Pharmacophore Modeling and Binding Affinity of Secondary Metabolites from Angelica keiskei to HMG Co-A Reductase.

Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba's compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole-1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (ΔG). Pitavastatin, as the comparator drug (ΔG = -8.24 kcal/mol; Ki = 2.11 µM), had a lower ΔG and inhibition constant (Ki) than the native ligand 4HI (ΔG = -7.84 kcal/mol; Ki = 7.96µM). From ashitaba's compounds, it was found that 4'-O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3'-carboxymethyl-4,2'-dihydroxy-4'-methoxychalcone have low ΔG of below -6 kcal/mol. The lowest ΔG value was found in 3'-carboxymethyl-4,2'-dihydroxy-4'-methoxy chalcone with a ΔG of -6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ΔG value of the other comparator drugs, atorvastatin (ΔG = -5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (ΔG = -6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity.

Characterization of Drug with Good Glass-Forming Ability Loaded Mesoporous Silica Nanoparticles and Its Impact Toward in vitro and in vivo Studies.

Solid oral dosage forms are mostly preferred in pharmaceutical formulation development due to patient convenience, ease of product handling, high throughput, low manufacturing costs, with good physical and chemical stability. However, 70% of drug candidates have poor water solubility leading to compromised bioavailability. This phenomenon occurs because drug molecules are often absorbed after dissolving in gastrointestinal fluid. To address this limitation, delivery systems designed to improve the pharmacokinetics of drug molecules are needed to allow controlled release and target-specific delivery. Among various strategies, amorphous formulations show significantly high potential, particularly for molecules with solubility-limited dissolution rates. The ease of drug molecules to amorphized is known as their glass-forming ability (GFA). Specifically, drug molecules categorized into class III based on the Taylor classification have a low recrystallization tendency and high GFA after cooling, with substantial "glass stability" when heated. In the last decades, the application of mesoporous silica nanoparticles (MSNs) as drug delivery systems (DDS) has gained significant attention in various investigations and the pharmaceutical industry. This is attributed to the unique physicochemical properties of MSNs, including high loading capacity, recrystallization inhibition, excellent biocompatibility, and easy functionalization. Therefore, this study aimed to discuss the current state of good glass former drug loaded mesoporous silica and shows its impact on the pharmaceutical properties including dissolution and physical stability, along with in vivo study. The results show the importance of determining whether mesoporous structures are needed in amorphous formulations to improve the pharmaceutical properties of drug with a favorable GFA.

The pharmacology activities of Angelica keiskei Koidzumi and its efficacy and safety in humans.

Chronic exposure to elevated levels of pro-oxidant factors may cause structural failings at the mitochondrial DNA level and alteration of antioxidant enzymes (glutathione peroxidase, catalase, and superoxide dismutase). Oxidative stress is an imbalance between the capacity of endogenous non-enzymatic antioxidants (glutathione, alpha-lipoic acid, uric acid, ferritin, metallothionein, melatonin, and bilirubin) and the occurrence of pro-oxidant factors which may lead to the pathogenesis of various diseases that affects the kidneys, pancreas, central nervous system, and cardiovascular system. Therefore, the utilization of medicinal plants with antioxidant activity, e.g., Angelica keiskei Koidzumi which contains chalcones, is interesting to be explored. Chalcones exhibit direct and indirect antioxidant activity and prevent oxidative stress by decreasing ROS, RNS, and superoxide production. In this review, we discuss the pharmacology activities of A. keiskei Koidzumi and its efficacy in humans. The articles were explored on PubMed and Google Scholar databases and based on the titles and abstracts related to the topic of interest, and 55 articles were selected. Two main chalcones of this plant, 4-hydroxyderricin and xanthoangelol, have been reported for their various pharmacology activities. The efficacy of A. keiskei was confirmed in anti-obesity, hepatoprotective, anti-diabetes mellitus, and increasing plasma antioxidants in patients with metabolic syndrome. A keiskei is safe as proven by only mild or no adverse events reported, thus it is prospective to be further developed as an antioxidant nutraceutical.

