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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.

Background: Hot-melt extrusion (HME) significantly affects pharmaceutical manufacturing by enhancing drug solubility and bioavailability. Advancements in HME technology to produce FDA-approved drugs have highlighted its reliability and innovative potential in the pharmaceutical industry. Optimization of the processing parameters of HME-based drug products is aligned with the importance of high-quality drug production through an advanced manufacturing system. Area covered: This review covers the advancements in HME technology, focusing on pharmaceutical quality aspects and addressing unmet patient needs. Additionally, this review addresses the benefits of continuous manufacturing advancements for drug product quality and the importance of process analytical technology (PAT) tools. These tools are essential for monitoring product quality and consistency, maintaining the traceability of raw materials, and ensuring quality control during continuous pharmaceutical manufacturing. Expert opinion: The ongoing evolution of HME technology is a significant step towards creating more efficient and patient-focused drug products. Advances in processing parameters and PAT tools not only improve the quality and effectiveness of HME-based drug products but also satisfy unmet patient needs. The future of HME technology appears promising, with the potential to further refine drug delivery mechanisms and address both current and future unmet needs in pharmaceutical care.

Background: The inherent poor druggability of numerous active pharmaceutical ingredients (APIs) necessitate the modification of their physicochemical and biopharmaceutical properties to enhance their bioavailability and therapeutic effectiveness. Fatty acid conjugation, termed fattigation technology by our research group, represents a versatile pharmaceutical platform in drug delivery by chemically binding of carboxyl group of fatty acids and hydroxy or amine group of target molecules, resulting in modifying the physicochemical and biopharmaceutical properties of APIs or target molecules and creating diverse self-assembled amphiphilic structures. These fattigated structures offer several advantageous features, including 1) improved solubility of many poorly water-soluble drugs via nanonization process, 2) enhanced the membrane permeability, 3) induced enzyme-oriented degradation for controlled release of peptides/drugs, 3) enabled long-acting drug performance, and 4) enhanced anti-tumor activity by receptor-mediated drug delivery. Area covered: This review covers recent advances and relevant researches on fattigation technology, encompassing various aspects of fatty acid conjugation, including design principles involving different types of fatty acids and conjugation strategies, and their applications in the pharmaceutical fields. Expert opinion: We address the pharmaceutical challenges associated with fattigation technology. Particularly, we focus on the choice and substitution content of fatty acids in conjugates for self-assembly and nanonization to achieve desirable physicochemical and biopharmaceutical characteristics, such as solubility, permeability, release rate, controlled-cytotoxicity, bioavailability, targetability and therapeutic effectiveness. Additionally, we offer insights into the future prospects of this fattigation technology by introducing the application of noninvasive delivery of fattigated peptide/protein drugs and the potential delivery of fatty acids for synergistic biological activities to boost therapeutic outcomes.

Background: Hydrophilic Hydroxypropyl Methylcellulose (HPMC) matrix tablets arethe standard role model of the oral controlled-release formulation. Nevertheless, the HPMC kineticsfor the mechanistic understanding of drug release and hydrodynamic behaviors are rarely investigated.This study aims to investigate the release behaviors of both HPMC and paracetamol(model drug) from the hydrophilic matrix tablet. Methods: Two different viscosity grades of HPMC were used (Low viscosity: 6 cps, High viscosity:4,000 cps). Three different ratios of drug/HPMC (H:38.08%, M:22.85%, and L:15.23% (w/w)of HPMC amounts in total weight) matrix tablets were prepared by wet granulation technique. Therelease profiles of the drug and HPMC in a matrix tablet were quantitatively analyzed by HPLCand 1H-Nuclear Magnetic Resonance (NMR) spectroscopy. The hydrodynamic changes of HPMCwere determined by the gravimetric behaviors such as swelling and erosion rates, gel layer thickness,front movement data,and distributive Near-Infrared (NIR) chemical imaging of HPMC in amatrix tablet during the dissolution process. Results: High viscosity HPMC tablets showed slower release of HPMC than the release rate ofdrug, suggesting that drug release preceded polymer release.Different hydration phenomenon wasqualitatively identified and corresponded to the release profiles. The release behaviors of HPMCand drug in the tablet could be distinguished with the significant difference with fitted dissolutionkinetics model (Low viscosity HPMC 6cps; Korsmeyer-Peppas model, High viscosity HPMC4000cps; Hopfenberg model, Paracetamol; Weibull model) according to the weight of ingredientsand types of HPMC. Conclusion: The determination of HPMC polymer release correlating with drug release, hydrodynamicbehavior, and NIR chemical imaging of HPMC can provide new insights into the drug release-modulating mechanism in the hydrophilic matrix system.

Aspirin has emerged as a promising intervention in cancer in the past decade. However, there are existing controversies regarding the anticancer properties of aspirin as its mechanism of action has not been clearly defined. In addition, the risk of bleeding in the gastrointestinal tract from aspirin is another consideration that requires medical and pharmaceutical scientists to work together to develop more potent and safe aspirin therapy in cancer. This review presents the most recent studies of aspirin with regard to its role in cancer prevention and treatment demonstrated by highlighted clinical trials, mechanisms of action as well as approaches to develop aspirin therapy best beneficial to cancer patients. Hence, this review provides readers with an overview of aspirin research in cancer that covers not only the unique features of aspirin, which differentiate aspirin from other non-steroidal anti-inflammatory drugs (NSAIDs), but also strategies that can be used in the development of drug delivery systems carrying aspirin for cancer management. These studies convey optimistic messages on the continuing efforts of the scientist on the way of developing an effective therapy for patients with a low response to current cancer treatments.

