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Background: While moderate-intensity statin therapy is recommended for primary prevention, statins may not be utilized at a recommended intensity due to dose-dependent adverse events, especially in an Asian population. However, evidence supporting the use of low-intensity statins in primary prevention is limited. Objective: We sought to compare clinical outcomes between a low-intensity statin plus ezetimibe and a moderate-intensity statin for primary prevention. Methods: This population-based retrospective cohort study used the Korean nationwide claims database (2002-2019). We included adults without atherosclerotic cardiovascular diseases who received moderate-intensity statins or low-intensity statins plus ezetimibe. The primary outcome was a composite of all-cause mortality, myocardial infarction, and ischemic stroke. The safety outcomes were liver and muscle injuries and new-onset diabetes mellitus (DM). We used standardized inverse probability of treatment weighting (sIPTW) and propensity score matching (PSM). Results: In the sIPTW model, 1717 and 36 683 patients used a low-intensity statin plus ezetimibe and a moderate-intensity statin, respectively. In the PSM model, each group included 1687 patients. Compared with moderate-intensity statin use, low-intensity statin plus ezetimibe use showed similar risks of the primary outcome (hazard ratio [HR] = 0.92, 95% CI = 0.81-1.12 in sIPTW and HR = 1.16, 95% CI = 0.87-1.56 in PSM model). Low-intensity statin plus ezetimibe use was associated with decreased risks of liver and muscle injuries (subHR [sHR] = 0.84, 95% CI = 0.74-0.96 and sHR = 0.87, 95% CI = 0.77-0.97 in sIPTW; sHR = 0.84, 95% CI = 0.72, 0.96 and sHR = 0.82, 95% CI = 0.72-0.94 in PSM model, respectively). For new-onset DM and hospitalization of liver and muscle injuries, no difference was observed. Conclusion and Relevance: Low-intensity statin plus ezetimibe may be an alternative to moderate-intensity statin for primary prevention. Our findings provide evidence on safety and efficacy of statin therapy in Asian population. [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]

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]

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]

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]

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]

This study aimed to verify, for the first time, the need for Good Pharmacy Practice (GPP) regulations as guidelines to provide pharmaceutical care services in community pharmacies in Korea. Statistical analyses were performed with demographic characteristics, institutional factors, and diversity factors of 3 pharmaceutical care services as independent variables and the favorability of GPP implementation as a dependent variable. In assessing the diversity of methods of providing pharmaceutical care services as an indicator of willingness to provide these services, this study understood such diversity as an innovative behavior that represents the efforts and willingness of pharmacists to provide better services. The results of descriptive statistics showed that most pharmacists in community pharmacy recognize that guidelines are necessary to provide better pharmaceutical care services. The statistical correlation analysis results confirmed that a greater need for guidelines was strongly related to higher GPP favorability. The institutional factors had the greatest influence on GPP favorability, rather than diversity factors of pharmaceutical care services, ultimately with the Korean perspectives to equate the GPP with the guidelines for pharmaceutical care services. Our study confirmed that it is a wish and a policy task of community pharmacists in Korea to enact GPP as soon as possible. [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]

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]

The aim of this study was to prepare various types of solid dispersions (SDs) by the hot-melt extrusion technique. Next, process analytical technology (PAT) such as Fourier transform-infrared (FT-IR) and Raman and near infrared (NIR) spectroscopy were applied to determine the solubilization effect. The SDs and its tablets were prepared. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) were performed to determine the morphological and crystalline characteristics of the SDs. Additionally, PAT analyses were performed to identify the solubilization of the celecoxib. Dissolution testing was performed using the paddle method indicated in the US Pharmacopeia Apparatus II. Based on SEM, DSC, and XRD analysis, all SDs changed successfully from the crystalline to the amorphous form. However, FT-IR, Raman, and NIR analysis used in PAT showed that SDs were divided into two groups. New peaks formed as the amount of drug loading increased to >50% in the SD and the dissolution rates were lower than those of the marketed drug. Drug loading levels of ≤50% showed no new peak and exhibited strong solubilization effects. PAT tools can be used to discriminate between extrudates with poor (<50% drug release after 120 min) and desirable (>75% drug release after 120 min) dissolution performance. [ABSTRACT FROM AUTHOR]