Plants with Anti-Ulcer Activity and Mechanism: A Review of Preclinical and Clinical Studies.

Ulcer disorders including the oral mucosa, large intestine, and stomach mucosa, cause significant global health burdens. Conventional treatments such as non-steroid anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), histamine H2 receptor antagonists (H2RAs), and cytoprotective agents have drawbacks like mucosal injury, diminish gastric acid secretion, and interact with concurrent medications. Therefore, alternative therapeutic approaches are needed to tackle this health concern. Plants are rich in active metabolites in the bark, roots, leaves, fruits, and seeds, and have been utilized for medicinal purposes since ancient times. The use of herbal therapy is crucial, and regulations are necessary to ensure the quality of products, particularly in randomized studies, to assess their efficacy and safety in treating ulcer disorders. This study aims to explore the anti-ulcer activity of medicinal plants in treating peptic ulcer disease, ulcerative colitis, and aphthous ulcers. Articles were searched in Scopus and PubMed, and filtered for publication from 2013 to 2023, resulting in a total of 460 from Scopus and 239 from PubMed. The articles were further screened by title and abstract and resulted in 55 articles. Natural products, rich in active metabolites, were described to manage ulcer disease by protecting the mucosa, reducing ulcer effects, inhibiting pro-inflammatory factors, and reducing bacterial load, thus improving patients' quality of life. Natural extracts have proven effective in managing other health problems, including ulcers by reducing pain and decreasing lesions. This review provides an overview of preclinical and clinical studies on medicinal plants, focusing on their effectiveness in treating conditions like peptic ulcers, ulcerative colitis, and aphthous ulcers.

Drug-Coformer Loaded-Mesoporous Silica Nanoparticles: A Review of the Preparation, Characterization, and Mechanism of Drug Release.

Drug-coformer systems, such as coamorphous and cocrystal, are gaining recognition as highly effective strategies for enhancing the stability, solubility, and dissolution of drugs. These systems depend on the interactions between drug and coformer to prevent the conversion of amorphous drugs into the crystalline form and improve the solubility. Furthermore, mesoporous silica (MPS) is also a promising carrier commonly used for stabilization, leading to solubility improvement of poorly water-soluble drugs. The surface interaction of drug-MPS and the nanoconfinement effect prevent amorphous drugs from crystallizing. A novel method has been developed recently, which entails the loading of drug-coformer into MPS to improve the solubility, dissolution, and physical stability of the amorphous drug. This method uses the synergistic effects of drug-coformer interactions and the nanoconfinement effect within MPS. Several studies have reported successful incorporation of drug-coformer into MPS, indicating the potential for significant improvement in dissolution characteristics and physical stability of the drug. Therefore, this study aimed to discuss the preparation and characterization of drug-coformer within MPS, particularly the interaction in the nanoconfinement, as well as the impact on drug release and physical stability.

Elucidation of Molecular Interactions Between Drug-Polymer in Amorphous Solid Dispersion by a Computational Approach Using Molecular Dynamics Simulations.

Introduction: Amorphous drug dispersion is frequently used to enhance the solubility and dissolution of poorly water-soluble drugs, thereby improving their oral bioavailability. The dispersion of these drugs into polymer matrix can inhibit their recrystallization. The inter-molecular interactions between drug and polymer plays a role in the improvement of the dissolution rate, solubility, and physical stability of drug. Aim: This study aims to investigate the formation and interactions of ritonavir (RTV)/poloxamer (PLX) amorphous formulation using a computational approach via molecular dynamics (MD) simulations, which mimicked solvent evaporation and melt-quenching method. Methods: TheRoot Mean Square Deviation (RMSD) value, Root Mean Square Fluctuation (RMSF), Radial Distribution Function (RDF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and hydrogen bond interactions were analyzed to determine interaction mechanisms between RTV and PLX in amorphous solid dispersion. Results: The pi-alkyl bonds between RTV and PLX were formed after simulations of solvent evaporation, while the hydrogen bond interactions of RTV-PLX was observed during melt method simulations. These results indicate the successful formulation of amorphous solid dispersion (ASD) from RTV and PLX. The RMSD values obtained from the solvent evaporation, melt-cooling-A, melt-cooling-B, and melt-cooling-C methods were 3.33 Å, 1.97 Å, 1.30 Å, and 1.29 Å, respectively, while the average RMSF values were 2.65 Å, 1.04 Å, 1.05 Å, and 1.07 Å, respectively. This indicates that the suppression of translational motion of RTV from the melt method can be stronger than solvent evaporation caused by the intermolecular interactions of RTV-PLX. Conclusion: MD simulations helped in understanding the formation and interaction mechanisms of ASD formulations that were difficult to detect by experimental approaches.

