Quantitative susceptibility mapping through model-based deep image prior (MoDIP).

The data-driven approach of supervised learning methods has limited applicability in solving dipole inversion in Quantitative Susceptibility Mapping (QSM) with varying scan parameters across different objects. To address this generalization issue in supervised QSM methods, we propose a novel training-free model-based unsupervised method called MoDIP (Model-based Deep Image Prior). MoDIP comprises a small, untrained network and a Data Fidelity Optimization (DFO) module. The network converges to an interim state, acting as an implicit prior for image regularization, while the optimization process enforces the physical model of QSM dipole inversion. Experimental results demonstrate MoDIP's excellent generalizability in solving QSM dipole inversion across different scan parameters. It exhibits robustness against pathological brain QSM, achieving over 32 % accuracy improvement than supervised deep learning methods. It is also 33 % more computationally efficient and runs 4 times faster than conventional DIP-based approaches, enabling 3D high-resolution image reconstruction in under 4.5 min.

Gene Polymorphisms and Drug-Drug Interactions Determine the Metabolic Profile of Blonanserin.

This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A microsomal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the concentrations of blonanserin and its metabolite. Compared with wild type CYP34A, the relative clearance of blonanserin by CYP3A4.29 significantly increased to 251.3%, while it decreased notably with CYP3A4.4, 5, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 23, 24, 28, 31, 33, and 34, ranging from 6.09% to 63.34%. Among 153 tested drugs, nimodipine, felodipine, and amlodipine were found to potently inhibit the metabolism of blonanserin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half-maximal inhibitory concentration and enzymatic kinetics assay demonstrated that the metabolism of blonanserin was noncompetitively inhibited by nimodipine in rat liver microsomes and was inhibited in a mixed manner by felodipine and amlodipine in both rat liver microsomes and human liver microsomes. When nimodipine and felodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-∞), and C max of blonanserin increased. When amlodipine and blonanserin were combined, the C max of blonanserin C increased remarkably. The vast majority of CYP3A4 variants have a low ability to catalyze blonanserin. With combined administration of nimodipine, felodipine, and amlodipine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin. SIGNIFICANCE STATEMENT: The enzyme kinetics of novel CYP3A4 enzymes for metabolizing blonanserin were investigated. Clearance of blonanserin by CYP3A4.4, 5, 7-10, 12-14, 16-18, 23-24, 28, 31, 33, and 34 decreased notably, but increased with CYP3A4.29. Additionally, we established a drug interaction spectrum for blonanserin, in which nimodipine, felodipine, and amlodipine kinetics exhibited mixed inhibition. Moreover, their inhibitory potencies decreased with CYP3A4.4 and 5 compared to CYP3A4.1. This study provides essential data for personalized clinical use of blonanserin.

Monitoring of Isothermal Crystallization and Time-Temperature Transformation of Amorphous Felodipine: The Time-Domain Nuclear Magnetic Resonance Method.

The isothermal crystallization process of felodipine has been investigated using the time-domain Nuclear Magnetic Resonance (NMR) method for amorphous bulk and ground samples. The obtained induction and crystallization times were then used to construct the time-temperature-transformation (TTT) diagram, both above and below the glass transition temperature (Tg). The Nose temperature was found equal to 363 K. Furthermore, the dynamics of crystalline and amorphous felodipine were compared across varying temperatures. Molecular dynamics simulations were also employed to explore the hydrogen-bond interactions and dynamic properties of both systems.

Inhomogeneous Phase Significantly Reduces Oral Bioavailability of Felodipine/PVPVA Amorphous Solid Dispersion.