The purpose of this study was to prepare sustained release (SR) matrix tablets using a direct compression incorporated with a post-heating process. Allopurinol was selected due to the water-soluble property and Compritol 888 ATO® (also known as glyceryl behenate) was used as an SR matrix-forming agent. The API, SR material, microcrystalline cellulose, and magnesium stearate (lubricant) were mixed and prepared into a tablet by a direct compression method. The compressed tablets were stored in a dry oven at four temperatures (60, 70, 80, and 90°C) and for three time periods (15, 30, 45 min). The DSC and PXRD data indicated that the crystallinity of the API was not altered by the post-heating method. However, SEM images demonstrated that Compritol 888 ATO® was melted by the post-heating method, and that the melted Compritol 888 ATO® could form a strong matrix. This strong matrix led to the significant sustained release behavior of hydrophilic APIs. As little as 3 mg of Compritol 888 ATO® (0.65% of total tablet weight), when heated at 80°C for 15 min, showed sustained release over 10 h. The post-heating method exerted a significant influence on lipid-based matrix tablets and allowed a reduction in the amount of material required for a water-soluble drug. This will also provide a valuable insight into lipid-based SR tablets and will allow their application to higher quality products and easier processing procedures. [ABSTRACT FROM AUTHOR]

The leaves of Vaccinium bracteatum Thunb. are a source of traditional herbal medicines found in East Asia. The present study aimed to evaluate the mechanisms underlying the antidepressant-like effects of water extract of V. bracteatum Thunb. leaves (VBLW) in a mouse model of chronic restraint stress (CRS) and to identify the possible molecular in vitro mechanisms of the neuroprotective effects. The CRS-exposed mice were orally administered VBLW (100 and 200 mg/kg) daily for 21 days consecutively. The behavioral effects of VBLW were assessed through the forced swim test (FST) and the open field test (OFT). The levels of serum corticosterone (CORT), corticotropin releasing hormone (CRH), and adrenocorticotropin hormone (ACTH), brain monoamines, such as serotonin, dopamine, and norepinephrine, and serotonin turnover by tryptophan hydroxylase 2 (TPH2), serotonin reuptake (SERT), and monoamine oxidase A (MAO-A) were evaluated, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway. CRS-exposed mice treated with VBLW (100 and 200 mg/kg) showed significantly reduced immobility time and increased swimming and climbing times in the FST, and increased locomotor activity in the OFT. Moreover, CRS mice treated with VBLW exhibited significantly decreased CORT and ACTH, but enhanced brain monoamine neurotransmitters. In addition, CRS mice treated with VBLW had dramatically decreased protein levels of MAO-A and SERT, but increased TPH2 protein levels in the hippocampus and the PFC. Similarly, VBLW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and the PFC. Furthermore, VBLW showed neuroprotective effects via increased CREB phosphorylation in CORT-induced cell injury that were mediated through the ERK/Akt/mTOR signaling pathways. These results suggested that the antidepressant-like effects of VBLW might be mediated by the regulation of the HPA axis, glucocorticoids, and serotonin turnover, such as TPH2, SERT, and MAO-A, as well as the concentration of monoamine neurotransmitters, and the activities of ERK and Akt phosphorylation, which were possibly associated with neuroprotective effects. [ABSTRACT FROM AUTHOR]

Amphiphilically-modified gelatin has the ability to form self-assembled NPs which own hydrophobic inner core for water-insoluble drugs loading and gelatin layer for circulation extension and biocompatibility. Gelatin-oleic acid conjugates (GOC) was synthesized from oleic acid (OA) and gelatin, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/ N-hydroxysuccinimide (EDC/NHS) in 60% ethanol. The effect of various gelatin concentrations, oleic acid-gelatin molar ratio and reaction time on the substitution of GOC was evaluated. Fourier transform infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance (H NMR) revealed the successful synthesis of GOC. The ratio of oleic acid-reacted amino groups within gelatin was above 50% as quantified using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) method. Based on the physicochemical changes of GOC upon the modification of various synthesis factors, the optimized process for the GOC synthesis was well established. Self-assembled gelatin-oleic acid nanoparticles (GON) were fabricated simply by the desolvation method using dialysis membrane, without adding a cross-linker. GON was formed at a lower critical micelle concentration (CMC) in water, 0.3 mg/mL. GON has a homogenous size of 100-300 nm, which was showed in the electrophoretic light scattering (ELS) results, scanning electron microscope (SEM) and transmission electron microscope (TEM) images. The zeta potential of GON indicated a slightly negative surface charge (-6 mV). The GON showed no toxicity in human embryonic kidney cells (HEK 293) and significantly improved coumarin loading in adenocarcinomic human alveolar basal epithelial cells (A549). The current GOC and GON could provide versatile strategies to deliver cargo into the body by acting as a safe and biocompatible nanoparticulate carrier. [ABSTRACT FROM AUTHOR]