Advancing Drug Delivery Paradigms: Polyvinyl Pyrolidone (PVP)-Based Amorphous Solid Dispersion for Enhanced Physicochemical Properties and Therapeutic Efficacy.

BACKGROUND: The current challenge in drug development lies in addressing the physicochemical issues that lead to low drug effectiveness. Solubility, a crucial physicochemical parameter, greatly influences various biopharmaceutical aspects of a drug, including dissolution rate, absorption, and bioavailability. Amorphous solid dispersion (ASD) has emerged as a widely explored approach to enhance drug solubility. OBJECTIVE: The objective of this review is to discuss and summarize the development of polyvinylpyrrolidone (PVP)-based amorphous solid dispersion in improving the physicochemical properties of drugs, with a focus on the use of PVP as a novel approach. METHODOLOGY: This review was conducted by examining relevant journals obtained from databases such as Scopus, PubMed, and Google Scholar, since 2018. The inclusion and exclusion criteria were applied to select suitable articles. RESULTS: This study demonstrated the versatility and efficacy of PVP in enhancing the solubility and bioavailability of poorly soluble drugs. Diverse preparation methods, including solvent evaporation, melt quenching, electrospinning, coprecipitation, and ball milling are discussed for the production of ASDs with tailored characteristics. CONCLUSION: PVP-based ASDs could offer significant advantages in the formulation strategies, stability, and performance of poorly soluble drugs to enhance their overall bioavailability. The diverse methodologies and findings presented in this review will pave the way for further advancements in the development of effective and tailored amorphous solid dispersions.

How Key Alterations of Mesoporous Silica Nanoparticles Affect Anti-Lung Cancer Therapy? A Comprehensive Review of the Literature.

In 2020, there were 2.21 million new instances of lung cancer, making it the top cause of mortality globally, responsible for close to 10 million deaths. The physicochemical problems of chemotherapy drugs are the primary challenge that now causes a drug's low effectiveness. Solubility is a physicochemical factor that has a significant impact on a drug's biopharmaceutical properties, starting with the rate at which it dissolves and extending through how well it is absorbed and bioavailable. One of the most well-known methods for addressing a drug's solubility is mesoporous silica, which has undergone excellent development due to the conjugation of polymers and ligands that increase its effectiveness. However, there are still very few papers addressing the success of this discovery, particularly those addressing its molecular pharmaceutics and mechanism. Our study's objectives were to explore and summarize the effects of targeting mediator on drug development using mesoporous silica with and without functionalized polymer. We specifically focused on highlighting the molecular pharmaceutics and mechanism in this study's innovative findings. Journals from the Scopus, PubMed, and Google Scholar databases that were released during the last ten years were used to compile this review. According to inclusion and exclusion standards adjusted. This improved approach produced very impressive results, a very significant change in the characteristics of mesoporous silica that can affect effectiveness. Mesoporous silica approaches have the capacity to greatly enhance a drug's physicochemical issues, boost therapeutic efficacy, and acquire superb features.

Ternary Solid Dispersions: A Review of the Preparation, Characterization, Mechanism of Drug Release, and Physical Stability.