Solid dispersions offer many advantages for oral drug delivery of poorly water-soluble drugs over other systems, including an increase in drug solubility and drug dissolution. An improvement in drug absorption and the higher bioavailability of active pharmaceutical ingredients in the gastrointestinal tract have been reported in various studies. In certain circumstances, a rapid pharmacological effect is required for patients. Fastdissolving solid dispersions provide an ideal formulation in such cases. This report will provide an overview of current studies on fast-dissolving solid dispersions, including not only solid dispersion powders with fast dissolution rates but also specific dose form for the controlled release of poorly water-soluble drugs. Specifically, the applications of fast-dissolving solid dispersions will be described in every specific case. Moreover, pharmaceutical approaches and the utilization of polymers will be summarized. The classification and analysis of fastdissolving solid dispersions could provide insight into strategies and potential applications in future drug delivery developments.

Extracellular vesicles have an excellent ability to transfer their contents to cells. Extracellular vesicles can also be engineered to deliver therapeutic molecules to target cells. Although a number of studies have exploited synthesized nanoparticles in the treatment of neurological disease in the past few years, extracellular vesicles have been investigated and shown tremendous promise for clinical applications because they are safe and have strong targeting specificity. Different types of extracellular vesicles have been studied and modified for delivering therapeutic factors in neurological disease, including extracellular vesicles loaded with natural therapeutic factors and therapeutic molecules. In this review, we discuss delivery systems using extracellular vesicles containing molecules of interest and then focus on main strategies used for EV loading and surface modification. Discussing these important issues will support and facilitate the design and development of promising techniques and products for neurological therapy.

This study aims to develop mucoadhesive tablets containing solid lipid particles for controlled release pattern through buccal delivery. The buccal tablets containing drug-loaded solid lipid particles (SLPs) were fabricated using the ultrasonication method and lyophilisation with the incorporation of bioadhesive excipients. The role of stearic acid in the lipid phase and the effects of different surfactant contents were thoroughly evaluated. The stearic acid in formulations showed its impacts on particle formation and release characteristics. Although liquid surfactants could create SLPs of nano-size, the dissolution profile resulted in low drug release. The combination of a solid surfactant and a liquid surfactant resulted in better tablet formation and an improvement in the dissolution rate of prednisolone in both immediate release and sustained release. Furthermore, an adaptable pH surface, long mucoadhesion time, and satisfactory permeation resulted in suitable conditions for buccal tablet design without causing any irritations. The success of this work could contribute to a new strategy for improving the bioavailability of poorly water-soluble drugs by buccal delivery.

Background: Recently, several strategies have been proposed for skin cancer therapy by transdermal delivery, and particularly the use of nanotechnology. Methods: This process disrupts the stratum corneum to deliver a drug through the skin, allowing it to accumulate at the tumor site. Results: Nanogels are drug delivery systems that can be applied to many diseases. Nanogel engineering has been widely studied for use in drug delivery, particularly in cancer theranostics. This review summarizes specific strategies for using nanogels to treat skin cancer, a topic that is limited in recent literature. Conclusion: Advanced techniques for effective skin cancer therapy based on the nanogel’s penetration and cellular uptake abilities will be discussed. Moreover, techniques for penetrating the skin, as well as drug release, permeation studies, and microscopic observations, will also be discussed.

Background: An increase in poorly water-soluble drugs makes the design of drug delivery systems challenging. Methods: Currently, a number of prospective solid dispersions have been investigated with potential applications for delivering a variety of poorly water-soluble drugs. A number of traditional solid dispersions and modifiedsolid dispersions offer attractive advantages in the fabrication, design and development of those drugs for effective therapeutics. Results: Although traditional solid dispersions can produce a higher release rate, resulting in higher bioavailability compared to conventional dosage forms, this method is not always a promising approach. Modified-solid dispersion has demonstrated both the ability of its polymers to transform drug crystals into amorphous forms and molecular interactivity, thereby improving drug dissolution rate and bioavailability, especially with tough drugs. However, the classification of modified-solid dispersion, which guides the selection of the right strategy in solid dispersion preparation, remains ill-defined. Conclusion: This review focused on effective strategies in using additives in solid dispersion for improving drug bioavailability.

The combination of gene therapy and chemotherapy has recently received considerable attention for cancer treatment. However, low transfection efficiency and poor endosomal escape of genes from nanocarriers strongly limit the success of the clinical use of small interfering RNA (siRNA). In this study, a novel pH-responsive, surface-modified single-walled carbon nanotube (SWCNT) was designed for the codelivery of doxorubicin (DOX) and survivin siRNA. Polyethylenimine (PEI) was covalently conjugated with betaine, and the resulting PEI–betaine (PB) was further synthesized with the oxidized SWCNT to form SWCNT–PB (SPB), which exhibits an excellent pH-responsive lysosomal escape of siRNA. SPB was modified with the targeting and penetrating peptide BR2 (SPBB), thereby achieving considerably higher uptake of siRNA than SWCNT-PEI (SP) or SPB. Furthermore, SPBB–siRNA presented substantially lower survivin expression and higher apoptotic index than Lipofectamine 2000. DOX and survivin siRNA were adsorbed onto SPB to form DOX–SPBB–siRNA, and siRNA/DOX was released into the cytoplasm and nuclei of adenocarcinomic human alveolar basal epithelial (A549) cells without lysosomal retention. Compared with SPBB–siRNA or DOX–SPBB treatment alone, DOX–SPBB–siRNA significantly reduced tumor volume in A549 cell-bearing nude mice, demonstrating the synergistic effects of DOX and survivin siRNA. Pathological analysis also indicated the potential therapeutic effects of DOX–SPBB–siRNA on tumors without distinct damages to normal tissues. In conclusion, the novel functionalized SWCNT loaded with DOX and survivin siRNA was successfully synthesized, and the nanocomplex exhibited effective antitumor effects both in vitro and in vivo, thereby providing an alternative strategy for the codelivery of antitumor drugs and genes.