Cancer cells in the tumor microenvironment are affected by fluid shear stress generated by blood flow in the vascular microenvironment and interstitial flows in the tumor microenvironment. Thus, we investigated how fluidic shear stress affects cellular uptake as well as the endocytosis mechanism of nanoparticles using a biomimetic microfluidic system that mimics the human dynamic environment. Positively charged amino-modified polystyrene nanoparticles (PSNs) at 100 μg/mL were delivered to cancer cells under static and biomimetic dynamic conditions (0.5 dyne/cm). Additionally, the experiment was done in the presence of endocytosis inhibitors specific for one of the endocytosis pathways. To evaluate cellular uptake of cationic PSNs, the fluorescence intensity of cationic PSNs in cancer cells was measured by flow cytometer and fluorescence images were taken using confocal laser scanning microscopy. Cancer cells in dynamic conditions exhibited higher cellular uptake of PSNs and showed different cellular uptake mechanisms compared with those in static conditions. From these results, it suggested that biomimetic dynamic conditions stimulated specific endocytosis and prompted cellular uptake. It was also important to consider fluidic shear stress as one of the critical factors because cellular uptake and drug delivery could play a key role in cancer cells and metastasis. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the gastrointestinal mucosa irritation of three platycodin formulations. Platycodin-loaded core pellets were prepared via extrusion-spheronization method and coated with Eudragit L100-55 (L100) or Eudragit S100 (S100) for pH-dependent release. The release of platycodin D from coated pellets exhibited pH dependent release profiles. The pharmacokinetic study in rats showed that T of the coated pellets were prolonged as compared to that of un-coated pellets. The S100-coated pellets possess a lower C and decreased AUC as compared to the L100-coated and uncoated pellets. Hematoxylin-eosin staining and nuclear factor Kappa B (NF-κB) measurement were carried out to observe the gastrointestinal mucosa irritations. The results revealed that the irritations of platycodin on the upper gastrointestinal mucosa are dose-dependent. However, no obvious irritation effect on the gastrointestinal tissues of rats was detected after oral administration of the coated pellets. In addition, the amount of NF-κB in the stomach of rats treated with the uncoated pellets was about fivefold higher as compared to that of the coated pellets. In summary, the L100-coated platycodin pellets exhibited higher oral bioavailability and less gastrointestinal mucosa irritations as compared to the other two formulations. [ABSTRACT FROM AUTHOR]

Clarithromycin (CAM) is known to be poorly water-soluble and acid-labile drug. Various alkalizers such as MgO, NaCO, NaHPO and NaHCO were utilized to modulate the microenvironmental pH (pH) and to improve the low stability and solubility of CAM in a crystalline-solid dispersion system (CSD). Polyvinylpyrrolidone (PVP K-30) and hydroxypropylmethylcellulose (HPMC) 4000-based CSDs containing alkalizers were prepared by cosolvent precipitation followed by evaporation process. The dried-CSDs mixed with microcrystalline cellulose, 2 % croscarmellose sodium, and 1 % magnesium stearate was then directly compressed into tablet. A dissolution test was carried out in 900 mL of pH 5.0 buffer solutions at 37 °C with a 50 rpm paddle speed. pH, surface morphology, and structural behaviors were investigated. The dissolution rates of CAM in CSD containing alkalizers were improved. The drug in CSD remained crystalline as observed by differential scanning calorimetry and powder X-ray diffraction. Scanning electron microscopy revealed nearly identical images regardless of the sorts and amounts of carriers. PVP-based CSD tablet without alkalizer showed greater drug release, while HPMC-based CSD tablet without alkalizer retarded drug release due to its greater swelling capability. However, when the alkalizers were added in CSD tablet, the drug release was sharply increased. NaHCO induced the most rapid drug release while MgO retarded drug dissolution. Alkalizers in CSD also could maintain the pH of the tablet above pH 5 under acidic conditions. The use of pH modifiers in CSDs could provide a useful method to improve the dissolution rate and stability of CAM via modulation of pH without changing drug crystallinity. [ABSTRACT FROM AUTHOR]