The prevalence of active pharmaceutical ingredients (APIs) with low water solubility has experienced a significant increase in recent years. These APIs present challenges in formulation, particularly for oral dosage forms, despite their considerable therapeutic potential. Therefore, the improvement of solubility has become a major concern for pharmaceutical enterprises to increase the bioavailability of APIs. A promising formulation approach that can effectively improve the dissolution profile and the bioavailability of poorly water-soluble drugs is the utilization of amorphous systems. Numerous formulation methods have been developed to enhance poorly water-soluble drugs through amorphization systems, including co-amorphous formulations, amorphous solid dispersions (ASDs), and the use of mesoporous silica as a carrier. Furthermore, the successful enhancement of certain drugs with poor aqueous solubility through amorphization has led to their incorporation into various commercially available preparations, such as ASDs, where the crystalline structure of APIs is transformed into an amorphous state within a hydrophilic matrix. A novel approach, known as ternary solid dispersions (TSDs), has emerged to address the solubility and bioavailability challenges associated with amorphous drugs. Meanwhile, the introduction of a third component in the ASD and co-amorphous systems has demonstrated the potential to improve performance in terms of solubility, physical stability, and processability. This comprehensive review discusses the preparation and characterization of poorly water-soluble drugs in ternary solid dispersions and their mechanisms of drug release and physical stability.

Amorphous Solid Dispersion as Drug Delivery Vehicles in Cancer.

Cancer treatment has improved over the past decades, but a major challenge lies in drug formulation, specifically for oral administration. Most anticancer drugs have poor water solubility which can affect their bioavailability. This causes suboptimal pharmacokinetic performance, resulting in limited efficacy and safety when administered orally. As a result, it is essential to develop a strategy to modify the solubility of anticancer drugs in oral formulations to improve their efficacy and safety. A promising approach that can be implemented is amorphous solid dispersion (ASD) which can enhance the aqueous solubility and bioavailability of poorly water-soluble drugs. The addition of a polymer can cause stability in the formulations and maintain a high supersaturation in bulk medium. Therefore, this study aimed to summarize and elucidate the mechanisms and impact of an amorphous solid dispersion system on cancer therapy. To gather relevant information, a comprehensive search was conducted using keywords such as "anticancer drug" and "amorphous solid dispersion" in the PubMed, Scopus, and Google Scholar databases. The review provides an overview and discussion of the issues related to the ASD system used to improve the bioavailability of anticancer drugs based on molecular pharmaceutics. A thorough understanding of anticancer drugs in this system at a molecular level is imperative for the rational design of the products.

Effect of Drug-Polymer Interaction in Amorphous Solid Dispersion on the Physical Stability and Dissolution of Drugs: The Case of Alpha-Mangostin.

Improving drug solubility is necessary for formulations of poorly water-soluble drugs, especially for oral administration. Amorphous solid dispersions (ASDs) are widely used in the pharmaceutical industry to improve the physical stability and solubility of drugs. Therefore, this study aims to characterize interaction between a drug and polymer in ASD, as well as evaluate the impact on the physical stability and dissolution of alpha-mangostin (AM). AM was used as a model of a poorly water-soluble drug, while polyvinylpyrrolidone (PVP) and eudragit were used as polymers. The amorphization of AM-eudragit and AM-PVP was confirmed as having a halo pattern with powder X-ray diffraction measurements and the absence of an AM melting peak in the differential scanning calorimetry (DSC) curve. The solubility of amorphous AM increased in the presence of either eudragit or PVP due to amorphization and interactions of AM-polymer. Furthermore, FT-IR spectroscopy and in silico studies revealed hydrogen bond interactions between the carbonyl group of AM and the proton of eudragit as well as PVP. AM-eudragit with a ratio of 1:1 recrystallized after 7 days of storage at 25 °C and 90% RH, while the AM-PVP 1:4 and 1:10 samples retained the X-ray halo patterns, even under humid conditions. In a dissolution test, the presence of polymer in ASD significantly improved the dissolution profile due to the intermolecular interaction of AM-polymer. AM-eudragit 1:4 maintained AM supersaturation for a longer time compared to the 1:1 sample. However, a high supersaturation was not achieved in AM-PVP 1:10 due to the formation of large agglomerations, leading to a slow dissolution rate. Based on the results, interaction of AM-polymer in ASD can significantly improve the pharmaceutical properties of AM including the physical stability and dissolution.