Inhomogeneity is a key factor that significantly influences the dissolution behavior of amorphous solid dispersion (ASD). However, the underlying mechanisms of the effects of inhomogeneous phase on the dissolution characteristics as well as the bioavailability of ASDs are still unclear. In this study, two types of felodipine/PVPVA based ASDs with 30 wt % drug loading but different homogeneity were prepared: homogeneous "30 wt % ASD" prepared by spray drying, as well as inhomogeneous "30 wt % PM" prepared by physically mixing the sprayed dried 70 wt % ASD with PVPVA. We aimed to investigate (1) drug-polymer interaction mechanism and "apparent" interaction strength within the two ASDs and (2) dissolution mechanism as well as in vivo performance of the two ASDs. DSC thermogram revealing a single Tg in 30 wt % ASD confirmed its homogeneous phase. 1H NMR, FT-IR, and DVS studies collectively proved that strong hydrogen bonding interactions formed between felodipine and PVPVA in ASDs. Moreover, homogeneous "30 wt % ASD" has more numbers of interacting drug-polymer pairs, and thus exhibits stronger "apparent" interaction strength comparing with that of inhomogeneous "30 wt % PM". Unexpectedly,in the in vitro dissolution studies, inhomogeneous "30 wt % PM" showed much faster dissolution and also generated drug concentration ∼4.4 times higher than that of homogeneous "30 wt % ASD". However, drug precipitate recrystallized much slower in homogeneous "30 wt % ASD", presumably because much more polymer coprecipitated with amorphous drug in this system, which helps inhibiting drug crystallization. Surprisingly, homogeneous "30 wt % ASD" showed a significantly higher bioavailability in the in vivo pharmacokinetic studies, with the maximum plasma concentrations (Cmax) and the area under the curve (AUC) values of about 2.7 and 2.3 times higher than those of inhomogeneous "30 wt % PM". The above findings indicated that the amorphous state of drug precipitate contributes significantly to increase bioavailability of ASDs, while traditional in vitro dissolution studies, for instance, if we only compare the dissolved drug in solution or the capability of an ASD to generate supersaturation, are inadequate to predict in vivo performance of ASDs. In conclusion, the phase behavior of ASDs directly impact the formation of drug-polymer interaction, which controls not only drug supersaturation in solution but also drug crystallization in precipitate, and ultimately affect the in vivo performance of ASDs.

Drug-Polymer Miscibility and the Overlap Concentration (C*) as Measured by Rheology: Variation of Polymer Structure.

OBJECTIVES: Amorphous solid dispersions (ASDs), wherein a drug is molecularly dispersed in a polymer, can improve physical stability and oral bioavailability of poorly soluble drugs. Risk of drug crystallization is usually averted using high polymer concentrations. However, we demonstrated recently that the overlap concentration, C*, of polymer in drug melt is the minimum polymer concentration required to maintain drug in the amorphous state following rapid quench. This conclusion was confirmed for several drugs mixed with poly(vinylpyrrolidone) (PVP). Here we assess the solid-state stability of ASDs formulated with a variety of polymers and drugs and at various polymer concentrations (C) and molecular weights (MWs). We further test the hypothesis that degree of drug crystallization decreases with increasing C/C* and vanishes when C>C*, where C* depends on polymer MW and strength of drug-polymer interaction. METHODS: We test our hypothesis with ASDs consisting of ketoconazole admixed with polyacrylic acid, polymethacrylic acid and poly (methacrylic acid-co-ethyl acrylate); and felodipine admixed with PVP and poly (vinylpyrrolidone-co-vinyl acetate). Values of C* for polymers in molten drug are rheologically determined. Crystallization behavior is assessed by measuring enthalpy of fusion, ΔHf  and by X-ray diffraction. RESULTS: We confirm that ΔHf/ΔHf, C = 0 = f(C/C∗), and essentially no crystallization occurs when C>C*. CONCLUSIONS: Our findings will aid researchers in designing or selecting appropriate polymers to inhibit crystallization of poorly soluble drugs. This research also suggests that C* as determined by rheology can be used to compare drug-polymer interactions for similar molecular weight polymers.

