore, the intravenous pharmacokinetics of fluvastatin (2mg/kg) was significantly altered by the pretreatment with fexofenadine (20mg/kg, p.o.). The plasma clearance of fluvastatin was reduced by 44% in the presence of fexofenadine. The effect of fluvastatin on the pharmacokinetics of fexofenadine was also investigated in rats. The pretreatment with fluvastatin (5 or 10mg/kg) decreased AUC and C max of oral fexofenadine (10mg/kg) by 47–53% and 28–60%, respectively, while it did not affect the intravenous pharmacokinetics of fexofenadine. Given that both fluvastatin and fexofenadine can interact with organic anion-transporting polypeptides (OATPs) expressed in intestine and liver, the present results suggest the potential drug interaction between fluvastatin and fexofenadine via the competition for the OATP-mediated cellular transport pathway during intestinal absorption and/or hepatic uptake of drugs. [Copyright &y& Elsevier]

Abstract: To enhance the solubility and bioavailability of poorly water-soluble Coenzyme Q10 (CoQ10), self-emulsifying drug delivery system (SEDDS) composed of oil, surfactant and cosurfactant for oral administration of CoQ10 was formulated. The solubility of CoQ10 was determined in various oils and surfactants. The formulations were prepared using two oils (Labrafil M 1944 and Labrafil M 2125), surfactant (Labrasol) and cosurfactant (Lauroglycol FCC and Capryol 90). In all the formulations, the level of CoQ10 was fixed at 6% (w/v) of the vehicle. These formulations were characterized by solubility of the drug in the vehicle, particle size of the dispersed emulsion, zeta potential and drug release profile. Ternary phase diagrams were used to evaluate the emulsification domain. The self-emulsification time following introduction into an aqueous medium under gentle agitation was evaluated. The optimized SEDDS formulation consist of 65% (v/v) Labrasol, 25% (v/v) Labrafil M 1944 CS and 10% (v/v) Capryol 90 of each excipient showed minimum mean droplet size (about 240nm) and optimal drug release profile in water. The pharmacokinetic study in rats for the optimized formulation was performed and compared to powder formulation. SEDDS have significantly increased the C max and area under the curve (AUC) of CoQ10 compared to powder (P <0.05). Thus, this self-micro emulsifying drug delivery system should be an effective oral dosage form for improving oral bioavailability of lipophilic drug, CoQ10. [Copyright &y& Elsevier]

The objectives of this study were to solubilize oxytetracycline hydrochloride (HCl) in reverse micelles to prepare poly-d,l-lactide-co-glycolide (PLGA) microspheres and to explore parameters affecting its encapsulation efficiency. Oxytetracycline HCl was dissolved in the reverse micelles consisting of cetyltrimethylammonium bromide, water, and ethyl formate. A PLGA polymer was then dissolved in the reverse micellar solution, and a modified solvent quenching procedure was carried out to prepare PLGA microspheres. Encapsulation efficiencies of oxytetracycline HCl ranged from 2.3 ± 0.2 to 24.9 ± 4.6%, depending on experimental conditions. Important parameters affecting its encapsulation efficiency included the amounts of water used to prepare the reverse micelles and PLGA polymer. With regard to microsphere morphology, the reverse micellar process produced the microspheres with smooth and pore-free surfaces. In particular, their internal matrices did not possess hollow cavities that were frequently observed when a typical double emulsion technique was used to make microspheres. In summary, it was possible to encapsulate oxytetracycline HCl into PLGA microspheres via the ethyl formate-based reverse micellar technique. We also anticipate that the use of ethyl formate could avoid environmental and human toxicity issues associated with methylene chloride. [ABSTRACT FROM AUTHOR]

[Display omitted] Fucoidan is well known to have various biological functions and is often investigated for pharmaceutical applications. Several studies have been conducted on clinical applications of fucoidan in recent years, especially regarding its oral drug delivery. Although fucoidan has shown promising results in various dosage forms, its potential applications as a dietary supplement have been demonstrated, and recent studies show that oral administration of fucoidan is preferred. However, the focus on the oral delivery of fucoidan in recent studies has caused its potency in therapy to be understudied. This review aims to provide results on the promising fucoidan activity by oral administration with in vivo studies. In addition to using it as an active ingredient, the utilization of fucoidan as an excipient in oral drug delivery systems will be discussed. An overview of fucoidan administration by oral delivery in recent promising studies will provide a direction for further investigations in clinical applications, particularly for fucoidan, which has a broad spectrum of bioactive properties. [ABSTRACT FROM AUTHOR]

[Display omitted] The freeze-drying process has been particularly attractive for preparing tablets for controlled drug release. Although traditional methods, such as granulation or direct compression methods, have been used in various studies to produce tablets with controlled release, freeze-drying processes have been utilized in certain circumstances due to their distinct advantages. However, overall, further development of these strategies, which started with early studies on orally disintegrating tablets, is still necessary. In this review, the incorporation of different formulations into freeze-dried tablets will be discussed. Moreover, the use of excipients, freeze-drying conditions, formulation reconstitution and tablet structure for optimizing the performance of freeze-dried tablets will be reported, including strategies with nanoformulations and natural materials. Generally, this discussion with potential approaches will benefit further development of freeze-dried tablets containing drugs in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, although commercial 20 mg TD-loaded tablets (TD-TAB, Cialis® tablet) may be taken with or without food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936–1.105 and 1.012–1.153, respectively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the Cmax T/R of 0.610–0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851–0.998 of TD-TAB and TDF. The predictive diffusion direction model for physical digestion of TD-TAB and TDF in the stomach after the first and second meal intake was successfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions. [ABSTRACT FROM AUTHOR]

This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) were developed. Additionally, a deformable variant of LON (d-LON) was originally developed by incorporating l-α-phosphatidylcholine into LON as an edge activator. The physicochemical properties of LON and d-LON, encompassing particle size, zeta potential, and deformability index (DI), were evaluated. MBFs containing LEU, LOC, and NPs (LON, d-LON) were prepared using the solvent casting method by varying the ratio of Eudragit RLPO and hydroxypropyl methylcellulose, with propylene glycol used as a plasticizer. The optimization of MBF formulations was based on their physicochemical properties, including in vitro residence time, dissolution, and permeability. The dissolution results demonstrated that the conjugation of oleic acid to LEU exhibited a more sustained LEU release pattern by cleaving the ester bond of the conjugate, as compared to the native LEU, with reduced variability. Moreover, the LOC and its self-assembled NPs (LON, d-LON), equivalent to 1 mg LEU doses in MBF, exhibited an amorphous state and demonstrated better permeability through the nanonization process than LEU alone, regardless of membrane types. The incorporation of lauroyl-L-carnitine into the films as a permeation enhancer synergistically augmented drug permeability. Most importantly, the d-LON-loaded buccal films showed the highest permeability, due to the deformability of NPs. Overall, MBF-containing peptide NPs and permeation enhancers have the potential to replace parenteral LEU administration by improving LEU druggability and patient compliance. [ABSTRACT FROM AUTHOR]