The application of single-walled carbon nanotubes (SWCNTs) as drug carriers is limited by their poor dispersal in aqueous medium. This study aimed to prepare chitosan (CS)-modified SWCNTs (CS-SWCNTs) and to evaluate their physicochemical properties and cytotoxicity. Oxidized SWCNTs (O-SWCNTs) were prepared with the use of strong acid, and the effects of acidizing conditions on the oxidation degree of the O-SWCNTs were investigated. CS was then non-covalently modified on the surfaces of O-SWCNTs. O-SWCNTs and CS-SWCNTs were characterized through ultraviolet spectroscopy, Fourier transform-infrared spectroscopy, Raman spectroscopy, and transmission electron microscopy. The cytotoxic effects of the functionalized SWCNTs were determined through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. O-SWCNTs with relatively complete structure were successfully synthesized through 5 h of treatment with 5 M acid. The amine group of the CS and the carboxyl group of O-SWCNTs interacted in CS-SWCNTs. The functionalized SWCNTs did not aggregate or precipitate in water and exerted no cytotoxic effects on A549 and MCF-7 tumor cells. The CS-SWCNTs possess the advantages of a simple preparation process, excellent water dispersibility, and biocompatibility for drug loading.

Sprouted grains, which is a natural polysaccharide, is the subject of increasing scientific interest due to many benefits for human health. The aim of the present work was to develop sprouted rice (SR) as a safe and useful material for application in dissolution enhancement of anticancer poorly water-soluble drugs such as curcumin by solid dispersions (SDs). SDs were prepared with pure SR and modified sprouted rice (MSR) by the melting method. The dissolution rate, drug crystallinity changes, molecular interactions and wettability were characterized and compared between the formulations. The use of MSR could result in a promising system for improving the dissolution rate of poorly water-soluble drugs. MSR could induce a greater amorphous state and improved wettability of drugs for dissolution enhancement compared to SR. Although both SR and MSR showed hydrogen bonding interaction, insignificant differences between SR and MSR were observed. We found that the crystallinity, interactions and wettability of the drug were significantly affected and modulated by MSR.

Background: Ternary solid dispersions have been demonstrated to be an effective strategy in the improvement of drug absorption and bioavailability. Method: The applications of the combination of hydrophilic polymers with the potential of hydrophobic polymer incorporation at moderate concentrations have been discussed in recent publications. Results: In this paper, the general review of this specific type of solid dispersion will be provided with comprehensive understanding of polymer blends of either hydrophilic or hydrophobic polymers. A detailed description of miscible polymers has been developed in recent studies. In addition to dissolution rate improvement, the role of second polymers in crystal growth inhibition and in maintaining the amorphous state will be mentioned. Conclusion: We also present a summary of characterization techniques commonly used to evaluate solid dispersion and polymer miscibility.

The aims of this work were to design pH-independent controlled release (CR) tablet containing nanonizing solid dispersion (SD) adsorbed on hydrophilic silica (Aeroperl®300/30). Valsartan (VAL) was chosen to simultaneously modulate solubility and release rate due to its poor water solubility in low pH condition and short elimination half-life. Based on extensive equilibrium solubility and compatibility studies, poloxamer 407 was selected as a SD carrier. The melted mixtures of drug and poloxamer 407 were adsorbed onto hydrophilic fumed silica (Aeroperl®300/30). Ternary SD system changed crystalline drug into an amorphous state and had intermolecular hydrogen bonding as confirmed by FT-IR with poloxamer 407. The dissolution rate of SD system was markedly enhanced as compared with pure VAL or commercial Diovan®tablet in simulated gastric fluid (pH 1.2). Interestingly, the particle size of SD system was gradually nanonized for 2 hr, ranging from 600 nm to 150 nm during dissolution process. The SD-loaded CR (SD-CR) tablets using hydroxypropylmethylcellulose (HPMC 4000) showed pH-independent zero-order release and good stability at accelerated conditions for six months. The SD-CR tablet showed minimized inter-subject variation of maximum plasma concentration as compared with commercial Diovan®tablets in healthy human volunteers.

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.

New blends of hydroxypropylmethylcellulose (HPMC, 4000 cps) and Gelucire®44/14 (GE) were utilized to modulate the solubility and release rate of poorly water-soluble drug in a controlled manner. HPMC was used as sustained release polymer while GE was blended as a solubilizing carrier. The binary blends of HPMC and GE with proportional ratios (0, 25, 50, 70, 100%) were prepared by three different preparation methods: simple physical mixing, solvent evaporation and hot-melting. The physical properties such as surface morphology, thermal behavior and crystallinity pattern of the binary blends without loading drugs were then characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), respectively. Finally, the ternary solid dispersions (SD) were prepared by dispersing model drugs in a binary blend. Two model drugs, water-soluble acetaminophen (AAP) and poorly water-soluble pranlukast (PLK) were applied to the binary blends. In case of AAP, HPMC retarded release rate but GE had no significant solubilizing effect due to the high AAP solubility, In contrast, the release rate of PLK was efficiently modulated release rate in a controlled manner with an aid of HPMC and GE. Surely, GE could play a key role in enhancing the dissolution rate while HPMC efficiently controlled release rate of drugs without losing drug crystallinity.