THE NITROSAMINE CONTAMINATION IN BETA BLOCKERS (BISOPROLOL/METOPROLOL), ACE INHIBITORS (LISINOPRIL/PERINDOPRIL), THIAZIDES DIURETICS (HCT), CALCIUM CHANNEL BLOCKERS (AMLODIPINE/FELODIPINE), SARTANS (CANDESARTAN) AND ТHE SUBSEQUENT SKIN CANCER DEVELOPMENT AND PROGRESSION: APOCALYPSE NOW.

The problem of contamination of the most commonly used medicines with nitrosamines is worsening worldwide. According to recent literature data, this "contamination" is the cause not only of skin cancer (keratinocytic/melanoma) but also of gastrointestinal neoplasms, brain tumours, neuroblastoma, rectal carcinoma, acute lymphoblastic leukaemia, and many others. It is these clinical manifestations that are associated with/ or already directly linked to the nitrosamine content of drugs and food products used by patients in previous periods. And it is this permissive availability/contamination that could prove to be the most likely, powerful inducer of acquired mutations underlying the worldwide cancer pandemic. Of further concern is the evidence of contamination of newer classes of medications by nitrosamines- namely: beta blockers, calcium antagonists and selective serotonin reuptake inhibitors (SSRIs). In practice, mankind faces the problem of certainly over 1 billion patients taking nitrosamine-contaminated drugs: 280 million patients with depression (antidepressants), over 1 billion patients with arterial hypertension (antihypertensive drugs), over half a billion patients with type 2 diabetes mellitus (oral antidiabetic drugs/metformin/ sitagliptin), over 4 billion patients with gastritis (ranitidine), over 5 million with tuberculosis (rifampicin), and probably a number of others. The calculations are apocalyptic, since even if only 20-30% of the groups were affected, the number of patients taking these drugs would, by a rough calculation, currently amount to over 1 billion. And there are certainly other classes of drugs yet to be announced. It is for this reason that we should not be surprised that the data on the development of keratinocyte cancer after intake of nitrosamine-contaminated preparations is growing at a breakneck pace. This data indirectly but strongly confirms the importance of a newly introduced concept in the medical science : Nitrosogenesis of skin cancer. A concept, until recently unknown, incomprehensible, but at the same time frightening and gradually accepted, imposing itself and which with each passing day is gaining more and more scientific significance and "visibility", "scientific tangibility, receptivity, and acceptability." This article presents, for the first time in the world literature, patients who developed single/multiple forms of keratinocytic cancer (partly in combination with melanoma precursors-dysplastic moles) after administration of two new classes of potentially nitrosamine-contaminated antihypertensive drugs: beta blockers (bisoprolol, metoprolol) and calcium antagonists (amlodipine, felodipine). For the first time in the scientific literature, the contributory pro-carcinogenic role of another potentially nitrosamine-contaminated ACE inhibitor- lisinopril , as well as that of candesartan: in the development of keratinocytic cancer is also discussed. For the first time in the world literature, the conclusion regarding the pathogenetic relationship between the intake of potentially contaminated drugs (from different drug groups) and cancer development is based on the model of the equivalent clinical manifestation of skin tumors (rather than on controlled long-term prospective analyses). Nitrosamine contamination in these drug groups appears to be the sole and major unifying factor or causative agent for these manifestations.

Water-Resistant Drug-Polymer Interaction Contributes to the Formation of Nano-Species during the Dissolution of Felodipine Amorphous Solid Dispersions.