A polyelectrolyte block copolymer, poly(aspartic acid-graft-imidazole)-block-poly(ethylene glycol) (P(Asp-g-Im)-PEG), with several advantages such as an easy synthesis, having a high molecular weight and the buffer capacity of a zwitterionic polymer backbone compared to poly(histidine) backbones, was presently investigated to evaluate its feasibility as a pH sensitive anticancer nanomedicine. Doxorubicin (DOX) loaded P(Asp-g-Im)-PEG micelles (DPHAIM) were prepared by the bottom flask and diafiltration methods, forming stable pH sensitive nano-systems. DPHAIM with a 28% loading capacity displayed a pH dependent behavior with respect to drug release and cytotoxicity. At pH values below 7.0, the cumulative DOX release and cell cytotoxicity were increased compared to those at physiological pH. Animal imaging after intravenous administration of the micelles revealed their accumulation by passive targeting to tumor tissue compared to other normal tissues. This pH sensitive nanovehicle based on P(Asp-g-Im)-PEG is implicated as a promising anticancer nanomedicine with less toxicity on normal tissues for effective tumor treatment. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to develop hydroxypropylmethylcellulose (HPMC)-based sustained release (SR) tablets for tolterodine tartrate with a low drug release variation. Methods: The SR tablets were prepared by formulating a combination of different grades of HPMC as the gelling agents. The comparative dissolution study for the HPMC-based SR tablet as a test and Detrusitol® SR capsule as a reference was carried out, and the bioequivalence study of the two products was also conducted in human volunteers. Results: The amount of HPMC, the grade of HPMC and the combination ratio of different grades of HPMC had remarkable effects on drug release from the SR tablets. Both the test and reference products had no significant difference in terms of comparative dissolution patterns in four different media ( f2 > 50). Furthermore, the dissolution method and rotation speed showed no effects on the drug release from the two products. The 90% confidence intervals of the AUC0-36 and Cmax ratios for the test and reference products were within the acceptable bioequivalence intervals of log0.8-log1.25. Conclusions: A HPMC-based SR tablet for tolterodine tartrate with a low release variation was successfully developed, which was bioequivalent to Detrusitol® SR capsule. [ABSTRACT FROM AUTHOR]

For the past few decades biomedical engineering has imprinted its significant impact on the map of science through its wide applications on many other fields. An important example obviously proving this fact is the versatile application of magnetic nanoparticles in theranostics. Due to preferable properties such as biocompatibility, non-toxicity compared to other metal derivations, iron oxide-based magnetic nanoparticles was chosen to be addressed in this review. Aim of this review is to give the readers a whole working window of these magnetic nanoparticles in the current context of science. Thus, preparation of magnetic iron oxide nanoparticles with the so-far techniques, methods of characterizing the nanoparticles as well as their most recent biomedical applications will be stated. [ABSTRACT FROM AUTHOR]

Biocompatible polymers have been of considerable interest in developing drug delivery systems (DDSs). However, physicochemical characterizations of the polymers and DDSs had been limited because of the difficulty in obtaining the same synthesized copolymers and achieving a similar drug loading ability with the differing properties of the drugs. Therefore, a correlational study of the relationships between copolymers and DDSs was required to estimate the properties of the DDSs and to develop optimal systems of delivery depending on the drug. In this study, we presented several relationship correlation equations of physicochemical properties and copolymers according to their molecular weights (MWs) using amphiphilic block copolymers composed of poly( L-lactide)- block-methoxy-poly(ethylene glycol) (PLA- b-mPEG). The PLA- b-mPEG was characterized by nuclear magnetic resonance and gel permeation chromatography, and the critical micelle concentration (CMC), sizes, and drug loading capacity (DLC) of the self-assembling micelles from the copolymers with different MWs were all measured. The increase in MW of the PLA led to a decrease in CMC and DLC with an increase of the particle sizes. The relationship between the MW of the PLA and the physicochemical properties of the micelles demonstrated a good correlation, which provides excellent information for the use in the development of tailor-made DDSs based on copolymers pursuing optimal particle size, DLC, CMC, and so on. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