Characterizing the Impact of Chitosan on the Nucleation and Crystal Growth of Ritonavir from Supersaturated Solutions.

The addition of polymeric materials is often used to delay nucleation or crystal growth and maintain the high supersaturation of amorphous drugs. Therefore, this study aimed to investigate the impact of chitosan on the supersaturation behavior of drugs with a low recrystallization tendency and elucidate the mechanism of its crystallization inhibition in an aqueous solution. It was carried out using ritonavir (RTV) as a model of poorly water-soluble drugs categorized as class III of Taylor's classification, while chitosan was used as a polymer, and hypromellose (HPMC) was used for comparison. The inhibition of the nucleation and crystal growth of RTV by chitosan was examined by measuring the induction time. The interactions of RTV with chitosan and HPMC were evaluated by NMR measurements, FT-IR, and an in silico analysis. The results showed that the solubilities of amorphous RTV with and without HPMC were quite similar, while the amorphous solubility was significantly increased by the chitosan addition due to the solubilization effect. In the absence of the polymer, RTV started to precipitate after 30 min, indicating that it is a slow crystallizer. Chitosan and HPMC effectively inhibited the nucleation of RTV, as reflected by a 48-64-fold enhancement in the induction time. Furthermore, NMR, FT-IR, and in silico analysis demonstrated that the hydrogen bond interaction between the amine group of RTV and a proton of chitosan, as well as the carbonyl group of RTV and a proton of HPMC, was observed. This indicated that the hydrogen bond interaction between RTV and chitosan as well as HPMC can contribute to the crystallization inhibition and maintenance of RTV in a supersaturated state. Therefore, the addition of chitosan can delay nucleation, which is crucial for stabilizing supersaturated drug solutions, specifically for a drug with a low crystallization tendency.

Current Techniques of Water Solubility Improvement for Antioxidant Compounds and Their Correlation with Its Activity: Molecular Pharmaceutics.

The aqueous solubility of a drug is important in the oral formulation because the drug can be absorbed from intestinal sites after being dissolved in the gastrointestinal fluid, leading to its bioavailability. Almost 80% of active pharmaceutical ingredients are poorly water-soluble, including antioxidant compounds. This makes antioxidant activity inefficient in preventing disease, particularly for orally administered formulations. Although several investigations have been carried out to improve the solubility of antioxidant compounds, there is still limited research fully discussing the subject. Therefore, this study aimed to provide an overview and discussion of the issues related to the methods that have been used to improve the solubility and activity of antioxidant compounds. Articles were found using the keywords "antioxidant" and "water solubility improvement" in the Scopus, PubMed, and Google Scholar databases. The selected articles were published within the last five years to ensure all information was up-to-date with the same objectives. The most popular methods of the strategies employed were solid dispersion, co-amorphous, and nanoparticle drug delivery systems, which were used to enhance the solubility of antioxidant compounds. These investigations produced impressive results, with a detailed discussion of the mechanism of improvement in the solubility and antioxidant activity of the compounds developed. This review shows that the strategies used to increase the solubility of antioxidant compounds successfully improved their antioxidant activity with enhanced free radical scavenging abilities.

Inhibition of Crystal Nucleation and Growth in Aqueous Drug Solutions: Impact of Different Polymers on the Supersaturation Profiles of Amorphous Drugs-The Case of Alpha-Mangostin.