Drug-polymer interactions are of great importance in amorphous solid dispersion (ASD) formulation for both dissolution performance and physical stability considerations. In this work, three felodipine ASD systems with drug loading ranging from 5 to 20% were prepared using PVP, PVP-VA, or HPMC-AS as the polymer matrix. The amorphization and homogeneity were confirmed by differential scanning calorimetry and powder X-ray diffraction. The intrinsic dissolution behavior of these ASDs was studied in 0.05 M HCl and phosphate-buffered saline (PBS) (pH 6.5). In 0.05 M HCl, PVP-VA ASDs with low drug loading (<15%) showed rapid dissolution accompanied with nano-species generation, while in the PVP system, rapid dissolution and nano-species generation were observed only when drug loading was less than 10%, and HPMC-AS ASDs always released slowly with no nano-species formation. In PBS, PVP-VA ASDs with drug loading less than 10% showed rapid dissolution accompanied with nano-species generation, while for PVP ASDs, rapid dissolution and nano-species generation were observed only when drug loading was 5%. However, 20% drug loading HPMC-AS ASDs exhibited rapid dissolution of felodipine and nano-species generation. When the drug loading was above the transition point of PVP-VA ASDs and PVP ASDs, the release rate was significantly lowered, and no nano-species was generated. To understand this phenomenon, drug-polymer interactions were studied using the melting point depression method and the Flory-Huggins model fitting. The Flory-Huggins interaction parameters (χ) for felodipine/HPMC-AS, felodipine/PVP, and felodipine/PVP-VA were determined to be 0.62 ± 0.07, -0.55 ± 0.20, and -1.02 ± 0.21, respectively, indicating the existence of the strongest attractive molecular interaction between felodipine and PVP-VA, followed by felodipine/PVP, but not in felodipine/HPMC-AS. Furthermore, dynamic vapor sorption further revealed that the molecular interactions between felodipine and PVP or PVP-VA were resistant to water. We concluded that water-resistant drug-polymer interactions in felodipine/polymer systems were responsible for the formation of nano-species, which further facilitated the rapid initial drug dissolution.

Multicomponent Droplet Drying Modeling Based on Conservation and Population Balance Equations.

The aim of this work is to present a modeling tool to describe drying kinetics and delineate evolving physical and chemical behavior of multicomponent droplets during drying. Conservation equations coupled with population balance equations (PBE) are used to achieve this goal. Modeling results are gauged with single salt-water droplet drying from literature and show congruent trends. This model is then extended to a more complex system: various droplet sizes containing methanol (solvent), Felodipine (active ingredient), and PVP (polyvinylpyrrolidone as excipient). The FIB-SEM (Focused-Ion Beam Scanning Electron Microscopy) imaging results from spray-dried particles produced with similar formulation and processing conditions are consistent with phase behavior predicted by the model. The results show competing impacts of transport phenomena on the intermittent shell formation process and final particle structure and chemical heterogeneity. Solute diffusion, solvent efflux, and intra-drop flow impact the model system. It is found that shell formation follows a fluctuating profile where the initial precipitation of the dissolved species on the droplet surface is dampened, and nucleated particles become dispersed periodically until the shell becomes strong enough to withstand internal circulations. These internal effects are dependent on droplet size and are pronounced for larger droplets. That is, the particle phase behavior and physical nature are functions of the atomized droplet size. Stemming understating from this study would inform an optimized unit, operating in target design space. This would provide better product quality control and minimize discrepancies observed in process development during the early phase vs. commercial scale.

Efficacy of felodipine and enalapril in the treatment of essential hypertension with coronary artery disease and the effect on levels of Salusin-ß, Apelin, and PON1 gene expression in patients.