The aim of this study was to develop esomeprazole magnesium (EMZ-Mg) enteric-coated pellets and pellet-based tablets, as well as to investigate the effects of pellet size and compression method on acid tolerance, content uniformity, compressibility, and stability of preparations. This study used two types of pellet cores, namely, microcrystalline cellulose (MCC) core with a particle size of 150–300 μm and sucrose core with a particle size of 600–700 μm. Enteric-coated pellets, which consisted of a drug-free core, a drug layer, a sub-coating layer (hydroxypropyl methylcellulose, 6 cps), and an enteric-coating layer (Eudragit®L30D-55), were prepared by using a bottom-spray fluidized bed-coating technique. Pellet-based tablets were prepared by using a direct compression method or a wet granulation method. The acid tolerances of the two types of enteric-coated pellets (MCC and sucrose cores) reached up to 98% in simulated gastric fluid (pH 1.0) within 2 h, and the dissolution rates in simulated intestinal fluid (pH 6.8) reached up to 85% of the labeled amount within 15 min. When compressed into tablets, the pellets based on MCC core (smaller particle size) displayed a significantly higher acid tolerance (up to 92%) compared with the pellets based on sucrose core (larger particle size). In addition, the MCC core-based tablets (F8), especially those prepared by using a granulation method, showed higher drug content uniformity and compressibility than the sucrose core-based tablets (F10), and no lamination phenomenon was observed during compression. The crystallinity of EMZ-Mg was altered during drug layering process, and some physicochemical interactions were observed between the drug and excipients. Moreover, the two types of enteric-coated pellets showed a relatively high stability after storage under high temperature and strong light. However, they showed poor stability under high humidity, resulting in remarkable degradation of active compound. The EMZ-Mg enteric-coated pellets and pellet-based tablets were successfully developed, and reduction in pellet size and wet granulation reduced the differences in content uniformity and better protected the pellet coating from damages during compression.

The aim of this new work was to improve the dissolution rate of poorly water-soluble cilostazol (CLT) by adsorbing dissolved drug molecules onto the surface of undissolved carriers via reprecipitation and deposition process as the solvent (methylene chloride) was evaporated. The adsorption mixtures of CLT with Aerosil 300 and lactose monohydrate provided better drug dissolution rate as compared to mannitol. However, Aerosil-based adsorption powders were unable to be compressed into tablet due to low and unsatisfactory compressibility. The optimized CLT-loaded tablets containing lactose-based adsorption powders displayed almost complete dissolution within 90 min and showed significantly higher dissolution in intestinal fluid (pH 6.8) containing 0.2% sodium lauryl sulfate than the control tablet and the commercial reference product Pletaal®(Otsuka). Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) indicated that the crystalline property of CLT remained in adsorption powders with diminutive peak intensity. Fourier transform infrared spectroscopy (FT-IR) spectra indicated that the intermolecular hydrogen bond was formed between drug molecule and lactose monohydrate. Field-emission scanning electron microscope (Fe-SEM) clearly confirmed that CLT crystals with reduced size around 10 μm were adsorbed and deposited onto the surface of adsorbent material.

Background: The aim of this research was to engineer solid dispersion lipid particles (SDSLs) in which a solid dispersion (SD) was encapsulated to form the core of solid lipid particles (SLs), thereby achieving an efficient enhancement in the dissolution of a poorly water-soluble drug. Methods: Ultrasonication was introduced into the process to obtain micro/nanoscale SLs. The mechanism of dissolution enhancement was investigated by analysing the crystalline structure, molecular interactions, and particle size of the formulations. Results: The drug release from the SD-SLs was significantly greater than that from the SD or SLs alone. This enhancement in drug release was dependent on the preparation method and the drug-topolymer ratio of the SD. With an appropriate amount of polymer in the SD, the solidification method had the potential to alter the drug crystallinity to an amorphous state, resulting in particle uniformity and molecular interactions in the SD-SLs. Conclusions: The proposed system provides a new strategy for enhancing the dissolution rate of poorly water-soluble drugs and further improving their bioavailability.

The combination of immunotherapy and chemotherapy is becoming a very promising cancer treatment method. However, the effective delivery of chemical drug or immune molecule to targeting tissues is a scientific issue to be solved urgently. A novel core–shell structure of single-walled carbon nanohorns (SWCNHs) and pH-sensitive liposome (PSL) was constructed for doxorubicin (DOX) and tumor-associated macrophage (TAM) polarization factor interleukin-21 (IL-21) codelivery in this study. The physicochemical properties, cytotoxicity, cellular uptake, macrophage polarization, and antitumor efficacy of functionalized nanocarriers were fully evaluated. DOX was incorporated into oxidized SWCNHs via π–π interaction (DOX-O-SWCNH) and then coated with IL-21-loaded PSL to obtain IL-21-loaded PSL (IL-21-PSL)-DOX-O-SWCNHs. The release rates of IL-21 and DOX from functionalized nanocarriers at the pH 7.4 of were lower than those at the pH of 5.5, thereby indicating a pH-sensitive drug release. Blank nanocarriers showed relatively low cytotoxicity to A549 cells and 293T cells. The half maximal inhibitory concentration (IC50) value of PSL-DOX-O-SWCNHs for A549 cells was 164.85 μg/mL. The PSL-DOX-O-SWCNHs can be effectively uptaken by A549 cells and the IL-21-PSL-DOX-O-SWCNHs can significantly downregulate the expression of M2 macrophage-related factors (IL-10 levels) and upregulate that of M1 macrophage-related factors (iNOs levels). The IL-21-PSL-DOX-O-SWCNHs also showed significantly high tumor targeting and distribution and significantly low tumor volume of A549 lung cancer cell-bearing nude mice, showing the cooperating effects of DOX and IL-21. The functionalized nanocarriers were mainly distributed in the tumor tissues and liver and less in the spleen, lung, and heart of mice. In conclusion, the functionalized IL-21-PSL-DOX-O-SWCNHs showed high drug loading, excellent cellular uptake, pH-sensitive release, TAM polarization, and remarkable antitumor efficacy in vivo.