For the quality evaluation of raw materials, the influence of various types of solvents on the polymorphic crystallization behaviors and dissolution rates of two sources of valsartan (VAL) from China and India was investigated. Samples were prepared by recrystallization from water or organic solvents, such as acetonitrile, acetone and ethanol, using methods with and without heating. Recrystallization behaviors were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Scanning electron microscopy (SEM) was also used to observe the morphology of samples. The dissolution rate of recrystallized samples in water was evaluated and compared to the original VAL sample. There were significant differences in morphology, crystal structure and dissolution rate among the samples recrystallized using organic solvents. VAL was transformed into another polymorphic form by the solvents and recrystallization conditions. These physical properties of VAL also differed between the two sources of VAL. Thus, the physicochemical differences of raw materials should be carefully considered in early dosage formulation approaches. [ABSTRACT FROM AUTHOR]

Background: Drug release from a solid form of self-emulsifying drug delivery system (SEDDS) has greatly been limited due to strong adsorption and physical interaction with carriers. To facilitate drug release process in the stomach, an acid-soluble powderizing carrier, Fujicalin® was evaluated together with different disintegrants and hydrophilic lubricants. Method: Immediate-release self-emulsifying tablets (IR-SETs) of ibuprofen (IBU) was prepared with solidified SEDDS of IBU, various disintegrants, and lubricants, and drug release was evaluated to develop IR-SET that can release IBU with a similar IBU release rate to that obtained with liquid SEDDS. Results: The liquid SEDDS consisted of Capryol 90, Cremophor EL, Labrasol, and IBU at a ratio of 3:4:3:3, and was solidified with various adsorbents. The powderized SEDDS was tabletted by a direct compression. Fujicalin®-based SEDDS tablets demonstrated remarkably higher dissolution rate of IBU compared with Neusilin® and Neosyl®-based SEDDS tablets. The IR-SET formula of IBU prepared with Fujicalin® as an adsorbent, Polyplasdone® as a disintegrant, and sodium bicarbonate as a co-disintegrant showed over 90% of initially loaded dose of IBU released within 5 min in a stimulated gastric juice (pH 1.2), exhibiting almost equivalent rate of IBU release to that shown by liquid SEDDS. The particle size analysis revealed no significant differences in droplet sizes of the microemulsions formed from liquid (116 nm) and IR-SET (110 nm). Conclusion: The novel IR-SET can be promising as a fast-releasing SEDDS tablet of IBU for fast onset of action. [ABSTRACT FROM AUTHOR]

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system. [ABSTRACT FROM AUTHOR]

The roles of magnesium oxide (MgO) release from solid dispersions (SDs) in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and water were investigated to elucidate the enhanced dissolution and reduced intestinal damages of telmisartan as a model drug. The polyethylene glycol 6000 (PEG 6000) was used to prepare the SDs. Three SDs were prepared: SD1 (PEG, MgO, TEL), SD2 (PEG 6000, TEL), SD3 (MgO, TEL). The physical mixture (PM) consisting of SD2 and MgO was also prepared. A binary SD without MgO (SD2) was also prepared for comparison in microenvironmental pH (pH) modulation. The faster MgO released, the less control of pH and the less enhanced dissolution of TEL were in consequences. SD3 increased dissolution in SIF and water (about 67%). Interestingly, ternary SD1 showed almost complete dissolution in all three media but dissolution of PM was the lowest due to the fast release of MgO and poor modulation of pH. MgO did not change the drug crystallinity but did have a strong molecular interaction with the drug. Additionally, the SD3-bearing tablet quickly increased pH but then gradually decreased due to faster release of MgO while the SD1-bearing tablet gradually increased pH at all fractional dimensions of the tablet by the MgO slowly released. The pH of PM-bearing tablets was not varied as a function of time. Thus, the MgO-bearing SD1 also minimized gastrointestinal tissue damage caused by the model drug. [ABSTRACT FROM AUTHOR]

The aim was to design a pH-sensitive pulsatile drug delivery system that allows for an on-off pulsed release of a drug using polyacrylic acid (PAA) blended with ethyl cellulose (EC) in different ratios. PAA, a polyelectrolyte polymer, exhibits a highly coiled conformation at low pH but a highly extended structure at high pH. Fumaric acid, which is an internal acidifying agent, was incorporated into the hydroxypropyl methylcellulose-based core tablets to create an acidic microenvironmental pH (pH). The concentration of fumaric acid inside the core tablet and the ratio of PAA/EC in the coating layer were very crucial in modulating drug release behaviors. When the fumaric acid was retained in the core tablet, it gave a more acidic pH, so that the PAA was kept in a highly coiled state in the coated film, which hindered drug release ('off' release pattern). Interestingly, the release profiles of the drug and fumaric acid from coated tablets showed the on-off pulsed pattern upon dissolution. Imaging analyses using scanning electron microscopy, near-infrared imaging, confocal laser scanning microscopy, and Fourier transform infrared spectroscopy confirmed this on-off release behavior of the drug and fumaric acid from coated tablets. [ABSTRACT FROM AUTHOR]