Although zein is a natural protein derived from corn, it has attracted much interest in pharmaceutical and biomedical sciences. Recent remarkable investigations on the use of zein in controlled drug delivery have contributed both important knowledge and potential applications of various products, particularly in the delivery of poorly water-soluble drugs. Zein has also been approved by the Food and Drug Administration for oral delivery. Substantial research has been performed to demonstrate the roles and promise of materials containing zein for pharmaceutical applications. Significant efforts have focused on the biodegradable and hydrophobic properties of zein and on technology using zein as a nanocarrier specifically for nanomedicine. However, important issues concerning the use of zein in technical advances and in the development of poorly water-soluble drugs must be addressed in order to use zein in translational research. This review aims to focus on the classification of potential approaches for using zein in the controlled release of poorly water-soluble drugs and to discuss recommended techniques for creating high-quality products from zein. [ABSTRACT FROM AUTHOR]

This study aimed to originally investigate the roles of a surfactant in hydrophilic-hydrophobic polymer blend solid dispersions (SDs) to enhance drug dissolution. Different formulations of SDs containing a hydrophilic polymer, a hydrophobic polymer or a hydrophilic-hydrophobic blend were prepared with/without surfactant, and the crystal changes, wettability, and molecular interactions were investigated. The wettability was investigated by analysing the contact angle. Powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) spectroscopy were used to study the physicochemical properties of the SDs. This study showed that the surfactant improved the wettability of hydrophilic-hydrophobic blend SDs. Moreover, the incorporation of the surfactant led to the minimization of drug crystals in SDs. In particular, the surfactant showed an effectiveness in drug crystalline changes with hydrophobic polymers compared to hydrophilic polymers. The maximization of reducing drug crystals was observed in an optimized blending ratio of hydrophilic-hydrophobic polymers. This result indicated that the surfactant played a key role in assisting a hydrophilic-hydrophobic polymer blend, which has been demonstrated as a dominant strategy for SDs, to enhance the dissolution rate of a poorly water-soluble drug. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the enhancement of cannabinoid acid solubility and stability through the formation of a cannabinoid acid/cyclodextrin (CD) inclusion complex. Two cannabinoid acids, tetrahydro-cannabinolic acid (THCA) and cannabidiolic acid (CBDA), were selected as a model drug along with five types of CD: α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), and methylated-β-cyclodextrin (M-β-CD). Phase solubility studies were conducted using various types of CD to determine the complex stoichiometry. The preparation methods of the CD inclusion complex were optimized by adjusting the loading pH solution and the drying processes (spray-drying, freeze-drying, spray-freeze-drying). The drying process of the cannabinoid acid/M-β-CD inclusion complex was further optimized through the spray-freeze-drying method. These CD complexes were characterized using solubility determination, differential scanning calorimetry (DSC), field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and 1H NMR spectroscopy. DSC, XRD, and FE-SEM studies confirmed the non-crystalline state of the cannabinoid acid/CD inclusion complex. The permeation of THCA or CBDA from the M-β-CD spray-freeze-dried inclusion complex was highly improved compared to those of cannabis ethanolic extracts under simulated physiological conditions. The stability of the cannabinoid acid/M-β-CD inclusion complex was maintained for 7 days in a simulated physiological condition. Furthermore, the minimum inhibitory concentration of cannabinoid acid/M-β-CD inclusion complex had superior anti-cancer activity in MCF-7 breast cancer cell lines compared to cannabinoid acid alone. The improved physicochemical and biological performances indicated that these CD inclusion complexes could provide a promising option for loading lipophilic cannabinoids in cannabis-derived drug products. [ABSTRACT FROM AUTHOR]

Herein, we aimed to prepare porous granules of pravastatin and evaluate their applicability to orally disintegrating tablets (ODTs). Pravastatin solid dispersion granules (PSDGs-A) were prepared by dispersing pravastatin sodium in D-mannitol (the dispersion medium) in the presence of ammonium bicarbonate (the sublimation agent) using a spray-drying process. The PSDGs-A were round, irregularly shaped, mesoporous agglomerates with appropriate particle size, bulk density, and flowability for the tableting process. The mesopore formation in PSDGs-A resulted from the complete sublimation of ammonium bicarbonate during spray-drying and resulted in a notably high surface area. When the PSDGs-A were blended with ODT excipients and then directly compressed into ODTs (PSDGs-A-ODTs), they were readily incorporated into ODTs without tableting problems and had desirable ODT characteristics. They demonstrated rapid disintegration times because of the fast water uptake of mesoporous PSDGs-A caused by their high surface area. This rapid disintegration of PSDGs-A-ODTs was reflected also by their quick initial dissolution. The mesoporous PSDGs-A prepared with ammonium bicarbonate using the spray-drying process can be used to develop pravastatin ODTs. This spray-dried, mannitol-based solid dispersion of drugs using sublimation solids is a potential formulation technology for ODT product development. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effectiveness of organ-on-chip system investigating simultaneous cellular efficacy and real-time reactive oxygen species (ROS) occurrence of anticancer drug-loaded nanoparticles (NPs) using hepatocarcinoma cells (HepG2) chip system under static and hepatomimicking shear stress conditions (5 dyne/cm2). Then, the role of hepatomimetic shear stress exposed to HepG2 and drug solubility were compared. The highly soluble doxorubicin (DOX) and poorly soluble paclitaxel (PTX) were chosen. Fattigated NPs (AONs) were formed via self-assembly of amphiphilic albumin (HSA)-oleic acid conjugate (AOC). Then, drug-loaded AONs (DOX-AON or PTX-AON) were exposed to a serum-free HepG2 medium at 37 °C and 5% carbon dioxide for 24 h using a real-time ROS sensor chip-based microfluidic system. The cellular efficacy and simultaneous ROS occurrence of free drugs and drug-loaded AONs were compared. The cellular efficacy of drug-loaded AONs varied in a dose-dependent manner and were consistently correlated with real-time of ROS occurrence. Drug-loaded AONs increased the intracellular fluorescence intensity and decreased the cellular efficacy compared to free drugs under dynamic conditions. The half-maximal inhibitory concentration (IC50) values of free DOX (13.4 μg/mL) and PTX (54.44 μg/mL) under static conditions decreased to 11.79 and 38.43 μg/mL, respectively, under dynamic conditions. Furthermore, DOX- and PTX-AONs showed highly decreased IC50 values of 5.613 and 21.86 μg/mL, respectively, as compared to free drugs under dynamic conditions. It was evident that cellular efficacy and real-time ROS occurrence were well-correlated and highly dependent on the drug-loaded nanostructure, drug solubility and physiological shear stress. [ABSTRACT FROM AUTHOR]

The concept of click chemistry (CC), first introduced by K.B. Sharpless, has been widely adopted for use in drug discovery, novel drug delivery systems (DDS), polymer chemistry, and material sciences. In this review, we outline novel aspects of CC related to drug discovery and drug delivery, with a brief overview of molecular mechanisms underlying each click reaction commonly used by researchers, and the main patents that paved the way for further diverse medicinal applications. We also describe recent progress in drug discovery and polymeric and carbon material-based drug delivery for potential pharmaceutical applications and advancements based on the CC approach, and discuss some intrinsic limitations of this popular conjugation reaction. The use of CC is likely to significantly advance drug discovery and bioconjugation development. [ABSTRACT FROM AUTHOR]