The aim of this study was to develop an innovative fixed-dose combination (FDC) containing the sustained release of acetaminophen (AAP) and solubilized ibuprofen (IBF) using double-melt extrusion (DME) technology. The hot-melt extrusion (HME)-based formulation of AAP was screened by seven types of polymers (Polyvinyl alcohol, polyvinylpyrrolidone (Kollidon 30), polyvinyl acetate-polyvinylpyrrolidone mixture (Kollidon SR), hydroxypropyl cellulose (Klucel™ LF, Klucel™ HF), ethylcellulose (Aqualon™ N7, Aqualon™ N100). Poloxamer, polyethyleneglycol (PEG), and (meth)acrylate copolymers (Eudragit E PO, Eudragit E 100) were screened to optimize the IBF composition of the final DME formulations. Based on the transition temperature of the polymers, single-melt extrudates (SME) with AAP and Klucel™ LF were processed into pellets in a core, and the AAP SME pellets were covered with second extrudates of IBF and Eudragit E PO to achieve the final DME formulations. TGA, PXRD, and FT-IR analyses were employed to determine the physicochemical characteristics of the formulations containing APIs. These analyses were to evaluate the potential impact of the HME manufacturing process on the crystalline state of each API and to assess their stability when subjected to the temperatures involved in HME processing. Reference products, raw APIs, physical mixtures, and HME-based formulations were analyzed using a pH-shift dissolution method to compare the drug release behavior. Structural analysis of drug distribution was also performed using confocal laser scanning microscopy (CLSM) with different fluorescent dyes. As the DME extrudates were manufactured in a two-stage process, the green color for coumarin-6 (for AAP) added in the first HME process could easily be distinguished from rhodamine B (for IBF) that was added in the second HME. Furthermore, the dissolution rate of IBF in DME increased 6.7 times compared to the Raw API. Additionally, the AAP in DME formulation constantly released a 65.2% drug for 2 h without any fluctuations or interruptions. Consequently, these findings suggested that different drugs in one dosage form could be combined to achieve sustained release as well as immediate release with solubilizing effects using DME technology.

In this study, apotransferrin (Tf)-stearic acid conjugate was newly synthesized via “fattigation method” to form self-assembled nanoparticles (NPs) containing a hydrophobic model drug, paclitaxel (PAC). Then, physicochemical properties and cellular behaviors such as transferrin receptor-driven targeting and cytotoxic efficiencies were evaluated. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) studies showed that the NPs had spherical shape and smooth surface. The particle size of PAC-loaded NPs was 326.97 ± 2.03 nm with a loading and encapsulation efficiency of 7.94 ± 1.60% (w/w) and 71.10 ± 4.12% (w/w), respectively. In comparison to free PAC, PAC-loaded NPs showed a 7-fold reduction in the LC50 value in breast carcinoma cells (MCF-7), which indicated an increase in cytotoxicity owing to the effective targeting of cells. This observation was confirmed via confocal microscopy images that showed that transferrin receptor blocking inhibited NP uptake. This was further confirmed via flow cytometry data which showed the time-dependent uptake of NPs and their inhibition by transferrin receptor blockage. The results of this study reveal the advantages of NP-based drug delivery systems consisting of Tf as a core of NP for the receptor-driven targeting and subsequent killing of cancer cells.

Drug release from a polymeric nanocarrier is affected by several factors including the sort of composition (drug, polymer, and excipient), the ratio of composition, physical or chemical interaction between components, and manufacturing methods. Depending on the mechanism of drug release from the vehicles, it can be divided into four categories (diffusion, solvent, chemical interaction, and stimulated release). Recently, lipids have attracted great interest as carriers for water-insoluble drug delivery. Lipid-based drug-delivery systems have received a lot of interest because of their ability to improve solubility and bioavailability of drugs that are poorly soluble in water. The lipid carrier, formulation strategy, and rational drug-delivery system should be selected appropriately for a lipid-based drug-delivery system to be successful. In this review, the general release characteristics and mechanisms of drug from nanocarriers will be discussed.

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 vitrodrug 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.

Fluidic shear stress generated by fluid flow in human body contributes to the interactions between nanoparticles (NPs) and cells and may affect cellular distribution and delivery of NPs. Furthermore, different NPs properties may differently influence the cellular delivery and targeting of NPs under the in vivo dynamic environments. Thus, we reviewed and discussed how fluidic shear stress affects to drug delivery and cellular distribution of diverse NPs under the biomimetic microfluidic shear stress. Among different physicochemical properties of NPs, size, shape, material type and surface functionality, and surface charge of NPs are critical factors to cellular uptake in presence of fluidic shear stress in dynamic cellular environment. From previous studies, it suggested that fluidic shear stress stimulated specific endocytosis and prompted cell signaling pathway. The cellular interactions between NPs and cells in drug delivery should be carefully investigated in presence of shear stress which is one of critical factors to show the difference of in vitro and in vivo drug distribution and therapy. The shear-activated drug delivery using NPs were also the scope of this review.