This study aimed to analyze the effect of felodipine combined with enalapril in the treatment of patients with essential hypertension and coronary artery disease. Also, the effect of these medicines was evaluated on the peripheral blood Salusin-ß, Apelin levels, and PON1 gene expression. For this purpose, 110 patients with essential hypertension combined with coronary heart disease, admitted to the hospital from January 2019 to January 2021, were selected and randomly divided into two groups. The control group was given felodipine treatment alone, and the study group was treated with combined application of felodipine and enalapril. The treatment effect, peripheral blood Salusin-ß, Apelin, PON1 gene expression, and the safety of medication were compared between the two groups. The results showed that the post-treatment systolic blood pressure in the study group was 119.77 ± 5.23 mm Hg and diastolic blood pressure was 86.84 ± 5.42 mm Hg, both of which were significantly lower than those in the control group (127.81 ± 6.92 mm Hg and 95.13 ± 6.08 mm Hg), with statistically significant differences (p<0.05). The effective rates of the study group and the control group were 92.73% and 74.54% respectively, with statistically significant differences (P<0.05). The post-treatment peripheral blood Salusin-ßlevel in the study group was 3.77±0.53mmol/L, and Apelin was 1.94±0.58µg/L, with statistically significant differences compared to the control group (P<0.05). The PON1 gene expression in the study group was higher than those in the control group after treatment (P<0.05). Also, the results showed that there was no statistical difference in adverse reactions between the two groups (P>0.05). According to these results, the combination of felodipine and enalapril in patients with essential hypertension combined with coronary artery disease can effectively lower the patients' blood pressure and improve their peripheral blood Salusin-ß, Apelin levels, and PON1 gene expression, thus enhancing the patients' therapeutic effect with few adverse effects and high safety.

Micellar-emphasized simultaneous determination of ivabradine hydrochloride and felodipine using synchronous spectrofluorimetry.

A sensitive and green micellar spectrofluorimetric approach was applied for the simultaneous estimation of ivabradine hydrochloride (IVB) and felodipine (FLD) in the ng/ml concentration range. The approach depended on measuring the first derivative synchronous peak amplitude (1 D) of both drugs at ∆λ = 60 nm in a Tween-80 micellar system. The method was rectilinear alongside the concentration ranges 0.02-0.4 µg/ml and 0.05-1.0 µg/ml at 269.5 nm and 378.5 nm for IVB and FLD, respectively. The proposed method was validated by following the International Council for Harmonization guidelines. The method was successfully applied without interference for laboratory-prepared synthetic mixtures, single pharmaceutical preparations, and within spiked biological fluids with acceptable percentage recoveries. A comparison of the performance of the suggested method with other methods, showed no discrepancy. The method's ecofriendly property evaluated using three different tools, confirming an excellent green method.

Cell culture-based production and in vivo characterization of purely clonal defective interfering influenza virus particles.

BACKGROUND: Infections with influenza A virus (IAV) cause high morbidity and mortality in humans. Additional to vaccination, antiviral drugs are a treatment option. Besides FDA-approved drugs such as oseltamivir or zanamivir, virus-derived defective interfering (DI) particles (DIPs) are considered promising new agents. IAV DIPs typically contain a large internal deletion in one of their eight genomic viral RNA (vRNA) segments. Consequently, DIPs miss the genetic information necessary for replication and can usually only propagate by co-infection with infectious standard virus (STV), compensating for their defect. In such a co-infection scenario, DIPs interfere with and suppress STV replication, which constitutes their antiviral potential. RESULTS: In the present study, we generated a genetically engineered MDCK suspension cell line for production of a purely clonal DIP preparation that has a large deletion in its segment 1 (DI244) and is not contaminated with infectious STV as egg-derived material. First, the impact of the multiplicity of DIP (MODIP) per cell on DI244 yield was investigated in batch cultivations in shake flasks. Here, the highest interfering efficacy was observed for material produced at a MODIP of 1E-2 using an in vitro interference assay. Results of RT-PCR suggested that DI244 material produced was hardly contaminated with other defective particles. Next, the process was successfully transferred to a stirred tank bioreactor (500 mL working volume) with a yield of 6.0E+8 PFU/mL determined in genetically modified adherent MDCK cells. The produced material was purified and concentrated about 40-fold by membrane-based steric exclusion chromatography (SXC). The DI244 yield was 92.3% with a host cell DNA clearance of 97.1% (99.95% with nuclease digestion prior to SXC) and a total protein reduction of 97.2%. Finally, the DIP material was tested in animal experiments in D2(B6).A2G-Mx1r/r mice. Mice infected with a lethal dose of IAV and treated with DIP material showed a reduced body weight loss and all animals survived. CONCLUSION: In summary, experiments not only demonstrated that purely clonal influenza virus DIP preparations can be obtained with high titers from animal cell cultures but confirmed the potential of cell culture-derived DIPs as an antiviral agent.