The polymer used in supersaturated solutions plays a critical role in maintaining supersaturation levels of amorphous drugs. The prevention of drug crystallization in the supersaturated solutions by adding polymers depends on their ability to inhibit nucleation and crystal growth of drugs. This showed that understanding the mechanism of nucleation inhibition by polymers is necessary to develop the drug formulation in supersaturated solutions. Therefore, this study aims to evaluate the impact of water-soluble polymers on the supersaturation behavior of drugs and elucidate the mechanism of maintaining the supersaturation levels in an aqueous solution. It was carried out using alpha-mangostin (AM) as a model of the poorly water-soluble drug, while hypromellose (HPMC), polyvinylpyrrolidone (PVP), and eudragit were used as polymers. Their ability to inhibit the nucleation and crystal growth of AM was also evaluated. The supersaturation profiles of AM were measured in biorelevant dissolution media, while the crystal growth rate of AM was evaluated from the decrease in dissolved drug concentration by determining the induction time for AM nucleation. The interaction of AM with each polymer was evaluated and predicted by FT-IR, NMR measurement, and an in silico study, respectively. Based on observation, the PVP effectively maintained AM in a supersaturated state for the long term while eudragit conserved for 15 min. Meanwhile, an inhibitory effect of HPMC on the AM crystal nucleation was not observed. It was also \]-+discovered that the effectiveness of the various polymers depends on the interaction between the polymer and the drug. FT-IR and in silico studies demonstrated that the interaction of PVP-AM had the best polymer compared to eudragit and HPMC. NMR analysis suggested that the interaction between the methyl group from PVP with the carbonyl group of AM occurred in the PVP solution. The viscosity measurement revealed that the inhibition of nucleation and crystal growth of AM was not caused by increasing the viscosity. These results indicated that polymer-AM interactions could contribute to the crystallization inhibition and maintenance of AM in a supersaturated state. Therefore, an investigation of the mechanism of drug nucleation inhibition by polymers is recommended in the selection of crystallization inhibitors and a planned strategy to develop supersaturated formulations of drugs.

The Impact of Water-Soluble Chitosan on the Inhibition of Crystal Nucleation of Alpha-Mangostin from Supersaturated Solutions.

The use of an amorphous drugs system to generate supersaturated solutions is generally developed to improve the solubility and dissolution of poorly soluble drugs. This is because the drug in the supersaturation system has a high energy state with a tendency to precipitate. In the amorphous solid dispersion (ASD) formulation, it was discovered that polymer plays a critical role in inhibiting nucleation or crystal growth of the drugs. Therefore, this study aimed to evaluate the crystallization inhibition of water-soluble chitosan (WSC) on nucleation as well as crystal growth from alpha-mangostin (AM) and elucidate its inhibition mechanism in the supersaturated solutions. During the experiment, WSC was used as a polymer to evaluate its ability to inhibit AM nucleation. The interaction between WSC and AM was also estimated using FT-IR, NMR, and in silico study. The result showed that in the absence of polymer, the concentration of AM rapidly decreased due to the precipitation in one minute. Meanwhile, the addition of WSC effectively inhibited AM crystallization and maintained a supersaturated state for the long term. FT-IR measurement also revealed that the shift in the amine primer of WSC occurred because of the interaction between WSC and AM. In the 1H NMR spectra, the proton peaks of WSC showed an upfield shift with the presence of AM, indicating the intermolecular interactions between AM and WSC. Moreover, in silico study revealed the hydrogen bond interaction between the carbonyl group of AM with hydrocarbon groups of WSC. This indicated that WSC interacted with AM in the supersaturated solution and suppressed their molecular mobility, thereby inhibiting the formation of the crystal nucleus. Based on these results, it can be concluded that the interaction between drug polymers contributed to the maintenance of the drug supersaturation by inhibiting both nucleation and growth.

A Comparative Study of the Pharmaceutical Properties between Amorphous Drugs Loaded-Mesoporous Silica and Pure Amorphous Drugs Prepared by Solvent Evaporation.