Due to the instability of esomeprazole magnesium dihydrate (EPM), a proton pump inhibitor, in gastric fluid, enteric-coated dosage form is commonly used for therapeutic application. In this study, we prepared new gastric fluid resistant solid dispersions (SDs) containing alkalizers. Then, new mechanistic evidence regarding the effects of pharmaceutical alkalizers on the aqueous stability of EPM in simulated gastric fluid was investigated. The alkalizer-loaded SD were prepared by dissolving or dispersing EPM, hydroxypropyl methylcellulose (HPMC) 6 cps, and an alkalizer, in ethanol 50% (v/v) followed by spray drying. Nine different alkalizers were assessed for in vitro stability in two media, simulated gastric fluid (pH 1.2 buffer) and simulated intestinal fluid (pH 6.8 buffer). The microenvironmental pH (pH M ) was measured to evaluate the effect of the alkalizer on the pH M of SDs. Drug crystallinity and morphology of the SDs were also examined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The interactions among EPM, the polymer, and the alkalizer were elucidated by Fourier transform infrared (FTIR) spectroscopy. The in vivo absorption studies of the optimized alkalizer-containing SD and the enteric-coated reference tablet Nexium ® were then conducted in beagle dogs. Among alkalizers, MgO loaded in SDs proved to be the best alkalizer to stabilize EPM in simulated gastric fluid. pH M values of the alkalizer-containing SDs were significantly higher than that of the SD without alkalizer. The pH M values decreased in the following order: MgO, Na 2 CO 3 , Ca(OH) 2 , and no alkalizer. DSC and PXRD data exhibited a change in the drug crystallinity of the SDs from crystalline to amorphous form. SEM data showed a relatively spherical shape of the MgO-loaded SD compared to the less-defined shape of pure drug. FTIR indicated a strong molecular interaction among EPM, alkalizer and polymer; in particular, MgO showed the strongest interaction with EPM. It was evident that alkalizer interacts with benzimidazole ring and/or sulfonyl group of EPM for enhancing EPM stability in gastric fluid. Regarding the in vivo absorption studies in beagle dogs, the optimized SD (C16) was bioequivalent to the reference Nexium ® and had a considerable greater absorption at the early stages. The current alkalizer-containing SD could provide a promising approach for aqueous stabilization of acid-labile drugs without using enteric coating method. [ABSTRACT FROM AUTHOR]

The objectives of the present study were to develop a controlled-release bilayered tablet of aceclofenac (AFN) 200 mg with dual release and to gain a mechanistic understanding of the enhanced sustained release capability achieved by utilizing a binary mixture of the sustained release materials. Different formulations of the sustained-release layer were formulated by employing hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) as the major retarding polymers. The in vitro dissolution studies of AFN bilayered tablets were carried out in intestinal fluid (pH 6.8 buffer). The mechanism of the synergistic rate-retarding effect of the polymer mixture containing HPC and carbomer was elucidated by the rate of swelling and erosion in intestinal fluid and the molecular interactions in the polymer network. The optimized bilayered tablets had similar in vitro dissolution profiles to the marketed tablet Clanza ® CR based on the similarity factor (f2) in combination with their satisfactory micromeritic, physicochemical properties, and stability profiles. Drug release from HPMC-based matrix was controlled by non-Fickian transport, while drug release from HPC-based matrix was solely governed by drug diffusion. The swelling and erosion data exhibited a dramatic increase of water uptake and a reduction of weight loss in the polymer mixture-loaded tablet. Fourier transform infrared (FTIR) spectra revealed strong hydrogen bonding between HPC and carbomer in the polymer mixture. Regarding spatial distribution of polymers in the polymer mixture-loaded tablet, carbomer was found to be the main component of the gel layer during the first 2 h of the hydration process, which was responsible for retarding drug release at initial stage. This process was then followed by a gradual transition of HPC from the glassy core to the gel layer for further increasing gel strength. [ABSTRACT FROM AUTHOR]

Leuprolide is a synthetic nonapeptide drug (pyroGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt) that acts as a gonadotropin-releasing hormone agonist. The continuous administration of therapeutic doses of leuprolide inhibits gonadotropin secretion, which is used in androgen-deprivation therapy for the treatment of advanced prostate cancer, central precocious puberty, endometriosis, uterine fibroids, and other sex-hormone-related conditions. To improve the pharmacokinetic properties of peptide drugs, a fatty acid was conjugated with leuprolide for long-term action. In this study, we developed a simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of leuprolide and leuprolide–oleic acid conjugate (LOC) levels. The developed method was validated in terms of linearity, precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guidelines, and the parameters were within acceptable limits. Subsequently, the pharmacokinetics of leuprolide and LOCs were evaluated. In vivo rat subcutaneous studies revealed that conjugation with fatty acids significantly altered the pharmacokinetics of leuprolide. After the subcutaneous administration of fatty-acid-conjugated leuprolide, the mean absorption time and half-life were prolonged. To the best of our knowledge, this is the first study showing the effects of fatty acid conjugates on the pharmacokinetics of leuprolide using a newly developed UPLC-MS/MS method for the simultaneous quantification of leuprolide and LOCs. [ABSTRACT FROM AUTHOR]

Rizatriptan (RZT) is an efficient anti-migraine drug which belongs to the class of selective 5 HT (1B/1D) serotonin receptor agonists. Nevertheless, RZT elicits several adverse effects and RZT nasal sprays have a limited half-life, requiring repeated doses that could cause patient noncompliance or harm to the nasopharynx and cilia. The current research aimed to develop orally disintegrating films (ODFs) of RZT employing maltodextrin (MTX) and pullulan (PUL) as film-forming polymers, as well as propylene glycol (PG) as a plasticizer. The ODFs were prepared by solvent casting method (SCM). The technique was optimized using Box–Behnken design (BBD), contemplating the ratios of PUL: MTX and different levels of PG (%) as factor variables. The influence of these factors was systematically analyzed on the selected dependent variables, including film thickness, disintegration time (D-time), folding endurance (FE), tensile strength (TS), percent elongation (%E), moisture content (%), and water uptake (%). In addition, the surface morphology, solid state analysis, drug content uniformity (%), drug release (%), and pH of the RZT-ODFs were also studied. The results demonstrated a satisfactory stable RZT-ODFs formulation that exhibited surface homogeneity and amorphous RZT in films with no discernible interactions between the model drug and polymeric materials. The optimized film showed a rapid D-time of 16 s and remarkable mechanical features. The in vitro dissolution kinetics showed that 100% RZT was released from optimized film compared to 61% RZT released from conventional RZT formulation in the initial 5 min. An animal pharmacokinetic (PK) investigation revealed that RZT-ODFs had a shorter time to achieve peak plasma concentration (Tmax), a higher maximum plasma concentration (Cmax), and area under the curve (AUC0−t) than traditional oral mini capsules. These findings proposed a progressive approach for developing anti-migraine drugs that could be useful in reducing the complications of dysphagia in geriatric and pediatric sufferers. [ABSTRACT FROM AUTHOR]