L-Type Ca2+ Channel Inhibition Rescues the LPS-Induced Neuroinflammatory Response and Impairments in Spatial Memory and Dendritic Spine Formation.

Ca2+ signaling is implicated in the transition between microglial surveillance and activation. Several L-type Ca2+ channel blockers (CCBs) have been shown to ameliorate neuroinflammation by modulating microglial activity. In this study, we examined the effects of the L-type CCB felodipine on LPS-mediated proinflammatory responses. We found that felodipine treatment significantly diminished LPS-evoked proinflammatory cytokine levels in BV2 microglial cells in an L-type Ca2+ channel-dependent manner. In addition, felodipine leads to the inhibition of TLR4/AKT/STAT3 signaling in BV2 microglial cells. We further examined the effects of felodipine on LPS-stimulated neuroinflammation in vivo and found that daily administration (3 or 7 days, i.p.) significantly reduced LPS-mediated gliosis and COX-2 and IL-1ß levels in C57BL/6 (wild-type) mice. Moreover, felodipine administration significantly reduced chronic neuroinflammation-induced spatial memory impairment, dendritic spine number, and microgliosis in C57BL/6 mice. Taken together, our results suggest that the L-type CCB felodipine could be repurposed for the treatment of neuroinflammation/cognitive function-associated diseases.

The Physical Stability of Felodipine and Its Recrystallization from an Amorphous Solid Dispersion Studied by NMR Relaxometry.

The 1H nuclear magnetic resonance (NMR) relaxometry method was applied to investigate the physical stability of an active pharmaceutical ingredient (API) and, for the first time, its recrystallization process in an amorphous solid dispersion system (ASD). The ASD of felodipine and polyvinylpyrrolidone (PVP) was prepared using the solvent evaporation method in a mass ratio of 50:50. In the first stage of the study (250 days), the sample was stored at 0% relative humidity (RH). The recovery of magnetization was described by one-exponential function. In the second stage (300 days in 75% relative humidity), the recrystallization process of felodipine was studied, showing in the sample three components of equilibrium magnetization related to (i) crystalline felodipine, (ii) water, and (iii) felodipine and PVP remaining in the ASD. The study shows that the 1H NMR relaxometry method is a very useful tool for analysing the composition of a three-phase system mixed at the molecular level and for the investigation of recrystallization process of API in amorphous solid dispersion system.

Identification of novel pregnane X receptor (PXR) agonists by In silico and biological activity analyses and reversal of cigarette smoke-induced PXR downregulation.

Cigarette smoke (CS) contains many toxins that collectively harm nearly every organ in the body, and smoking is a key risk factor for many chronic diseases. Aside from its toxic actions, CS may alter expression of the drug- and steroid-binding pregnane X receptor (PXR), which when activated upregulates expression of cytochrome P450 (CYP) enzymes, glutathione transferases (GSTs), and multidrug resistance protein 1 (MDR1), an adaptive metabolic array that mediates clearance of CS component toxins. We sought to identify new PXR agonists that may be useful for restoring PXR activity in conditions wherein it is suppressed, and their mechanisms of PXR binding and activation. PXR has a uniquely larger, hydrophobic, and highly flexible ligand-binding domain (LBD) vs. other nuclear receptors, enabling it to interact with structurally diverse molecules. We tested certain calcium channel blockers (CCBs) as a pharmacological subset of potential PXR ligands, analyzing by molecular docking methods, and identified a putative active site in the PXR LBD, along with the relevant bonds and bonding energies. We analyzed felodipine binding and agonist activity in detail, as it showed the lowest binding energy among CCBs tested. We found felodipine was a potent PXR agonist as measured by luciferase reporter assay, whereas CCBs with higher binding energies were less potent (amlodipine) or nearly inactive (manidipine), and it induced CYP3A4 expression in HepG2 cells, a known target of PXR agonism. Felodipine also both induced PXR mRNA in HepG2 hepatocytes and reduced CS extract-induced diminution of PXR levels, indicating it modulates PXR expression. The results illuminate mechanisms of ligand-induced PXR activation and identify felodipine as a novel PXR agonist.

