Low-Intensity Statin Plus Ezetimibe Versus Moderate-Intensity Statin for Primary Prevention: A Population-Based Retrospective Cohort Study in Asian Population.

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.

Determination of Leuprolide-Fatty Acid Conjugate in Rat Plasma Using LC-MS/MS and Its Pharmacokinetics after Subcutaneous Administration in Rats.

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.

Preparation of celecoxib tablet by hot melt extrusion technology and application of process analysis technology to discriminate solubilization effect.

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.

Development of film-forming gel containing nanoparticles for transdermal drug delivery.

Despite several studies on film-forming systems with the advantages of both the film and the hydrogel, there are still no effective systems for fast film formation with a high level of control over permeability. In this study, a film-forming system for the delivery of nanomedicine, termed a film-forming nanogel (FFN), was produced and investigated for the first time to meet this need. The objective of this research was to study a new generation of film-forming hydrogels (FFHs) loaded with curcumin nanoparticles (CUR-GNPs) for transdermal applications. FFHs were prepared by employing zein and HPMC 4000 as film-forming polymers. Meanwhile, CUR-GNPs were obtained by sonoprecipitation. The film-forming time, particle characteristics and FFN drug release profile were assessed. The optimized FFH had a smooth surface and a fast drying time of 6 min and 4.5 min in vitro and ex vivo, respectively. Additionally, high, sustained drug permeation from the FFN was observed after 24 h. The FFH containing CUR-GNPs showed potential for application in transdermal drug delivery with a fast film-forming time, uniform particle dispersion and high, sustained drug permeation.

Enzymatic Weight Update Algorithm for DNA-Based Molecular Learning.

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.

Preparation of Sustained Release Tablet with Minimized Usage of Glyceryl Behenate Using Post-Heating Method.

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.

Process Analytical Quality Control of Tailored Drug Release Formulation Prepared via Hot-Melt Extrusion Technology.

The objective of the present study was to compare the influence of Eudragit® RS PO and RL PO blends on the release of water-soluble and insoluble drugs from hot-melt extruded formulations. In addition, we aimed to evaluate drug content uniformity and distribution by Fourier transform-infrared (FT-IR) chemical imaging. Theophylline (TP) and carbamazepine (CBZ) were selected as the water-soluble and insoluble model drugs, respectively. Eudragit® RS PO and RL PO were selected as the polymeric matrices. FT-IR chemical imaging clearly demonstrated the content uniformity and distribution for both drugs in the extrudates, which was confirmed by HPLC. Increasing the ratio of Eudragit® RL PO led to an increase in the in vitro drug release, whereas an increase in the ratio of Eudragit® RS PO sustained the drug release for up to 12 h. The hot-melt extrusion of TP and CBZ with varying ratios of Eudragit® RS PO and RL PO can be employed to tailor the drug release profiles. In this study, we demonstrated, for the first time, the use of FT-IR chemical imaging as a process analytical technique to determine the drug content uniformity and distribution. Our data correlated well with the results of HPLC analysis in the study of tailored drug release from the prepared hot-melt extruded formulation.

Novel pH-Responsive Structural Rearrangement of Myristic Acid-Conjugated Quetiapine Nanosuspension for Enhanced Long-Acting Delivery Performance.

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.

Self-assembled nanonization of fatty acid-conjugated vaccine antigen for enhanced thermal stability.

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.

Effects of Postprandial Factors and Second Meal Intake Time on Bioequivalence Investigation of Tadalafil-Loaded Orodispersible Films in Human Volunteers.

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.

Nanonization and Deformable Behavior of Fattigated Peptide Drug in Mucoadhesive Buccal Films.

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.

A formulation approach for development of HPMC-based sustained release tablets for tolterodine tartrate with a low release variation.

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 AUC(0-36) and C(max) 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.

Clinical outcomes and predictors of a gap in direct-acting oral anticoagulant therapy in the elderly: A time-varying analysis of a nationwide cohort study.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS AND CONCLUSIONS: 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.

Mucoadhesive buccal tablet of leuprolide and its fatty acid conjugate: Design, in vitro evaluation and formulation strategies.

This study aimed to design mucoadhesive buccal tablets of leuprolide (LEU) and to manufacture and evaluate the properties of buccal tablets containing LEU-oleic acid conjugate (LOC) and self-assembled LEU-oleic acid nanoparticles (LON), which were developed in a previous study. Hydroxypropyl methylcellulose (HPMC 4000) was used as the mucoadhesive polymer, and tablets were prepared by direct compression. The formulations were characterized by weight, content uniformity, thickness, hardness, swelling index, disintegration time, mucoadhesion time, and drug release. The chosen formulation maintained an adhesion time of up to 6.43 h and a disintegration time of 4.10 h. Drug stability in the mucoadhesive tablets was confirmed after 2 h of storage in human mimic saliva (Phosphate buffer solution pH 6.8). Furthermore, the designed LEU formulation and the LOC and LON developed in a previous study were prepared as buccal tablets and compared. In the dissolution and permeation studies, LON-loaded buccal tablets showed the highest permeation rate. This study suggests that mucoadhesive buccal tablets containing self-assembled LON may effectively increase the medication adherence for pediatric and geriatric patients by improving the bioavailability and permeation rate of LEU.

Investigation of Cannabinoid Acid/Cyclodextrin Inclusion Complex for Improving Physicochemical and Biological Performance.

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), ß-cyclodextrin (ß-CD), γ-cyclodextrin (γ-CD), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and methylated-ß-cyclodextrin (M-ß-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-ß-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-ß-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-ß-CD inclusion complex was maintained for 7 days in a simulated physiological condition. Furthermore, the minimum inhibitory concentration of cannabinoid acid/M-ß-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.