The objective of this study was to design and evaluate an orodispersible film (ODF) composed of aripiprazole (ARP), prepared using a conventional solvent casting technique, and to fuse a three-dimensional (3D) printing technique with a hot-melt extrusion (HME) filament. Klucel® LF (hydroxypropyl cellulose, HPC) and PE-05JPS® (polyvinyl alcohol, PVA) were used as backbone polymers for 3D printing and solvent casting. HPC-, PVA-, and ARP-loaded filaments were applied for 3D printing using HME. The physicochemical and mechanical properties of the 3D printing filaments and films were optimized based on the composition of the polymers and the processing parameters. The crystalline states of drug and drug-loaded formulations were investigated using differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). The dissolution and disintegration of the 3D-printed films were faster than those of solvent-cast films. HPC-3D printed film was fully disintegrated within 45 ± 3.5 s. The dissolution rate of HPC films reached 80% within 30 min at pH 1.2 and pH 4.0 USP buffer. There was a difference in the dissolution rate of about 5 to 10% compared to PVA films at the same sampling time. The root mean square of the roughness (Rq) values of each sample were evaluated using atomic force microscopy. The higher the Rq value, the rougher the surface, and the larger the surface area, the more salivary fluid penetrated the film, resulting in faster drug release and disintegration. Specifically, The HPC 3D-printed film showed the highest Rq value (102.868 nm) and average surface roughness (85.007 nm). The puncture strength of 3D-printed films had desirable strength with HPC (0.65 ± 0.27 N/mm2) and PVA (0.93 ± 0.15 N/mm2) to prevent deformation compared to those of marketed film products (over 0.34 N/mm2). In conclusion, combining polymer selection and 3D printing technology could innovatively design ODFs composed of ARP to solve the unmet medical needs of psychiatric patients. [ABSTRACT FROM AUTHOR]

Abstract: Over 40% of active pharmaceutical ingredients (API) in development pipelines are poorly water-soluble drugs which limit formulation approaches, clinical application and marketability because of their low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in overcoming these issues with several successfully marketed products. A number of key references that describe state-of-the-art technologies have been collected in this review, which addresses various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs according to the four generations of solid dispersions. This article reviews critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products. [Copyright &y& Elsevier]

Abstract: Recently, we synthesized novel amphiphilic gelatin–oleic acid (GO) conjugate to prepare self-assembled nanoparticles for drug delivery. The aim of this study was to investigate pharmaceutical potentialities of self-assembled GO nanoparticles for solubility enhancement and modified release of poorly water-soluble drugs. Three poorly water-soluble model drugs with different pH-dependent solubility (valsartan and aceclofenac, insoluble at pH 1.2; telmisartan, insoluble at pH 6.8) were chosen to investigate the potential contributions of self-assembled GO nanoparticles to solubility enhancement and controlled release. The particle size of the drug-loaded nanoparticles was 200–250nm. Zeta potential was calculated, and instrumental analysis such as powder X-ray diffraction (PXRD) and Fourier transform infrared (FT-IR) spectroscopy were used to investigate the physicochemical properties of the drug-loaded nanoparticles. Compared to the drug alone, the drug-loaded nanoparticles showed enhanced solubility. Furthermore, the release profiles of the model drugs were modified in a controlled manner. The current self-assembled GO nanoparticles can provide a versatile potential in drug delivery and tumor targeting. [Copyright &y& Elsevier]

Abstract: The present study aimed to develop the intranasal delivery system of fexofenadine for the prolonged drug release via the preparation of mucoadhesive liposome. By using thin layer film hydration method, liposome of fexofenadine was prepared with DPPC/DPPG, resulting in the small lipid vesicles (359±5.5 nm) with narrow size distribution (PI<0.1). Subsequently, the surface of anionic liposome was coated by chitosan and in vitro characteristics of liposomes were evaluated along with the pharmacokinetic studies in rats. Chitosan coated liposomes were stable for 6-month storage at 4°C without any significant size change and drug leakage. Furthermore, it exhibited strong mucoadhesive properties in mucin adsorption test, which was 3-fold higher than uncoated liposomes. Compared to the oral delivery of powder formulation, the intranasal delivery of fexofenadine significantly (p <0.05) increased systemic exposure of fexofenadine in rats. Particularly, the intranasal administration of chitosan coated liposome exhibited approximately 5 fold enhancement of AUC with more sustained drug release in rats compared to the oral delivery. In conclusion, intranasal administration of chitosan coated liposome appeared to be effective to enhance the bioavailability as well as prolonged exposure of fexofenadine in rats. [Copyright &y& Elsevier]

Abstract: We examined how melatonin absorption was affected by pharmaceutical excipients using the Ussing chamber technique with mounted rat gastrointestinal (GI) segments. Melatonin absorption occurs throughout the GI tract, with the greatest absorption being in the rectum and ileum and the least in the stomach. Melatonin can be classified as a low permeability drug. P-glycoprotein (P-gp) does not affect melatonin absorption but transported rhodamine 123, a well-known P-gp substrate. The possibility of saturating P-gp by melatonin was excluded. Sodium cholate (0.5%) increased melatonin absorption, but decreased absorption at higher concentrations (1.0% and 5.0%). Sodium oleate (0.5% and 1.0%) consistently decreased melatonin absorption. Pharmaceutical excipients increased the absorption of Lucifer yellow (100μg/mL), a paracellular probe but decreased the absorption of melatonin above the critical micelle concentration (cmc), suggesting that melatonin was transported mainly by transcellular pathway. Sodium cholate and sodium oleate, when above the cmc, resulted in micellar complexes as revealed by 1H NMR spectra and particle size distribution. Histology tests showed mucosal damage of jejunum tissues in the presence of these excipients. The balance of tissue damage by the formation of micellar complexes could affect the melatonin absorption. This information on melatonin absorption behaviors and its modulation by pharmaceutical excipients can be used in further oral dosage formulations to affect circadian rhythm. [Copyright &y& Elsevier]

Abstract: We investigated the dissolution-modulating mechanism of alkalizers and polymers in nanoemulsifying Gelucire 44/14 (GUC)-based solid dispersions (SDs) for controlled release. Aceclofenac (AFC), an ionizable and poorly water-soluble drug, was chosen because of its extremely low solubility at low pH. Nanoemulsifying SD systems containing alkalizers and/or polymers were prepared by the melting method. Drug crystallinity, microenvironmental pH (pHM), dissolution rate, and droplet size in the media from nanoemulsifying SD were then characterized. Ternary SD containing alkalizers, mainly Na2CO3 and NaHCO3, enhanced the initial release rate of AFC in simulated gastric fluid (pH 1.2), but resulted in spring-like precipitation. However, adding a secondary polymer, Poloxamer 407, prevented precipitation in the quaternary SD system. Poloxamer 407 and alkalizer (Na2CO3) facilitated nanoemulsion formation (80–140nm) with a smaller droplet size in a medium of pH 1.2 as visualized by TEM. The surface and inner pHM were also modulated by the alkalizers, but not by the polymers. The drug’s crystalline structure was further changed to partially or almost amorphous form by the alkalizers and polymers in SD as characterized by instrumental analysis. The synergistic effects of alkalizers and secondary polymers in SD on reduction of drug crystallinity and modulation of pHM via molecular interactions could modulate dissolution rates of ionizable and poorly water-soluble model drug without spring-like precipitation by providing more favorable nanoemulsion-forming environment. [Copyright &y& Elsevier]