The low solubility of tadalafil (TDF) normally retards the dissolution rate and permeability of the drug in oral mucosa and gastrointestinal tract. The aim of this study was to optimize and evaluate novel orodispersible films (ODFs) loaded with TDF or micronized TDF (MTDF) to enhance the solubility and permeability of the drug. The TDF(or MTDF)-loaded ODFs with polyvinyl alcohol 1788 as a film-forming material, sodium alginate as a disintegrant, polyethylene glycol 400 as a plasticizer, and polysorbate 80 (Tween 80) or sodium lauryl sulfate (SLS) as a surfactant was prepared by using a solvent casting method. In addition, the formulation composition of TDF-loaded ODFs was also optimized in terms of appearance, thickness, disintegration time, mechanical properties, and dissolution rate of films. The SLS-incorporatedODFs showed more reliable dissolution profiles than Tween 80-incorporated ODFs in pH 7.4 PBS (0.5% SLS and 1% Tween 80) as compared to commercial tablet (Cialis®). The dissolution rates of optimal TDF-loaded ODFs (F11) at pH1.2 and pH7.4 were 68.74% and 74.81% at 15 min, 83.04% and 84.95% at 30min, respectively. Compared with Cialis® and F11, MTDF-loaded ODFs (F12) showed faster dissolution rate at 10 min in pH 7.4 PBS (0.5% SLS). There was no significant difference in the in vitro permeability between F11 and F12 in the media containing Tween 80. However, the permeability of F12 was higher than that of F11 if Tween 80 was absent in the dissolution media. In conclusion, novel TDF or MTDF-loaded ODFs were successfully formulated and the ODFs incorporated with MTDF showed higher drug dissolution and membrane permeability, indicating that the ODFs formulated with MTDF may be an alternative to commercial tablets for the treatment of male erectile dysfunction.

A needs-based approach is desirable for the transformation of pharmaceutical education, and to link pharmaceutical education with the health needs of populations and national priorities. There are varying levels of data in the literature on the status of pharmaceutical education in all six World Health Organization (WHO) regions, especially in the context of needs identification and evidence-based policy interventions. The framework for this study was the FIP Development Goals.

The purpose of this study was to improve the dissolution rate of poorly water-soluble celecoxib (CXB) via a new adsorption method. CXB was dissolved in a co-solvent (ethanol:dichloromethane = 40:60 v/v) and then adsorbed on the surface of various diluent carriers by wet grinding. The physicochemical properties, such as the morphology and crystal structure, of the resulting adsorption powders were characterized. The adsorption powders were compressed into tablets after the wet granulation process. The in vitrodissolution rate of the CXB-loaded tablet was assessed in intestinal fluid (pH 6.8) containing 1% sodium lauryl sulfate. The differential scanning calorimetry and powder X-ray diffraction data showed that the crystallinity of CXB was maintained in the adsorption powders. Fourier transform infrared spectra indicated a molecular hydrogen-bonding between CXB and the adsorption carriers. Lactose monohydrate was the most effective at improving the dissolution rate of CXB via strong hydrogen bonding, followed by mannitol, Avicel®PH102, A-tab®, and Di-tab®. The CXB-loaded tablet was also stable during storage conditions (ambient: 25 °C, 60% RH, accelerated: 40 °C, 75% RH). Adsorption of CXB onto a hydrophilic diluent carrier provides an effective pharmaceutical strategy to enhance the dissolution rate of CXB-loaded tablets without changing drug crystallinity.

Effects of shear stress on the intracellular uptake of nanoparticles were originally investigated using a calibrated biomimetic microfluidic system (BMS) that mimics the dynamic environment of cells. Positively or negatively charged polystyrene nanoparticles (PSNs) were chosen as a model. PSNs were delivered to HEK 293T and MS1 cell lines using a BMS. To evaluate intracellular uptake of PSNs under static and dynamic conditions (0.5, 1.0, 3.0 dyne/cm2), the fluorescence intensity of intracellular PSNs was measured by flow cytometric analysis and confocal laser scanning microscopy. When delivering cationic PSNs to cells, the intracellular uptake increased as the exposure time and PSN concentration increased under both static and dynamic conditions. Under dynamic conditions, the intracellular uptake of cationic PSN was highly increased in both HEK 293T and MS1 cell lines compared to static conditions. However, intracellular uptake of cationic PSNs was maximized when shear stress was at 0.5 dyne/cm2and then gradually decreased as the magnitude of fluidic shear stress increased to 3.0 dyne/cm2. Contrarily, the anionic PSNs showed no significant difference of cellular uptake in presence of shear stress. Thus, shear stress should be considered to investigate the cellular distribution of various nanoparticles and drug delivery systems.

The aim of this study was to design and evaluate extended-release formulations of a model drug, nicorandil, in order to achieve the desired steady-state plasma concentration of drug in vivo. Simulation was employed to estimate optimum dissolution and absorption rate of nicorandil. The dissolution test was employed using pH 1.2, 4.0, 6.8 buffer solution, or water, to measure the in vitrorelease behaviors of nicorandil formulations. A single dose (15 mg) of each formulation was orally administered to four beagle dogs under fasted conditions, and the pharmacokinetic parameters were calculated. The in vitro/in vivorelationship of the extended-release formulation was confirmed using in vitrodissolution profiles and plasma concentrations of drug in beagle dogs. Nicorandil was released completely within 30 min from the immediate-release tablets and released for 24 h from the extended-release tablets. The nicorandil plasma concentration could be modified by adjusting the drug release rate from the extended-release formulation. The release rate of nicorandil was the rate-limiting step in the overall absorption of drug from the extended-release formulations. These results highlight the potential of a nicorandil extended-release formulation in the treatment of angina pectoris.

