Counter-intuitive discovery in the formulation of poorly water-soluble drugs: Amorphous small-molecule gels.

Amorphous strategies have been extensively used in improving the dissolution of insoluble drugs for decades due to their high free energy. However, the formation of amorphous small-molecule gels (ASMGs) presents a counter-intuitive discovery that significantly limits their practical application. Recently, ASMGs have garnered attention because of their noncovalent structures, excellent biodegradability, and significant potential in various drug delivery systems in the pharmaceutical field. Hence, a comprehensive review is necessary to contribute to a better understanding of recent advances in ASMGs. This review aimed to introduce the main formation mechanisms, summarize possible influencing factors, generalize unique properties, outline elimination strategies, and discuss clinical application potential with preclinical cases of ASMGs. Moreover, few ASMGs are advanced to clinical stages. Intensive clinical research is needed for further development. We hope that this review can provide more efficient and rational guidance for exploring further clinical applications of ASMGs.

Symbiotic Bacteria Modulate Lymantria dispar Immunity by Altering Community Proportions after Infection with LdMNPV.

The symbiotic bacteria-insect interaction is considered to be associated with immunity and drug resistance. However, the wide variety of insect species and habitats is thought to have a significant impact on the symbiotic community, leading to disparate results. Here, we demonstrated that symbiotic bacteria regulated the immune response by changing the proportion of the Gram-positive and the Gram-negative bacterial community in Lymantria dispar (L. dispar) after infection with its viral pathogen, L. dispar Nucleopolyhedrovirus (LdMNPV). After oral infection, the immune deficiency pathway was activated immediately, and the expression of Relish was up-regulated to promote the secretion of antimicrobial peptides. Meanwhile, the abundance of the Gram-negative bacterial community increased at the same time. Moreover, the Toll pathway was not regulated in the same way as the Imd pathway was after infection. However, the change in the Toll pathway's expression remained positively correlated to the abundance of Gram-positive bacteria. This finding implied that the ratio of Gram-negative to Gram-positive bacteria in the LdMNPV infected larvae had an effect on the immune response. Our findings revealed that the immune regulation of L. dispar was regulated by the relative abundance of its symbiotic bacteria at different infection times with LdMNPV, which provides a new way to understand symbiotic bacteria-insect interactions.

Association of weight-adjusted-waist index with all-cause and cardiovascular mortality in China: A prospective cohort study.

BACKGROUND AND AIMS: As a new simple anthropometric index, the weight-adjusted-waist index (WWI) appears to be superior to body mass index (BMI) and waist circumference (WC) in assessing both muscle and fat mass. We aimed to explore the association of WWI with all-cause and cardiovascular mortality in southern China. METHODS AND RESULTS: A total of 12,447 participants (mean age, 59.0 ± 13.3 years; 40.6% men) in Jiangxi Province from the China Hypertension Survey study were included. WWI was defined as WC divided by the square root of weight. The outcome was all-cause and cardiovascular mortality. During a median follow-up of 5.6 years, 838 all-cause deaths occurred, with 390 cardiovascular deaths. Overall, there was a nonlinear positive relationship of WWI with all-cause and cardiovascular mortality. Accordingly, compared with participants in quartiles 1-3 (<11.2 cm/√kg), a significant higher risk of all-cause mortality (HR: 1.36, 95% CI: 1.17, 1.58) and cardiovascular mortality (HR: 1.43, 95% CI: 1.15, 1.77) were found in quartile 4 (≥11.2 cm/√kg). Further adjustment for BMI and WC did not substantially alter the results. No significant interactions were found in any of the subgroups (sex, age, area, physical activity, current smoking, current alcohol drinking, hypertension, and stroke). CONCLUSION: Higher WWI levels (≥11.2 cm/√kg) were associated with increased the risk of all-cause and cardiovascular mortality in southern China. These findings, if confirmed by further studies, suggested that WWI may serve as a simple and effective anthropometric index in clinical practice.

Co-Amorphization of Acemetacin with Basic Amino Acids as Co-Formers for Solubility Improvement and Gastric Ulcer Mitigation.

Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and basic amino acids have the potential to protect the gastrointestinal tract. In order to develop a highly efficient and low-toxic ACM formulation, we prepared ACM CAM systems, with basic amino acids (lysine, arginine, and histidine) as co-formers, using a cryo-milling method. The solid-state behaviors of the ACM CAM systems were characterized by polarizing light microscopy, differential scanning calorimetry, and powder X-ray diffraction. Fourier transform infrared spectroscopy and molecular docking were carried out to understand the formation mechanism. Moreover, the gastro-protective effects of ACM CAM systems were evaluated in a rat gastric ulcer model. The results demonstrated that the CAM systems improved the dissolution rates of ACM compared with the neat amorphous counterpart. Furthermore, ACM CAM systems are significantly effective in mitigating the ACM-induced gastric ulcer in rats, and the ulcer inhibition rates were almost 90%. More importantly, this study provided a useful method for mitigating drug-induced gastrointestinal damage and broadened the applications of drug-amino acid CAM systems.

Drug-drug co-amorphous systems: An emerging formulation strategy for poorly water-soluble drugs.