Abstract: This study was originally undertaken to establish the in vitro metabolic conditions and then evaluate the effect of pharmaceutical excipients (PEs) on drug metabolism in uridine diphosphoglucuronic acid-supplemented human liver microsomes. Poorly bioavailable raloxifene was chosen as a model drug. Intact drug and its two glucuronide metabolites were successfully isolated using gradient HPLC analysis and LC/MS analysis. Formation of raloxifene metabolites was affected by buffer compositions, incubation time and initial raloxifene concentrations. Under optimized metabolic conditions, 41.0% of raloxifene was converted to its metabolites after 2h incubation. This metabolic inhibition of raloxifene by the PEs occurred in a dose-dependent manner and accordingly formed two glucuronide metabolites. In the metabolic kinetics using Lineweaver-Burk analyses, Cremophor® EL competitively inhibited formation of metabolites while sodium lauryl sulfate (SLS), polyvinylpyrrolidone K30 (PVP) and Tween® 80 significantly inhibited in a mixed competition. Although some PEs showed inhibition on glucuronidation of raloxifene in vitro, their effects on in vivo bioavailability of raloxifene need to be confirmed directly due to the dilution factors and other complicated situations influencing the bioavailability. [Copyright &y& Elsevier]

Abstract: The present work is an original evaluation of the microenvironmental pH (pHM) and crystallinity of an ionizable drug in order to enhance its dissolution using alkalizers in polyethylene glycol 6000 (PEG 6000) based solid dispersions (SDs). Telmisartan (TEL) was chosen as a model drug due to its poor and pH-dependent water solubility. The nine alkalizers used to modify the pH of TEL were MgO, NaOH, KOH, Na2CO3, NaHCO3, bentonite, Na2HPO4, K2HPO4 and arginine. MgO, NaOH, KOH and Na2CO3 in the SD system significantly increased the drug dissolution rate in intestinal fluid (pH 6.8) and water. Modulation of pHM was clearly observed as a function of time at different fractional dimensions of tablet. Structural change in drug crystallinity to an amorphous form was also a contributing factor based on differential scanning calorimetry (DSC) thermograms and powder X-ray diffraction (PXRD) patterns. The drug frequency of the Ccreased and the O–H broad band in the Fourier transform infrared (FTIR) spectra disappeared when these alkalizers were added. It was evident that the alkalizers in PEG 6000 based SDs synergistically enhanced dissolution of TEL not only by modulating pHM but also by changing drug crystallinity to an amorphous form via molecular interactions. [Copyright &y& Elsevier]

Abstract: A colonic-release delivery system containing naproxen inclusion complex with 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) was originally proposed. The core tablets consisting of the naproxen inclusion complex and disintegrants (Ac-Di-Sol®, Primojel®, Avicel® or Polyplasdone®) were formed by direct compression, and then coated with the polymers, either pH-dependent Eudragit® S100 and/or pH-independent Eudragit® RS100 with plasticizers like dibutyl sebacate (DBS) and aluminum tristearate (AT). The in vitro release characteristics were evaluated in simulated gastric fluid for 2h and then subsequently in simulated intestinal fluid for 12h. The potential histological changes were also evaluated after direct dosing of suspensions of naproxen alone and powdered mixtures of inclusion complex-loaded tablet into rat intestinal segments. No distinct colonic release was observed when disintegrants were excluded in the single-layered coated tablets regardless of coated structures, giving a zero-order fashion over 12h. The coated tablet with double-layered structures of Eudragit® S100 and Eudragit® RS100 was not also applicable. In contrast, colonic release was achieved when the core tablet containing inclusion complex and disintegrant was coated with only Eudragit® S100 in a single-layered structure. The colonic-release tablet was resistant in gastric fluid for 2h and for 2–4h in intestinal fluid, followed by rapid release of the drug after a total of 4–6h of lag time depending on the type of disintegrants. The lag time was advanced in case of DBS while delayed in case of AT. On histological examination, the inclusion complex-loaded suspension caused less intestinal tissue damage than naproxen alone. Based on these findings, the colonic-release tablet with enteric coatings which contains inclusion complex and disintegrants could be useful to deliver drugs like naproxen to the lower small intestine and upper colon with increased dissolution and reduced intestinal tissue damage. [Copyright &y& Elsevier]

Abstract: Two types of the carnauba wax-based lipophilic matrix tablet using spray-dried granules (SDT) or directly compressible powdered mixtures (DCT) were prepared for sustained release. The model drug was a highly water-soluble potassium citrate and loaded about 74% of the total tablet weight. The SDT slowly eroded and disintegrated during the release study without showing sustained release when the hydrophilic excipients were added. In contrast, the DCT was more efficient for sustained release. The release rate decreased with increasing carnauba wax concentration. In particular, the sustained release rate was markedly pronounced when the lipophilic stearyl alcohol and stearic acid were combined with the carnauba wax. The surface of the intact DCT appeared to be smooth and rusty. The DCT rose to the surface from the bottom of the vessel during the release test, and numerous pores and cracks with no signs of disintegration were also observed after the release test. The release profile was dependent on the formulation composition and preparation method of the matrix tablet. Diffusion-controlled leaching through the channels of the pores and cracks of the lipophilic matrix tablet (DCT) is a key to the sustained release. [Copyright &y& Elsevier]

Enhanced delivery of bifidobacteria and fecal changes were compared following multiple oral administrations of protected bifidobacteria-loaded alginate poly-l-lysine microparticles (bap-microparticles) and unprotected bifidobacteria cultures over a period of 1 month to healthy human volunteers as preliminary in vivo studies. When bap-microparticles were orally administered, enhanced delivery of bifidobacteria was achieved. The viability of the bifidobacteria was significantly increased ∼ 11.5-30 times (1.06-1.48 log cycles) during the ingestion period when compared with the bifidobacteria culture group (p < 0.05). However, other gut microflora such as bifidobacteria, enterobacteriaceae, lactic acid bacteria, and staphylococci in feces were not significantly different between the two groups. Encapsulated bifidobacteria resulted in more frequent defecation and decreased fecal viscosity. [ABSTRACT FROM AUTHOR]

The safe maintenance of Node.js modules is critical in the software security industry. Most server-side web applications are built on Node.js, an environment that is highly dependent on modules. However, there is clear lack of research on Node.js module security. This study focuses particularly on prototype pollution vulnerability, which is an emerging security vulnerability type that has also not been studied widely. To this point, the main goal of this paper is to propose patterns that can identify prototype pollution vulnerabilities. We developed an automatic static analysis tool called DAPP, which targets all the real-world modules registered in the Node Package Manager. DAPP can discover the proposed patterns in each Node.js module in a matter of a few seconds, and it mainly performs and integrates a static analysis based on abstract syntax tree and control flow graph. This study suggests an improved and efficient analysis methodology. We conducted multiple empirical tests to evaluate and compare our state-of-the-art methodology with previous analysis tools, and we found that our tool is exhaustive and works well with modern JavaScript syntax. To this end, our research demonstrates how DAPP found over 37 previously undiscovered prototype pollution vulnerabilities among 30,000 of the most downloaded Node.js modules. To evaluate DAPP, we expanded the experiment and ran our tool on 100,000 Node.js modules. The evaluation results show a high level of performance for DAPP along with the root causes for false positives and false negatives. Finally, we reported the 37 vulnerabilities, respectively, and obtained 24 CVE IDs mostly with 9.8 CVSS scores. [ABSTRACT FROM AUTHOR]