Dual thermal stabilizing effects of xanthan gums via glycosylation and hydrogen bonding and in vivo human bioavailability of desmopressin in orodispersible film.

Desmopressin acetate (DDAVP), a nonapeptide drug, is easily destroyed by heat in the manufacturing process of orodispersible film (ODF). A new challenging study was conducted to improve thermal stability through glycosylation and hydrogen bonding using carbohydrate gums (agar, arabic gum, carrageenan, xanthan gum) using the solvent casting method. Among gum types, xanthan gum strongly showed dual stabilizing effects of DDAVP via covalent glycosylation and hydrogen bonding, minimizing total impurities and optimizing physicochemical properties of ODF under accelerated conditions for six months. The optimized ODF formulation (O-DDAVP ODF) at a DDAVP and xanthan gum ratio of 1:1.5 had a pharmaceutically equivalent dissolution profile as compared with a commercial 0.2 mg commercial Minirin® tablet in four different media: pH 1.2, pH 4.0, and pH 6.8 buffers and deionized water. Furthermore, O-DDAVP ODF showed in vivo bioequivalence to Minirin® tablets in healthy human volunteers. Glycosylation-oriented stabilization of peptide drug using pharmaceutically active excipients against thermal denaturation could be challenged to design patient-friendly ODF.

Roles of Fatty Acid Chain Length and Enzyme-Oriented Drug Controlled Release from pH-Triggering Self-Assembled Fatty Acid Conjugated Quetiapine Nanosuspensions.

Background: Quetiapine (QTP) is a first-line antipsychotic drug, but its therapeutic druggability and patient adherence were limited due to high oral dose strength, low bioavailability and physicochemical/biopharmaceutical issues. Purpose: To investigate the roles of fatty acid chain length and enzyme-oriented QTP controlled release from pH-triggering self-assembled fatty acid conjugated QTP nanosuspensions (NSPs). Methods: QTP was conjugated with different chain length fatty acids (C10-decanoic acid, C14-myristic acid, C18-stearic acid) to obtain QTP-fatty acid conjugates (QFCs: QD, QM, QS) by exploiting 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/4-dimethylaminopyridine (EDC/DMAP) conjugation chemistry. Then, the solubility, partitioning coefficient (log P), cell viability and cleavage kinetics of QFCs were evaluated. The pH-triggering self-assembled behaviors of QFCs to form QTP-fatty acid NSPs (QDN, QMN, QSN) by varying pH, QFC concentration and proton-to-QTP ratios were characterized. The morphological images, critical micelle concentration (CMC), physicochemical properties and enzyme-oriented QTP controlled release of NSPs were examined. Results: Three QFCs were synthesized with different chain length fatty acids from QTP after desalting fumarate from QTP fumarate. The pH, QFC concentration and proton-to-quetiapine molar ratio could influence physicochemical properties and nanonization behaviors of QFCs. All three QFCs showed no effect on the viability of myoblast cells. The pH-triggering self-assembly of amphiphilic QFCs to form nanoparticles (NPs) occurred as the amine moiety of QTP was readily ionized in a strongly acidic environment (pH 1.2). Interestingly, the longer the fatty acid chain length, the lower water solubility, the higher log P (lipophilicity) and the smaller NP particle size were observed. The conversion rate of QFCs to liberate QTP by esterase in human plasma and liver S9 fractions was also inversely proportional to the fatty acid carbon chain length. Interestingly, the freeze-dried QMN showed the esterase-oriented controlled release of QTP over one month, unlike the initial burst release of QDN or the slowly delayed release pattern of QSN. Conclusion: A new pH-triggering self-assembled nanonization platform was developed using different chain length fatty acid conjugated QTP in low pH environment. By varying fatty acid chain length, the enzyme-oriented QTP controlled release dosage form was challenged to enhance the therapeutic effectiveness of QTP.

Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity.

Background: Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity. Purpose: To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs). Methods: LEU-fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3. Results: Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days. Conclusion: The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.

Cellular Efficacy of Fattigated Nanoparticles and Real-Time ROS Occurrence Using Microfluidic Hepatocarcinoma Chip System: Effect of Anticancer Drug Solubility and Shear Stress.

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.

Polyelectrolyte-based solid dispersions for enhanced dissolution and pH-Independent controlled release of sildenafil citrate.

The aim of this study was to design a novel matrix tablet with enhanced dissolution and pH-independent controlled release of sildenafil citrate (SIL), a drug with pH-dependent solubility, by using solid dispersions (SDs) and polyelectrostatic interactions. SIL-loaded SDs were prepared using various polymeric carriers such as poloxamer 188, poloxamer 407, Soluplus®, polyvinylpyrrolidone (PVP) K 12, and PVP K 17 by the solvent evaporation method. Among these polymers, Soluplus® was found to be the most effective in SDs for enhancing the drug dissolution over 6 h in pH 6.8 intestinal fluid. SIL was well dispersed in Soluplus®-based SDs in an amorphous form. When the Soluplus®-based SDs were added in the tablet containing positively charged chitosan and negatively charged Eudragit® L100, the drug release rate was further modulated in a controlled manner. The charge density of the tablet was higher at pH 6.8 than at pH 1.2 due to the polyelectrostatic interaction between chitosan and Eudragit® L100. This interaction could provide a pH-independent controlled release of SIL. Our study demonstrates that a combinatory approach of Soluplus®-based SDs and polyelectrostatic interactions can improve the dissolution and pH-independent release performance of SIL. This approach could be a promising pharmaceutical strategy to design a matrix tablet of poorly water-soluble drugs for the enhanced bioavailability.