Impact of Simulated Intestinal Fluids on Dissolution, Solution Chemistry, and Membrane Transport of Amorphous Multidrug Formulations.

The solution behavior and membrane transport of multidrug formulations were herein investigated in a biorelevant medium simulating fasted conditions. Amorphous multidrug formulations were prepared by the solvent evaporation method. Combinations of atazanavir (ATV) and ritonavir (RTV) and felodipine (FDN) and indapamide (IPM) were prepared and stabilized by a polymer for studying their dissolution (under non-sink conditions) and membrane transport in fasted state simulated intestinal fluid (FaSSIF). The micellar solubilization by FaSSIF enhanced the amorphous solubility of the drugs to different extents. Similar to buffer, the maximum achievable concentration of drugs in combination was reduced in FaSSIF, but the extent of reduction was affected by the degree of FaSSIF solubilization. Dissolution studies of ATV and IPM revealed that the amorphous solubility of these two drugs was not affected by FaSSIF solubilization. In contrast, RTV was significantly affected by FaSSIF solubilization with a 30% reduction in the maximum achievable concentration upon combination to ATV, compared to 50% reduction in buffer. This positive deviation by FaSSIF solubilization was not reflected in the mass transport-time profiles. Interestingly, FDN concentrations remain constant until the amount of IPM added was over 1000 µg/mL. No decrease in the membrane transport of FDN was observed for a 1:1 M ratio of FDN-IPM combination. This study demonstrates the importance of studying amorphous multidrug formulations under physiologically relevant conditions to obtain insights into the performance of these formulations after oral administration.

Felodipine blocks osteoclast differentiation and ameliorates estrogen-dependent bone loss in mice by modulating p38 signaling pathway.

Postmenopausal osteoporosis is one of the most common types of osteoporosis resulting from estrogen deficiency in elderly women. In addition, hypertension is another common disease in the elderly, and it has become an independent risk factor for osteoporosis and osteoporotic fractures. Here, we report for the first time that felodipine, a first-line antihypertensive agent, significantly prevents postmenopausal osteoporosis in addition to its vasodilation properties. Quantitative RT-PCR analysis revealed that treatment with felodipine significantly downregulated the genes associated with osteoclast differentiation. RNA-sequencing and western blotting suggested that felodipine could inhibit bone resorption by suppressing MAPK pathway phosphorylation. Moreover, micro-CT scanning and histological analysis in an ovariectomy (OVX)-induced bone-loss mouse model indicated that felodipine might be a potent drug for preventing osteoporotic fractures. Therefore, this study proposes an attractive and promising agent with vasodilation properties to treat postmenopausal osteoporosis.

Insights into Dissolution and Solution Chemistry of Multidrug Formulations of Antihypertensive Drugs.