We asked whether Bifidobacterium bifidum regulates the synthesis of IgA by mucosal lymphoid cells. B. bifidum alone, but not Clostridium perfringens, significantly induced total IgA and IgM synthesis by both mesenteric lymph nodes (MLN) and Peyer’s patch (PP) cells. We, further, investigated the mucosal antibody production following peroral administration of B. bifidum to mice. Ingested B. bifidum significantly increased the number of Ig (IgM, IgG, and IgA) secreting cells in the culture of both MLN and spleen cells. Nonetheless, B. bifidum itself does not induce the own specific antibody responses, implying that B. bifidum does not provoke unnecessary immune reaction. Subsequently, it was found that encapsulation of B. bifidum further augments the total IgA production in the culture of both MLN and spleen cells. Finally, we found that the immuno-stimulating activity of B. bifidum is due to its cellular components but not due to any actively secreting component(s) from bacteria. [Copyright &y& Elsevier]

[Display omitted] The aim of this study was to evaluate the enhanced thermal stability and physicochemical properties of fattigated vaccine antigens. High molecular weight influenza hemagglutinin (Heg) was used as a model antigen because of low heat stability requiring cold chamber. Heg was conjugated with long-chain oleic acid (C18) and short-chain 3-decenoic acid (C10) to prepare fattigated Heg. Circular dichroism analysis revealed no significant changes in the three-dimensional structure post-conjugation. In the liquid state, the fattigated Heg was self-assembled into nanoparticles (NPs) due to its amphiphilic nature, with sizes of 136.27 ± 12.78 nm for oleic acid-conjugated Heg (HOC) and 88.73 ± 3.27 nm for 3-decenoic acid-conjugated Heg (HDC). Accelerated thermal stability studies at 60 °C for 7 days demonstrated that fattigated Heg exhibited higher thermal stability than Heg in various liquid or solid states. The longer-chained HOC showed better thermal stability than HDC in the liquid state, attributed to increased hydrophobic interactions during self-assembly. In bio-mimicking liquid states at 37 °C, HOC exhibited higher thermal stability than Heg. Furthermore, solid-state HOC with cryoprotectants (trehalose, mannitol, and Tween® 80) had significantly increased thermal stability due to reduced exposure of protein surface area via nanonization behavior. The current fattigation platform could be a promising strategy for developing thermostable nano vaccines of heat-labile vaccine antigens. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersions (ASDs) improve the oral delivery of poorly water-soluble drugs. ASDs of olanzapine (OLZ), which have a high melting point and low solubility, are performed using a complicated process. Three-dimensional (3D) printing based on hot-melt pneumatic extrusion (HMPE) is a simplified method for producing ASDs. Unlike general 3D printing, printlet extrusion is possible without the preparation of drug-loaded filaments. By heating powder blends, direct fused deposition modeling (FDM) printing through a nozzle is possible, and this step produces ASDs of drugs. In this study, we developed orodispersible films (ODFs) loaded with OLZ as a poorly water-soluble drug. Various ratios of film-forming polymers and plasticizers were investigated to enhance the printability and optimize the printing temperature. Scanning electron microscopy (SEM) showed the surface morphology of the film for the optimization of the polymer carrier ratios. Differential scanning calorimetry (DSC) was used to evaluate thermal properties. Powder X-ray diffraction (PXRD) confirmed the physical form of the drug during printing. The 3D printed ODF formulations successfully loaded ASDs of OLZ using HMPE. Our ODFs showed fast disintegration patterns within 22 s, and rapidly dissolved and reached up to 88% dissolution within 5 min in the dissolution test. ODFs fabricated using HMPE in a single process of 3D printing increased the dissolution rates of the poorly water-soluble drug, which could be a suitable formulation for fast drug absorption. Moreover, this new technology showed prompt fabrication feasibility of various formulations and ASD formation of poorly water-soluble drugs as a single process. The immediate dissolution within a few minutes of ODFs with OLZ, an atypical antipsychotic, is preferred for drug compliance and administration convenience. [ABSTRACT FROM AUTHOR]

• An acid-base neutralization rapidly formed nanosuspensions to enhance dissolution. • Nanonization was attributed by the salt-induced effect and poloxamer micellization. • Drug nanosuspension gave amorphous structure and intermolecular interactions. An acid-base neutralization technique has generated interest for the ability to achieve an enhanced dissolution of pH-dependent weakly basic or acidic poorly water-soluble drugs. However, the underlying nanonization mechanism, following acid-base neutralization, requires further elucidation. We hypothesized that the nanosuspensions (NSPs) via nanonization of drug particles could be attributed to the "salt-induced effect" and surfactant-driven micellization after acid-base neutralization. Rebamipide (RBM) and valsartan (VAL) were chosen as model drugs owing to poor water solubility and pH-dependent aqueous solubility. The drug NSP was rapidly obtained via salt formation (NaCl) after neutralization of the drug in basic NaOH solution and poloxamer 407 (POX 407) in acidic HCl solution. The NSP surrounded by NaCl salt was further stabilized by POX 407. The resulting NaCl salt modulated the critical micelle aggregation of POX 407, stabilizing the drug-loaded NSP in a cage of salt and micellar surfactant. In non-assisted homogenization, size analysis indicated the relationship between salt concentration and size reduction. Fourier transform infrared (FTIR) spectra revealed that the existence of hydrogen bonding between the drug and surfactant after neutralization, attributed to NSP size reduction. Changes in drug crystallinity to the nano-amorphous state were confirmed by powder X-ray diffraction (PXRD). Overall, the salt-induced drug NSP synergistically enhanced the dissolution rate, narrowing a gap between drug dissolution profiles in different pH environments. [ABSTRACT FROM AUTHOR]

The aims of this study were to design different chain length fatty acid-conjugated albumin nanoparticles (ANPs) and evaluate their anticancer activity in the HCT116 human colorectal cancer xenograft mouse model. Doxorubicin hydrochloride (DOX·HCl) was chosen as a model drug. The different chain lengths of fatty acids (butyric acid; C4, and stearic acid; C18) in albumin conjugates exhibited different physicochemical properties and anticancer activity. Fatty acid-conjugated albumin aided the formation of self-assembled structures with an average size of approximately 200 nm and a negative charge when incubated with excess DOX in an aqueous solution. DOX-loaded long-chain C18-conjugated ANPs allowed efficient encapsulation of hydrophobic DOX into the core of the self-assembled structure, enabling higher drug loading, enhanced colloidal stability and controlled release behavior in PBS pH 7.4 medium as compared with free DOX·HCl or non-fatty acid conjugated ANPs. Furthermore, DOX-loaded fatty acid-conjugated ANPs showed an increased cellular uptake intensity and cytotoxic effects in vitro. In vivo , HCT116 xenograft model experiments confirmed that DOX-loaded C18-conjugated ANPs showed improved anticancer activity and reduced side effects compared with the DOX-treated groups. The long-chain fatty acid-conjugated ANPs synergistically activated the interaction with the free-fatty acid receptor (FFAR) on HCT116 colorectal cancer cells as compared with short-chain C4 or other non-conjugated ANPs. Specifically, DOX-loaded C18-conjugated NPs exhibited significant performance to overexpressed FFAR4 on HCT116 colorectal cancer cells. The fatty acid chain length in the fattigation-platform system could be a promising molecular moiety to improve targeting efficiency and drug accumulation in various cancer therapy. Unlabelled Image [ABSTRACT FROM AUTHOR]