Many new drugs have been discovered in pharmaceutical industry and exposed their surprised potential therapeutic effects. Unfortunately, these drugs possess low absorption and bioavailability since their solubility limitation in water. Solid dispersion (SD) is the current technique gaining so many attractions from scientists due to its effect on improving solubility and dissolution rate of poorly water-soluble drugs. A number of patents including the most recent inventions have been undertaken in this review to address various respects of this strategy in solubilization of poorly watersoluble drugs including type of carriers, preparation methods and view of technologies used to detect SD properties and mechanisms with the aim to accomplish a SD not only effective on enhanced bioavailability but also overcome difficulties associated with stability and production. Future prospects are as well discussed with an only hope that many developments and researches in this field will be successfully reached and contributed to commercial use for treatment as much as possible.

The aim of this study was to classify some markers of common herbs used in Western medicine according to the Biopharmaceutical Classification System (BCS). The BCS is a scientific approach to classify drug substances based upon their intestinal permeability and their solubility, at the highest single dose used, within the physiologically relevant pH ranges. Known marker components of twelve herbs were chosen from the USP Dietary Supplement Compendium Monographs. Different BCS parameters such as intestinal permeability (Peff) and solubility (Cs) were predicted using the ADMET Predictor,which is a software program to estimate biopharmaceutical relevant molecular descriptors. The dose number (D0) was calculated when information from the literature was available to identify an upper dose for individual markers. In these cases the herbs were classified according to the traditional BCS parameters using Peffand D0. When no upper dose could be determined, then the amount of a marker that is just soluble in 250 mL of water was calculated. This value, Mx, defines when a marker is changing from highly soluble to poorly soluble according to BCS criteria. This biopharmaceutically relevant value can be a useful tool for marker selection. The present study showed that a provisional BCS classification of herbs is possible but some special considerations need to be included into the classification strategy. The BCS classification can be used to choose appropriate quality control tests for products containing these markers. A provisional BCS classification of twelve common herbs and their 35 marker compounds is presented.

Background:The aim of this study was to investigate the physicochemical properties of polyethylene oxide (PEO)-based controlled release solid dispersions (CR-SDs) containing aceclofenac, Gelucire®44/14, poloxamer 407 and pH modifier (Na2CO3). Results:The immediate release solid dispersions containing the pH modifier greatly enhanced the drug dissolution rate to approximately 100%, while the CR-SDs with PEO showed controlled release. A bigger droplet size and a higher surface charge for the CR-SDs were observed compared with the immediate release solid dispersions. The pH modifier played an important role in modulating the release rate of the drug through changes in the drug crystallinity and the hydrogen-bonding interaction, as well as the microenvironmental pH. Near-infrared images revealed a modulation of the PEO concentration to preserve the pH modifier within the system for controlled release of the drug. Conclusion:The dissolution process of PEO-based solid dispersions containing a water-insoluble drug was governed by the changing net effect of the microenvironmental pH, the surface charge, the particle size and the release rate of the pH modifier, as well as the function of PEO in controlling drug release.

Importance of the field:Although the solid dispersion method has been known to increase the dissolution rate of poorly water-soluble drugs by dispersing them in hydrophilic carriers, one obstacle of the solid dispersion method is its limited solubilization capacity, especially for pH-dependent soluble drugs.Areas covered in this review:pH-modified solid dispersion, in which pH modifiers are incorporated, may be a useful method for increasing the dissolution rate of weakly acidic or basic drugs. Sufficient research, including the most recent reports, was undertaken in this review.What the reader will gain:How could the inclusion of the pH the pH modifiers in the solid dispersion system change drug structural behaviors, molecular interactions, microenvironmental pH, and/or release rate of pH modifiers, relating with the enhanced dissolution of weakly acidic or weakly basic drugs with poor water solubility? These questions have been investigated to determine the dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs.Take home message:It is believed that step-by-step mechanistic approaches could provide the ultimate solution for solubilizing several poorly water-soluble drugs with pH-dependent solubility from a solid dispersion system, as well as provide ideas for developing future dosage systems.

Summary:Intensive efforts were made to develop an efficient, novel microencapsulation system useful to encapsulate a model drug, risperidone, to PLGA microspheres. Methyl dichloroacetate was used as a dispersed solvent for the first time, since it possessed excellent solvency power on PLGA and readily underwent ammonolysis. A dispersed phase composed of methyl dichloroacetate, risperidone, and PLGA was emulsified in an aqueous phase to form an O/W emulsion. Adding ammonia solution into the emulsion rapidly converted methyl dichloroacetate into water‐soluble dichloroacetamide and methanol. As a result, emulsion droplets were immediately transformed into hardened microspheres. The new microencapsulation system allowed us to make PLGA microspheres with a drug payload of >40 wt.‐% and attain almost complete encapsulation efficiencies. In summary, preparing an O/W emulsion and subjecting the emulsion to ammonolysis led to development of an efficient, novel microencapsulation system. It was anticipated that the new system could make it possible to load other bioactive materials into microspheres made of various types of hydrophobic polymers.