Polymeric coating materials have been widely used to modify release rate of drug. We compared physical properties and release-controlling efficiency of polymeric coating materials using matrix-type casted film and diffusion-controlled coated tablet. Hydroxypropylmethyl cellulose (HPMC) with low or high viscosity grade, ethylcellulose (EC) and Eudragit® RS100 as pH-independent polymers and Eudragit S100 for enteric coatings were chosen to prepare the casted film and coated tablet. Tensile strength and contact angle of matrix-type casted film were invariably in the decreasing order: EC> Eudragit S100> HPMC 100000> Eudragit RS100>HPMC 4000. There was a strong linear correlation between tensile strength and contact angle of the casted films. In contrast, weight loss (film solubility) of the matrix-type casted films in three release media (gastric, intestinal fluid and water) was invariably in the increasing order: EC < HPMC 100000 < Eudragit RS100 < HPMC 4000 with an exception of Eudragit S100. The order of release rate of matrix-type casted films was EC > HPMC 100000 > Eudragit RS100 > HPMC 4000 > Eudragit S100. Interestingly, diffusion-controlled coated tablet also followed this rank order except Eudragit S100 although release profiles and lag time were highly dependent on the coating levels and type of polymeric coating materials. EC and Eudragit RS100 produced sustained release while HPMC and Eudragit S100 produced pulsed release. No molecular interactions occurred between drug and coating materials using 1H-NMR analysis. The current information on release-controlling power of five different coating materials as matrix carrier or diffusion-controlled film could be applicable in designing oral sustained drug delivery. [ABSTRACT FROM AUTHOR]

The primary objective of the study was to validate a simple and sensitive method of determining valsartan concentration in human plasma samples using high performance liquid chromatography (HPLC) combined with ultraviolet (UV) detection. Methanol appeared to be the best with a high recovery efficiency compared to other solvents such as acetonitrile, ethylacetate and methyl-tert-butyl ether. After a simple protein precipitation using methanol, the analytes were separated on a Phenomenex® Luna C18 column using 42% acetonitrile with 15 mM potassium dihydrogenphosphate in water (pH 2.0; adjusted with phosphoric acid) as the mobile phase at a flow rate of 1.2 mL/min. The standard calibration curve constructed in the concentration range of 50–2000 ng/mL showed good linearity (r2 >0.9997). Spironolactone was used as an internal standard (IS). Valsartan and IS eluted at 10.25 and 12.17 min, respectively. The intra-day and inter-day precision and accuracy were satisfactory with relative standard deviations of less than 15%. No interference peaks or matrix effects were observed in human plasma. Valsartan concentration in human plasma was well established following a single 80 mg oral dose (Diovan® capsule) to eight healthy volunteers. The current determination of valsartan concentration by protein precipitation using methanol followed by analysis using HPLC with UV detection was rapid and sensitive, and provide an alternative to the analysis of valsartan by studying its clinical applications. [ABSTRACT FROM AUTHOR]

A reliable method to assess in vitro metabolic stability of rabeprazole and its modulation by Generally Recognized As Safe (GRAS)-listed pharmaceutical excipients was established in human liver microsomes. The metabolic stability of rabeprazole decreased as a function of incubation time, resulting in the formation of thioether rabeprazole via nonenzymatic degradation and enzymatic metabolism. Buffer type was also a determining factor for the degree of both nonenzymatic degradation and enzymatic metabolism. The net extent of enzymatic drug metabolism, obtained by calculating the difference in drug degradation between a microsome-present reaction system and a microsome-free solution, was about 9.20 ± 0.67% in phosphate buffer and 2.27 ± 1.76% in Tris buffer, respectively. Rabeprazole exhibited first-order kinetics in microsome-free solution but showed non-linear kinetics in the microsome-present reaction system. The maximal velocity, Vmax, in phosphate buffer was 5.07 μg mL−1 h−1 and the Michaelis-Menten constant, Km, was 10.39 μg mL−1 by computer-fitting to the classical Michaelis-Menten equation for pattern of time-dependent change in the substrate concentration. The intact drug and its thioether form were well resolved and successfully identified by HPLC chromatography and liquid chromatography mass spectroscopy (LC/MS). The metabolic stability of rabeprazole was also modulated by the presence of pharmaceutical excipients. Among the five pharmaceutical excipients tested, poloxamer 188 and Gelucire 44/14 had potentially inhibitory effects on rabeprazole metabolism in human liver microsomes (p < 0.05). A greater understanding of metabolic stability and its modulation by pharmaceutical excipients would be useful for optimizing the bioavailability of rabeprazole at the early formulation stages. [ABSTRACT FROM AUTHOR]