• Fattigation-platform NMs were prepared by the EDC/NHS chemistry and film hydration method. • Fattigation-platform solubilization technology supported the nanonization of CCM and DTX. • The fatty acid chain length affected the nanonizing capacity of CCM and DTX in biorelevant medium. • Fattigation-platform NMs could improve the cellular activities of poorly water-soluble drugs. This study aimed to design the ideal nanonizing vehicle for poorly water-soluble model curcumin (CCM) using fattigation-platform nanotechnology, and to investigate the effects of fatty acid salts chain length on nanonizing CCM and its efficient delivery to different cancer cells. HSA-fatty acid conjugates were synthesized by EDC/NHS coupling. Fattigation-platform nanomicelles (NMs), prepared by film hydration, exhibited uniform and spherical morphology, although, each NM varied in particle size, zeta potential, and critical micelle concentration according to the types of fatty acid. Preliminary solubility studies of albumin conjugates with 5 types of fatty acid salts of different chain lengths revealed that C14 exhibited the highest solubilization of CCM. CCM-loaded HSA-C14 NMs demonstrated the highest drug content (5.35 ± 0.48%) and loading efficiency (95.93 ± 1.87%) compared to other NMs. It exhibited enhanced drug release rate and reduced micelle size in biorelevant dissolution medium. Interestingly, this solubilization approach was well applied in poorly water-soluble docetaxel trihydrate (DTX). Preliminary solubility results of DTX was also corresponded to the stable nanonization phenomenon in biorelevant dissolution medium. Compared to the CCM EtOH solution, HSA-C14 NMs showed higher internalization in cancer cell lines A549 and MCF-7, and consequently, exhibited significantly increased cytotoxicity against both cell lines. Therefore, this study provides a new solubilization approach for poorly water-soluble drugs using fatty acid salts of different chain lengths and their micellar formations via nanonization, which could be a promising tool for targeted cancer therapy using poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

In recent years, various oral dosage forms using biomaterials have been developed to deliver drugs to the colon for therapy due to the advantages of local treatment and its ideal location for drug delivery. To achieve site-specific delivery, the complete drug should be released in the colon, while the drug must be protected or their delivery minimized in the stomach and small intestine. The use of natural or synthetic polymers has been reported for these purposes. The roles of zein in drug delivery have been identified with various types of formulations for improving bioavailability, controlled drug release and targeted delivery. Although zein has been demonstrated as a potential material for pharmaceutical applications, a review of zein in the gastrointestinal tract for stabilizing drug- and colon-specific delivery is still missing. In the present review, we aim to provide typical strategies for using zein in formulations to minimize drug release/ensure drug protection in the upper part of the gastrointestinal tract. Furthermore, effective fabrications or modifications for drug release in the colon will be highlighted. This primary resource of related methods of using zein in the gastrointestinal tract will advance technologies for using it as a natural polymer for drug delivery. [ABSTRACT FROM AUTHOR]

Recent research in DNA nanotechnology has demonstrated that biological substrates can be used for computing at a molecular level. However, in vitro demonstrations of DNA computations use preprogrammed, rule-based methods which lack the adaptability that may be essential in developing molecular systems that function in dynamic environments. Here, we introduce an in vitro molecular algorithm that 'learns' molecular models from training data, opening the possibility of 'machine learning' in wet molecular systems. Our algorithm enables enzymatic weight update by targeting internal loop structures in DNA and ensemble learning, based on the hypernetwork model. This novel approach allows massively parallel processing of DNA with enzymes for specific structural selection for learning in an iterative manner. We also introduce an intuitive method of DNA data construction to dramatically reduce the number of unique DNA sequences needed to cover the large search space of feature sets. By combining molecular computing and machine learning the proposed algorithm makes a step closer to developing molecular computing technologies for future access to more intelligent molecular systems. [ABSTRACT FROM AUTHOR]

The development of oral tablet formulation for herbal medicines has been restricted by large drug loadings and the poor physicochemical and mechanical properties of dry herbal extracts (DHEs). Herein, statistical experimental designs were applied to herbal tablet formulation development and optimization using Wuzi Yanzong dry extract (WYE). The tablet disintegration time and hardness were identified as the critical quality attributes (CQAs) of the product. The tablet formulation was designed to achieve a high drug loading (50% or higher of WYE), shorter tablet disintegration time (less than 30 minutes), and suitable hardness (6.0 to 7.5 kp). A D-optimal mixture design was used to evaluate the effects of excipients on CQAs to minimize the risk compression failure and improve the tabletability in formulations containing WYE at 50% and 65% by weight. A partial least squares model was used to elucidate the multivariate relationships between a large number of formulation variables and product CQAs, and determine the maximum possible WYE loading. From overlaid plots of the effects of formulation variables on CQAs, it was found that a maximum WYE loading of 67% in tablet formulation satisfied the acceptance criteria of CQAs. In conclusion, this study shows that multivariate statistical tools are useful for developing tablet formulations containing high doses of herbal extracts and establishing control strategies that ensure product quality. [ABSTRACT FROM AUTHOR]