Administration-time differences of gentamicin pharmacokinetics were studied by crossover design after a single intravenous administration of gentamicin (80 mg) to 10 human subjects at 09:00 (morning time) and 22:00 (nighttime). The profiles of serum gentamicin concentration showed a significant statistical difference between 09:00 and 22:00, suggesting circadian variations of pharmacokinetic behaviors. A significant circadian rhythm of pharmacokinetic parameters as a function of time of day was noted in human subjects, showing lower total body clearance Clt and higher serum area under the curve (AUC) when given at nighttime. The half-life t1/2 was shorter in the morning (2.82h ± 0.43h) when compared to the nighttime (2.97h ± 0.36h), but the difference was not statistically significant. The AUC was significantly greater in the morning (23.4 ± 3.84 μg-h/mL) than that in the nighttime (26.3 ± 5.79 μg-h/mL) (p< .05), most likely because the Clt, was significantly higher when gentamicin was given in the morning (3.51 ± 0.57 L/h) versus in the nighttime (3.18 ± 0.65 L/h). Although the volume of distribution Vd decreased when given at nighttime, it was independent of the dosing time. From this study, there was an administration-time difference of gentamicin pharmacokinetics in human beings. The optimized dosing regimen of gentamicin can be decided by considering circadian rhythm and rest-activity routine so that minimized toxicity and effective therapy are established for patients. The current findings also can be applied to other drugs with circadian rhythms of pharmacokinetics and narrow therapeutic windows in clinical chronotherapeutics.

Melatonin (MT) is an indole amide pineal hormone. The sustained release dosage form which delivers MT in a circadian fashion over 8 h is of clinical value, because of its short half-life, for those who have disordered circadian rhythms. The purpose of this study was to prepare polymer reinforced and coated alginate beads and to evaluate in vitro release characteristics in simulated gastric and intestinal fluids, varying drug loadings, and the amount of polymer and plasticizer. The Eudragit® RS100 as a polymer and aluminium tristearate (AT) as a plasticizer were used, respectively. Plain (simple) alginate beads were prepared by dropping the mixture of MT and sodium alginate into 0.2 M CaCl2solution. The polymer reinforced alginate beads were prepared by dropping the mixture of drug, sodium alginate and polymer with plasticizer into 0.2 M CaCl2solution. The coated alginate beads were also prepared by adding plain alginate beads into polymer solution using the solvent evaporation method. Acetone was used as a solvent of polymer. The dissolution test was carried out using the basket method at a stirring speed of 100 rpm at 37°C in simulated gastric (pH 1.4) and intestinal fluid (pH 7.4). The concentration of MT was determined by reverse phase HPLC. In the study of scanning electron microscope (SEM), the surface crystal and roughness were reduced by polymeric reinforcing and coating alginate beads. However, higher coatings of alginate beads resulted in cracks and holes on the surface of coated alginate beads. The longer curing time into 0.2 M CaCl2solution, the lower trapping efficiency of MT was observed due to release of MT during gelling process. The release rate of MT in gastric and intestinal fluid when drug loading increased was not changed. The polymeric reinforcement of alginate beads on the release rate of MT was not significant in gastric fluid, but pronounced in intestinal fluid with initial burst out release for 1 h. The release rate of the drug from coated alginate beads was retarded, both in gastric and intestinal fluid when compared to plain alginate beads. As the polymer contents increased, the release rate was significantly decreased in the intestinal fluid due to hindrance of swelling and disintegration of coated alginate beads unlike gastric fluid. The release rate of drug from coated alginate beads was more efficiently sustained in the gastric and intestinal fluid when 0.1 g of AT as a plasticizer was used for coating. However, the higher amount of AT was not useful for retarding the release rate. From the current studies, the sustained release formulation of MT using alginate beads may provide as an alternative for oral delivery of MT.

Sugar spheres loaded with melatonin (MT) were coated with Aquacoatr`to control the release rate of MT. Dissolution of MT was evaluated using the USP basket method. With 18-20 mesh beads, T50% (time to release 50% of drug) for 5%, 10%. and 20% coatings was 10 min, 35 min, and 60 min, respectively. A desired release pattern over 8 hours was obtained with 20% coating on 8-10 mesh beads. T50% for 5%, 10%, and 20% coatings was about 1, 2, and 4 hours, respectively. MT in 20% coated beads was quite stable during storage at room temperature with less than 5% MT degraded during 6 months of storage. Dissolution profiles from 8-10 mesh beads with a 20% coating were unchanged after 6 months of storage at room temperature, Administration of the dosage form to human subjects maintained MT plasma concentrations over 100 pg/ml for approximately 8 hours.

Low encapsulation efficiency (EE) and high initial burst release are key issues for the development of microspheres loading highly water-soluble peptide drugs. In this study, novel triptorelin acetate-loaded microspheres with high EE and low initial burst release were prepared by a liquid/oil/oil (L/O/O) phase separation method using poly(lactic-co-glycolic acid) (PLGA) as the sustained-release carrier. The formulation of the microspheres and the preparation process were optimized in terms of particle size, surface morphology, EE, and in vitro drug release. Importantly, PLGA concentration, solvent and non-solvent ratio, solidification solvent volume, and solidification speed were found to significantly affect the properties of the obtained microspheres. The optimal microspheres present 50–100 μm spherical-shaped particles with remarkably high drug loading and EE. The in vitro drug release of these microspheres exhibit a delayed-release manner, starting to release drug at the third week and displaying approximately 20% drug release at day 28. Fourier transform infrared spectroscopy and differential scanning calorimetry results show that triptorelin acetate slightly interacted with PLGA, indicating that the drug was successfully encapsulated into PLGA microspheres. The drug content in the microspheres had no significant change after the 12-month storage at 4 °C, suggesting their excellent long-term stability. In conclusion, novel triptorelin acetate-loaded PLGA microspheres have been achieved via the L/O/O phase separation method to effectively improve the EE and reduce the initial burst release.