Overcoming the poor water solubility of small-molecule drugs is a major challenge in the development of clinical pharmaceuticals. Amorphization of crystalline drugs is a highly effective strategy to improve their aqueous solubility. However, amorphous drugs are thermodynamically unstable and likely to crystallize during manufacturing and storage. Recently, drug-drug co-amorphous systems have emerged as a novel strategy to not only enable enhanced dissolution and physical stability of the individual drugs within the system but also to provide a strategy for combination therapy of the same or different clinical indications. This review serves to highlight advances in the methods used to manufacture and characterize drug-drug co-amorphous systems, summarize drug-drug co-amorphous applications reported in recent decades, and provide an outlook on future possibilities and perspectives.

Investigation of the dissolution rate and oral bioavailability of atenolol-irbesartan co-amorphous systems.

Irbesartan (IBS), a common drug to treat hypertension, has poor oral bioavailability because of its limited aqueous solubility. Recently, co-amorphous systems (CAMs) have demonstrated the ability to improve the solubility of poorly water-soluble drugs. In this study, IBS was co-amorphized with a pharmacologically relevant drug atenolol (ATL) by melt-quenching. The structures of the resulting ATL-IBS CAMs, which were formulated in molar ratios of 2:1, 1:1, 1:2 and 1:4, were characterized by the polarizing microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier-infrared transform spectroscopy. ATL-IBS CAM1:1 showed higher IBS dissolution than crystalline IBS, amorphous IBS (IBS AM) and the other CAMs. The results of the supersaturated solution stability showed that ATL enhanced the supersaturation maintenance of IBS by extensive interactions. The CAMs exhibited excellent physical stability at 25°C/60% RH. The pharmacokinetics experiments showed that the relative oral bioavailability of IBS was 2.78-fold higher than bulk IBS (p < 0.001) after oral administration of ATL-IBS CAM1:1 to rats. The results of this study demonstrate that CAMs provide an alternative option for the development of fixed dose combination of ATL and IBS.

Effectiveness of integrated management on hypertension and mortality in rural China: A CHHRS study.

A study was conducted to investigate whether an integrated management (IM) model led by public healthcare providers is effective in reducing cardiovascular disease (CVD)-specific and all-cause mortality rates in low-income rural populations with hypertension. The study recruited 14,234 patients with hypertension aged 18 years or older and allocated them to either an IM group or a usual care (UC) group. During a median follow-up of 48.0 months, the incidences of CVD-specific and all-cause deaths were lower in the IM group than in the UC group. The hazard ratios for CVD-specific mortality and all-cause mortality among patients in the IM group were 0.60 and 0.62, respectively. The results showed that the IM model led by public health providers resulted in clinically significant reductions in CVD-specific and all-cause mortality rates in low-income rural populations with hypertension.

Association of plasma homocysteine with peripheral arterial disease in the hypertensive adults: A cross-sectional study.

Increased plasma homocysteine (Hcy) has been identified as one of the important risk factors for cardiovascular disease. However, the association between plasma Hcy and peripheral artery disease (PAD) is still controversial. This study aimed to investigate the association between plasma Hcy and PAD and the potential modifier factors in Chinese hypertensive adults. A total of 25 300 hypertensive patients aged 18 years or older were included in the analysis in this cross-sectional study. The outcome was PAD, which defined as an ankle-brachial index ≤0.90 in either limb. Multiple logistic regression was used to analyze the relationship between plasma Hcy and PAD. The median plasma Hcy was 14.00 (interquartile range: 11.60-17.80) µmol/L. There was a significant positive association between plasma Hcy and PAD (per SD increment; OR: 1.13; 95% CI: 1.06-1.19). Patients in the upper plasma Hcy tertile (≥16.16 µmol/L) were associated with a 53% increased risk of PAD compared with patients in the lower tertile (<12.33 µmol/L) after adjustment for multiple potential confounders. Subgroup analyses showed the association between Hcy and PAD was robust among various strata. Among Chinese adults with hypertension, plasma Hcy is an independent risk factor for PAD. This finding may improve the risk stratification of PAD.

Associations of total homocysteine and kidney function with all-cause and cause-specific mortality in hypertensive patients: a mediation and joint analysis.

Plasma total homocysteine (tHcy) and kidney function are both associated with mortality risk, but the degree to which kidney function modifies the impact of tHcy on mortality remains unknown. This prospective cohort study included a total of 14,225 hypertensive adults. Cox proportional hazard regression was used to analyze the separate and combined association of tHcy and estimated glomerular filtration rate (eGFR) with all-cause and cause-specific mortality. Mediation analysis was conducted to explore the mediating effect of eGFR. During a median follow-up of 4.0 years, 805 deaths were identified, including 397 deaths from cardiovascular disease (CVD). There were significant, positive relationships of tHcy with all-cause mortality (per 5 µmol/L; HR: 1.09; 95% CI: 1.07, 1.11), CVD mortality (HR: 1.11; 95% CI: 1.08, 1.13), and non-CVD mortality (HR: 1.07; 95% CI: 1.04, 1.10). The proportions of eGFR mediating these relationships were 39.1%, 35.7%, and 49.7%, respectively. There were additive interactions between tHcy and eGFR. Compared with those with low tHcy (<15 µmol/L) and high eGFR (≥90 mL·min-1·1.73 m-2), participants with high tHcy (≥20 µmol/L) and low eGFR (<60 mL·min-1·1.73 m-2) had the highest risk of all-cause mortality (HR: 4.89; 95% CI: 3.81, 6.28), CVD mortality (HR: 5.80; 95% CI: 4.01, 8.40), and non-CVD mortality (HR: 4.25; 95% CI: 3.02, 5.97). In conclusion, among Chinese hypertensive adults, high tHcy and impaired kidney function were independently and jointly associated with higher risks of all-cause and cause-specific mortality. Importantly, kidney function explained most (nearly 40%) of the increased risk of mortality conferred by high tHcy.