The formulation of poorly water-soluble drugs is one of the main challenges in the pharmaceutical industry, especially in the development of oral dosage forms. Meanwhile, there is an increase in the number of poorly soluble drugs that have been discovered as new chemical entities. It was also reported that the physical transformation of a drug from a crystalline form into an amorphous state could be used to increase its solubility. Therefore, this study aims to evaluate the pharmaceutical properties of amorphous drug loaded-mesoporous silica (MPS) and pure amorphous drugs. Ritonavir (RTV) was used as a model of a poorly water-soluble drug due to its low recrystallization tendency. RTV loaded-MPS (RTV/MPS) and RTV amorphous were prepared using the solvent evaporation method. Based on observation, a halo pattern in the powder X-ray diffraction pattern and a single glass transition (Tg) in the modulated differential scanning calorimetry (MDSC) curve was discovered in RTV amorphous, indicating its amorphization. The Tg was not detected in RTV/MPS, which showed that the loading RTV was completed. The solid-state NMR and FT-IR spectroscopy also showed the interaction between RTV and the surface of MPS in the mesopores. The high supersaturation of RTV was not achieved for both RTV/MPS and the amorphous state due to its strong interaction with the surface of MPS and was not properly dispersed in the medium, respectively. In the dissolution test, the molecular dispersion of RTV within MPS caused rapid dissolution at the beginning, while the amorphous showed a low rate due to its agglomeration. The stability examination showed that the loading process significantly improved the physical and chemical stability of RTV amorphous. These results indicated that the pharmaceutical properties of amorphous drugs could be improved by loaded-MPS.

Inhibitory activity of xanthoangelol isolated from Ashitaba (Angelica keiskei Koidzumi) towards α-glucosidase and dipeptidyl peptidase-IV: in silico and in vitro studies.

In Indonesia, the sap of Angelica keiskei Koidzumi has been utilized traditionally as a blood-sugar reducer, nonetheless, its molecular mechanism still needs to be studied. This study aimed to isolate xanthoangelol (XA) from the yellow sap of A. keiskei planted in Mount Rinjani, Indonesia, and to investigate its mechanism by in silico and in vitro methods towards α-glucosidase and dipeptidyl peptidase-IV (DPP-IV). The dried yellow sap was macerated using ethanol, subjected to liquid-liquid extraction using a different polarity of solvents, further gradient-eluted with column chromatography. The isolated compound, formed as yellow crystals, melting point 114-114.4 °C, λmax 368 nm, m/z 393.20 [M + H]+, was confirmed as XA. Acarbose, an α-glucosidase inhibitor, and sitagliptin, a DPP-IV inhibitor, respectively, were employed as the reference drugs for both the in silico and in vitro studies. XA interacts with essential amino acid residues 232-237 in the N-terminal N-loop of α-glucosidase by forming a hydrogen bond with Ala234, a salt-bridge with Asp232, and 9 hydrophobic interactions (binding energy -7.81 kcal/mol; Ki = 1.99 µM). These binding modes resemble those of acarbose. Moreover, XA forms hydrogen bonds with Glu205 and Glu206 in the subsite S2 and π-π interaction with Phe357 in the extensive subsite S2 of DPP-IV (binding energy -8.34 kcal/mol; Ki = 0.873 µM), which are similar to those of sitagliptin. XA inhibits both α-glucosidase (IC50 XA = 14.45 µM; IC50 acarbose = 207 µM) and DPP-IV (IC50 XA = 10.49 µM; IC50 sitagliptin = 0.87 µM). Taken together, XA isolated from the yellow sap of A. keiskei Koidzumi might possess the potential to be further developed as an inhibitor of α-glucosidase and DPP-IV.

Characterization of Drugs with Good Glass Formers in Loaded-Mesoporous Silica and Its Theoretical Value Relevance with Mesopores Surface and Pore-Filling Capacity.