Using fixed dose combinations of drugs instead of administering drugs separately can be beneficial for both patients and the health care system, but the current understanding of how multidrug formulations work at the molecular level is still in its infancy. Here, we explore dissolution, solubility, and supersaturation of various drug combinations in amorphous formulations. The effect of chemical structural similarity on combination behavior was investigated by using structurally related compounds of both drugs. The effect of polymer type on solution behavior was also evaluated using chemically diverse polymers. Indapamide (IPM) concentration decreased when combined with felodipine (FDN) or its analogues, which occurred even when the IPM solution was undersaturated. The extent of solubility decrease of FDN was less than that of IPM from the dissolution of an equimolar formulation of the drugs. No significant solubility decrease was observed for FDN at low contents of IPM which was also observed for other dihydropyridines, whereas FDN decreases at high contents of IPM. This was explained by the complex nature of the colloidal precipitates of the combinations which impacts the chemical potential of the drugs in solution at different levels. The maximum achievable concentration of FDN and IPM during dissolution of the polyvinylpyrrolidone-based amorphous solid dispersion was higher than the value measured with the hydroxypropyl methylcellulose acetate succinate-based formulation. This emphasizes the significance of molecular properties and chemical diversity of drugs and polymers on solution chemistry and solubility profiles. These findings may apply to drugs administered as a single dosage form or in separate dosage forms and hence need to be well controlled to assure effective treatments and patient safety.

Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*).

Amorphous solid dispersions (ASDs), in which polymers are admixed with a drug, retard or inhibit crystallization of the drug, increasing the drug's apparent solubility and oral bioavailability. To date, there are no guidelines regarding how much polymer should be added to stabilize the amorphous form of the drug. We hypothesized that only drug that is not within a "sphere of influence" of a polymer chain is able to nucleate and form crystals and that the degree of crystallization should depend primarily on the ratio C/C*, where C is the polymer concentration and C* is the overlap concentration. We tested this hypothesis by quenching dispersions of polyvinylpyrrolidone (PVP) dissolved in molten felodipine (FEL) or indomethacin (IMC) at four molecular weights of PVP. For each molecular weight of PVP, C* in the drug (as solvent) was determined by dynamic light scattering and intrinsic viscosity. The enthalpy of fusion (ΔHf), determined by DSC, was used to measure the fraction of drug that crystallized in an ASD. It was found, roughly, that ΔHf/ΔHf,C=0 = f(C/C*) and that no crystallization occurred when C > C*. XRD also showed that crystallization was completely inhibited up to ∼Tg + 75 °C when the polymer concentration was above C*. Our results suggest that stabilization of amorphous drugs can be achieved by incorporating a polymer just above C*, which is much lower than polymer concentrations customarily used in ASDs. This work reveals the importance of C* in selecting polymer concentrations when formulating drugs as ASDs.

Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.

Unconventional Passive Enhancement of Transdermal Drug Delivery: toward a Mechanistic Understanding of Penetration Enhancers Releasing from Acrylic Pressure-Sensitive Adhesive of Patches.

PURPOSE: Penetration enhancers (PEs) enhancing efficacy depends on two processes: PEs release from patches and action on skin. Compared with their action on skin, PEs release process was poorly understood. Therefore, the purpose of this study was to make a mechanistic understanding of PEs release from acrylic pressure-sensitive adhesive of patches and propose an unconventional enhancement of PEs efficacy. METHODS: PEs efficacy was evaluated both in drug permeation study and drug pharmacokinetic study. Confocal Raman spectroscopy was employed to observe PEs release behavior by mapping PEs dynamic distribution in skin. The mechanism of PEs release behavior was provided from molecular interaction and rheology using FT-IR, molecular docking, molecular dynamic simulation and rheometer, separately. RESULTS: The release behavior of PEs themselves greatly restricted their efficacy. By using PEG 400, an improvement of oleic acid (OA) release behavior was achieved, and the efficacy of OA was significantly enhanced with enhancing ratio (ER) from 2.69 to 4.10 and AUClast from 1574 ± 87 to 2664 ± 249 ng·h/mL, separately. The improvement of OA release behavior was primarily resulted from reduction of the interaction between OA and adhesive, which was caused by other small molecules with a strong ability in forming hydrogen bonds with adhesive. Also, the rigidity of adhesive was a factor in affecting PEs release behavior. CONCLUSIONS: An unconventional passive enhancement of transdermal drug delivery was achieved via improving PEs themselves releasing from acrylic pressure-sensitive adhesive. Graphical abstract Influence of PEs release behavior on drug permeation through skin and molecular mechanism.