This study was performed in order to validate an effective high performance liquid chromatograpy (HPLC) method to determine L-carnitine in biological samples such as plasma, milk and muscle in cows. An L-carnitine derivative for fluorescence absorption was synthesized with 1-aminoanthracene (16 mg/mL in acetone) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC; 160 mg/mL in 0.01 M NaH2PO4 buffer) as a precolumn fluorescent derivative reagent. γ-Butyrobetaine HCI was used as an internal standard. A reversed-phase column with fluorescence detection at the excitation and emission wavelengths of 248 and 418 nm were used. The mobile phase consisted of 30% acetonitrile with 0.1 M ammonium acetate in water (pH 3.5) adjusted with acetic acid and delivered at a flow rate of 1.5 mL/ min. The L-carnitine concentration in plasma, milk and muscle samples of cows after oral feeding with 24 g L-carnitine/day for 2 months was then determined. All biological samples were deproteinated by barium hydroxide and zinc sulfate heptahydrate before the derivative reaction. Blank cow plasma was dialyzed using cellulose membrane for standard calibration. The calibration curve showed good linearity (r2 >0.999) over the concentration range of 50 to 5000 ng/mL The precision and accuracy were also satisfactory with less than 15% intra- and inter-day coefficiency of variations. The peaks of L-carnitine and internal standard in HPLC chromatography were successfully separated in plasma, milk and muscle samples of cows. The current derivatization method of L-carnitine for fluorescence detection was simple and adequately sensitive and could be applied to determine L-carnitine in biological samples. [ABSTRACT FROM AUTHOR]

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 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]

A drug-containing polymeric dispersion was applied onto nonpareil sugar spheres (18/20 mesh) using a fluid-bed spray coater. Eudragit® RS30D was selected as the polymeric coating material. Melatonin secreted by the pineal gland in a circadian rhythm was used as a model drug. The release behaviors of the coated sugar spheres were investigated in gastric fluid (pH 1.4) for 2 h, and then continuously in intestinal fluid (pH 7.4) for 14 h. The release rate of the coated sugar spheres decreased with increasing coating levels. The solvent (ethanol) in the coating dispersions significantly decreased the release of the drug due to the good dispersion of the low solubility melatonin in the polymeric films. The polymer (polyvinylpyrrolidone, PVP) and drug contents in the coating dispersions did not affect the release rate. Most of all, the release profiles were drastically changed according to the type and concentration of plasticizers used. The current coating methods that use drug-containing polymeric dispersions could be useful for simultaneous drug loadings and their modified release. The solubilization and controlled release of poorly water-soluble drugs can be achieved as both the solubilizers and drugs are present in the drug-containing polymeric dispersions. [ABSTRACT FROM AUTHOR]

The objective of this study was to formulate itraconazole semisolid dosage forms and characterize their physicochemical properties. Itraconazole and excipients such as polysorbate 80, fatty acids, fatty alcohols, oils and organic acids were melted at 160°C. The fused solution was then cooled immediately at-10°C to make wax-like semisolid preparations. Their physicochemical attributes were first characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectrometry. The solubility of itraconazole in semisolid preparations and their dispersability in the simulated gastric fluid were also determined. Our semisolid preparations did not show any distinct endothermic peak of a crystalline form of itraconazole around 160–163°C. This suggested that it was changed into amorphous one, when it was formulated into semisolid preparations. In addition, the distinctive functional peaks and chemical shifts of itraconazole were well retained after processing into semisolid preparations. It could be inferred from the data that itraconazole was stable during incorporation into semisolid preparations by the hot melt technique. In particular, itraconazole semisolid preparations composed of polysorbate 80, fatty acids and organic acids showed good solubility and dissolution when dispersed in an aqueous medium. It was anticipated that the semisolid dosage forms would be industrially applicable to improving the bioavailability of poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]