Despite their great potential, the nano-sized extracellular vesicles are yet to become effective delivery systems for poorly water-soluble drugs. Here, we present a novel platform of exosomes as a drug delivery system by engineering of a poorly water-soluble drug into a poloxamer-based molecular nanostructured dispersion composed of a hydrophilic and a hydrophobic moiety for an enhanced anticancer efficacy. For the first time, aspirin was loaded into exosomes as an anticancer agent via a one-step fabrication combining the nano-matrix formation of the nanostructured dispersion and exosomes loading. Our approach could transform crystalline aspirin to a nanoamorphous form in the nano-matrix structured exosomes, leading to increased drug encapsulation efficiency for exosomes, improved dissolution and strongly enhanced cytotoxicity of aspirin to cancer cells. Interestingly, cytotoxicity of aspirin to both breast and colorectal cancer cells could be strongly enhanced by the nanoamorphous aspirin-loaded exosomes, and this cytotoxic effect was more pronounced to parental cells of the exosomes, reminiscent of homing effect. Hence, this study has pioneered a novel nanoplatform of nanoamorphous exosomal delivery system to transform an anti-inflammatory drug into a potent anti-cancer agent. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the impact of different chain length fatty acids on physicochemical properties and cancer targeting of fattigation-platform nanoparticles (NPs). Two different types of fatty acids (short chain , 2-hydroxybutyric acid, C4; long chain , oleic acid, C18:1) were successfully conjugated to human serum albumin (HSA) via simple 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) coupling reaction. These conjugates readily formed HSA-C4 and HSA-C18:1 NPs which showed good stability in serum and desirable biocompatibility with normal cell line (HEK293T). Doxorubicin hydrochloride (DOX) was efficiently loaded into NPs by incubation process via electrostatic interaction. The structure, morphology, and texture of DOX-loaded NPs were characterized by Transmission electron microscopy (TEM) equipped with Energy-dispersive X-ray spectroscopy (EDS). The initial burst release of DOX-loaded NPs was controlled by the presence and chain length of fatty acids. In vitro cytotoxicity studies with three cancer cell lines (A549, HT-29, and PANC-1) suggested that fattigation-platform NPs have distinctive cytotoxic effects compared to Doxil®. Confocal microscopy and flow cytometry exhibited that the cellular uptake of DOX-loaded NPs was varied by the different chain lengths of fatty acids. It was evident that the chain length of fatty acids in the fattigation-platform NPs could play a vital role in varying physicochemical properties and cancer cell targeting of NPs. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Commercially available cilostazol (CIL) tablet releases drug immediately and is given twice a day as an antiplatelet and vasodilatory agent. However, clinical usefulness of immediate release (IR) preparation is limited due to its extremely poor water solubility and the difficulty in sustaining the blood concentration, resulting in unwanted side effects such as headaches, pyknocardia and heavy-headed symptoms. To achieve once a day dosage form with enhanced solubility and controlled release, double controlled release CIL matrix tablets (DCRT) were designed by modulating a sol–gel process of binary polymeric blends of a pH-independent hydroxylpropylmethylcellulose (HPMC) and a pH-dependent polymer (carbomer) assisted with anionic surfactant (sodium lauryl sulfate, SLS). The release profiles of the DCRT were varied according to the ratio of the two polymers. This DCRT enhanced dissolution rate of CIL in a controlled manner due to the sol–gel and erosion process of HPMC, and SLS-driven modulation of charged carbomer via neutralization and micellar interaction. The near-infrared (NIR) chemical imaging and gravimetric behaviors of DCRT clearly showed dynamic modulation of CIL during the swelling and hydration process. Furthermore, the plasma concentration of CIL in DCRT was highly improved and sustained in beagle dogs in a controlled manner. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • BSA adsorption increase GON size, reduced GON zeta potential and stabilized GONs. • A lower cellular uptake of intact GONs was observed at a higher BSA concentration. • BSA pre-coated GON modified cellular uptake of GONs in complete media. Abstract Albumin is the most abundant protein in blood, and is the most frequently identified protein in the protein corona of nanoparticles (NPs). Thus, albumin plays an important role in modulating NPs’ physicochemical properties and bioavailability. In this study, the effect of bovine serum albumin (BSA) on gelatin-oleic nanoparticles’ (GONs) physicochemical properties and cellular uptake were evaluated. Coumarin-6 was used as indicator to track the cellular uptake of GONs. The binding of BSA onto the GON surface increased the size, slightly reduced the negative net charge of the GON, and improved GON stability. The presence of BSA in cell culture media reduced the cellular uptake of BSA-uncoated GONs on human embryonic kidney cells 293 (HEK 293) and human adenocarcinoma alveolar basal epithelial cells (A549) in the media without FBS addition. Pre-coated BSA corona decreased cellular uptake of GONs in A549 cells in the media, with and without supplemented with 10% fetal bovine serum (FBS) but drastically increased cellular uptake on HEK 293 cells. BSA could be used to modulate protein corona as an endogenous ligand in NP design simply by mixing or incubating BSA with NPs before in vivo administration to inhibit or induce cellular uptake in specific cell types. [ABSTRACT FROM AUTHOR]

The principles of bioorthogonal click chemistry and metabolic glycoengineering were applied to produce targeted anti-cancer drug delivery via fattigation-platform-based gelatin-oleic nanoparticles. A sialic acid precursor (Ac 4 ManNAz) was introduced to the cell surface. Gelatin and oleic acid were conjugated by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) chemistry with the subsequent covalent attachment of dibenzocyclooctyne (DBCO) in a click reaction on the cell surface. The physicochemical properties, drug release, in vitro cytotoxicity, and cellular uptake of DBCO-conjugated gelatin oleic nanoparticles (GON-DBCO; particle size, ∼240 nm; zeta potential, 6 mV) were evaluated. Doxorubicin (DOX) was used as a model drug and compared with the reference product, Caelyx®. A549 and MCF-7 cell lines were used for the in vitro studies. GON-DBCO showed high DOX loading and encapsulation efficiencies. In A549 cells, the IC50 value for GON-DBCO-DOX (1.29 µg/ml) was six times lower than that of Caelyx® (10.54 µg/ml); in MCF-7 cells, the IC50 values were 1.78 µg/ml and 2.84 µg/ml, respectively. Confocal microscopy confirmed the click reaction between GON-DBCO and Ac4ManNAz on the cell surface. Flow cytometry data revealed that the intracellular uptake of GON-DBCO-DOX was approximately two times greater than that of GON-DOX and Caelyx®. Thus, the newly designed GON-DBCO-DOX provided a safe and efficient drug delivery system to actively target the anticancer agents. [ABSTRACT FROM AUTHOR]

Introduction: As South Korea remains technically at war with the North, higher smoking prevalence in the military might adversely affect the South Korea's military power and contribute to lifetime smoking in men with mandatory military service. This study was to identify priorities among the anti-smoking strategies to improve the existing smoking cessation programs for the Korean military.Methods: The analytic hierarchy process model with a goal, decision criteria, and sub-criteria as well as candidate strategies, was developed following a literature search and expert group discussion. A survey for pairwise comparison was conducted to determine the priority of the (sub-)criteria and strategies by 14 experts. The Super-Decisions software was used to determine the priorities and to analyze their consistency ratios and sensitivities. The study was approved by the ethics committee of the Korea Ministry of Health and Welfare.Results: Eight candidate strategies were developed to improve the effectiveness of military anti-smoking interventions as follows: (1) development of outcome enhancement plans for smoking cessation programs for the military, (2) development of differentiated smoking cessation programs for specific groups, (3) building of community network for continuity and accessibility of anti-smoking project, (4) building of industry-academia-government networks for anti-smoking project, (5) improvement of the perception of and strengthen the reward for smoking cessation, (6) development of a training system for army clinicians for the delivery of smoking cessation services, (7) creation of a certification system for smoking cessation programs, and (8) development of an evaluation system of project performance for smoking cessation. Through the analytic hierarchy process survey, the military specificity and its sub-criterion of practicality were selected as the top concerns of decision criteria for the anti-smoking strategies among the decision criteria of outcome improvement, military specificity, publicness, and economic efficiency. The most important strategy was to improve the perception of and strengthen the reward for smoking cessation. This strategy was most focused on the creation of an anti-smoking environment and improvement of the effectiveness of the projects. The creation of a training system for army clinicians for the delivery of smoking cessation services ranked second.Conclusion: In conclusion, motivating smoking cessation and utilizing well-trained army clinicians were found to be the most important anti-smoking strategies for the Korean military. This study might provide valuable insights for policy makers to reduce tobacco use in the Korean military. [ABSTRACT FROM AUTHOR]