The incorporation of a drug into mesoporous silica (MPS) is a promising strategy to stabilize its amorphous form. However, the drug within MPS has shown incomplete release, despite a supersaturated solution being generated. This indicates the determination of maximum drug loading in MPS below what is experimentally necessary to maximize the drug doses in the system. Therefore, this study aimed to characterize the drugs with good glass former loaded-mesoporous silica, determine the maximum drug loading, and compare its theoretical value relevance to monolayer covering the mesoporous (MCM) surface, as well as pore-filling capacity (PFC). Solvent evaporation and melt methods were used to load each drug into MPS. In addition, the glass transition of ritonavir (RTV) and cyclosporine A (CYP), as well as the melting peak of indomethacin (IDM) and saccharin (SAC) in mesoporous silica, were not discovered in the modulated differential scanning calorimetry (MDSC) curve, demonstrating that each drug was successfully incorporated into the mesopores. The amorphization of RTV-loaded MPS (RTV/MPS), CYP-loaded MPS (CYP/MPS), and IDM-loaded MPS (IDM/MPS) were confirmed as a halo pattern in powder X-ray diffraction measurements and a single glass transition event in the MDSC curve. Additionally, the good glass formers, nanoconfinement effect of MPS and silica surface interaction contributed to the amorphization of RTV, CYP and IDM within MPS. Meanwhile, the crystallization of SAC was observed in SAC-loaded MPS (SAC/MPS) due to its weak silica surface interaction and high recrystallization tendency. The maximum loading amount of RTV/MPS was experimentally close to the theoretical amount of MCM, showing monomolecular adsorption of RTV on the silica surface. On the other hand, the maximum loading amount of CYP/MPS and IDM/MPS was experimentally lower than the theoretical amount of MCM due to the lack of surface interaction. However, neither CYP or IDM occupied the entire silica surface, even though some drugs were adsorbed on the MPS surface. Moreover, the maximum loading amount of SAC/MPS was experimentally close to the theoretical amount of PFC, suggesting the multilayers of SAC within the MPS. Therefore, this study demonstrates that the characterization of drugs within MPS, such as molecular size and interaction of drug-silica surface, affects the loading efficiency of drugs within MPS that influence its relevance with the theoretical value of drugs.

The Cytotoxicity and Nephroprotective Activity of the Ethanol Extracts of Angelica keiskei Koidzumi Stems and Leaves against the NAPQI-Induced Human Embryonic Kidney (HEK293) Cell Line.

MATERIALS AND METHODS: A. keiskei Koidzumi plant was collected from Mount Rinjani, Lombok, Indonesia, and was identified at the School of Biology Sciences and Technology, Bandung Institute of Technology, Indonesia. Extraction of the stems (ASE) and leaves (ALE) was performed by employing ethanol 70% for 3 × 24 h at 26°C. The cytotoxicity study of the extracts was assessed using the water-soluble tetrazolium salt-8 (WST-8) reagent on the HEK293 cell line, while the nephroprotective activity assay was determined on the NAPQI-induced HEK293 cell line. RESULTS: The WST-8 assay showed that the cytotoxicity IC50 of ASE = 2322 µg/mL and IC50 of ALE = 2283 µg/mL. The nephroprotective activity assay revealed that ASE possesses nephroprotective activity against the NAPQI-induced HEK293 cell line at 1161 µg/mL, while ALE does not show the nephroprotective activity. CONCLUSION: Taken together, lower concentrations of ASE and ALE (<2000 µg/mL) are not toxic to the HEK293 cell line, and only ASE indicates the activity to protect the HEK293 cell line against NAPQI damage. This Japanese celery could be further explored for its potential as a plant-based nephroprotective drug.

Encapsulation of drug into mesoporous silica by solvent evaporation: A comparative study of drug characterization in mesoporous silica with various molecular weights.

Mesoporous silica (MS) is a promising material as a drug carrier that is used in pharmaceutical applications. It was discovered that the incorporation of drugs into MS has the potential to improve their dissolution and bioavailability due to the large specific surface area. This study aimed to characterize the drugs with various molecular weights in MS as well as to elucidate their impact on the loading amount and the amorphization within MS. The solvent evaporation method was used to encapsulate itraconazole (ITZ), nifedipine (NIF), and nicotinamide (NIC), respectively, into MS. The result shows the absence of glass transition and the melting peak of ITZ, NIF, and SAC within MS signifying the successful encapsulation. A hallo pattern was found in ITZ and NIF within MS indicating the amorphization. The high molecular weight and the interaction between the drug with the silica surface is reportedly contributed to the formation of the amorphous state. Meanwhile, the characteristic diffraction peaks of NIC crystal were observed for NIC within MS. In conclusion, the molecular weight of the drug has a significant effect on the loading amount and the amorphization of the drug within MS.