Recrystallization Mediates the Gelation of Amorphous Drugs: The Case of Acemetacin.

Amorphization is widely used as an effective method of increasing the solubility of insoluble drugs. However, some amorphous drugs exhibit a much lower dissolution rate than their corresponding crystalline form due to their gelation. In this study, we reported the gels formed from amorphous acemetacin (ACM) for the first time. Gelation was promoted at conditions of lower pH, higher temperature and lower ionic strength. Solid-state characterizations suggested that ACM gels may be formed by recrystallization. This mechanism provides a new direction in facilitating the elimination of gelation for amorphous drugs. Moreover, it also provides the basis for the development of sustained-release formulations using the gelation properties.

Preparation and characterization of novel composite nanoparticles using zein and hyaluronic acid for efficient delivery of naringenin.

Hyaluronic acid (HA), a polymer mainly found in animal tissues, plays an important role in food research. In this study, it was used for delivery improvement of naringenin (NAR) by loading it into zein nanoparticles using an anti-solvent precipitation method. The optimal Nar/zein-HA nanoparticles were uniformly spherical with particle sizes of 209.2 ± 1.9 nm, polydispersity indexes of 0.146 ± 0.032 and zeta-potentials of -19.0 ± 0.7 mV. Moreover, the microstructure of Nar/zein-HA nanoparticles was maintained primarily by hydrophobic, electrostatic, and hydrogen-bonding interactions. Furthermore, Nar/zein-HA nanoparticles showed favorable physical stability and enhanced encapsulation efficiency. Additionally, the antioxidant capacity and release in simulated gastrointestinal digestion of Nar were significantly improved. Overall, these findings indicate that the delivery efficiency of Nar was improved by formulation of ternary nanoparticles.

Association between bilirubin and chronic kidney disease in hypertensive patients: The China hypertension registry study.

Limited data exists on the association between Direct bilirubin (DBIL) and Indirect bilirubin (IBIL) with the risk of chronic kidney disease (CKD) among patients with hypertension. This study aimed to assess the relationship between DBIL and IBIL with the risk of CKD in a cohort of Chinese adults diagnosed with hypertension. This study included 14 182 Chinese patients with hypertension between the ages of 27 and 96. CKD, the outcome variable, was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . The study employed multivariate linear and multivariate logistic regression analysis to evaluate the correlation between DBIL and IBIL with the risk of CKD. The prevalence of CKD in the study population was 9.77%. Multivariate logistic regression analysis showed that the increase in DBIL (OR: 0.66; 95% CI: 0.61, 0.71) and IBIL (OR: 0.75; 95% CI: 0.71, 0.81) were independently and negatively correlated with CKD. Further analyses using a restricted cubic spline (smooth-fitting curve) confirmed the linearly negative association between DBIL and IBIL with the risk of CKD. The subgroup analysis showed that the correlation between IBIL and CKD was stronger among men and populations <65 years of age (p for interaction <.05). DBIL and IBIL were independently and negatively associated with CKD. Furthermore, the correlation between DBIL and IBIL with CKD in the hypertensive population is more significant in those under 65 years of age. These findings may inform future strategies for the management of CKD.

Liquid-liquid phase separation drug aggregate: Merit for oral delivery of amorphous solid dispersions.

As a promising strategy, amorphous solid dispersion has been extensively employed in improving the oral bioavailability of insoluble drugs. Despite the numerous advantages, the problems associated with supersaturation stability limit its further application. Recently, the formation and stability of the liquid-liquid phase separation drug aggregate (LLPS-DA) have been found to be vital for supersaturation maintenance. An in-depth review of LLPS-DA was required to further explore the supersaturation maintenance mechanism in vivo. Hence, this study aimed to present a short review to introduce the LLPS-DA, highlight the in vivo advantages for oral administration, and discuss the prospects to help understand the in vivo behavior of LLPS-DA.

Programmed pH-responsive core-shell nanoparticles for precisely targeted therapy of ulcerative colitis.

pH-Responsive nanotherapeutics were recently developed for the treatment of ulcerative colitis (UC). However, they target the entire colon rather than the UC site, which leads to insufficient accumulation in inflamed colon lesions and causes side effects. Core-shell nanoparticles exhibit unique advantages in improving the precision of targeted delivery. In this study, Eudragit® EPO and L100, two pH-sensitive materials, were coated on nano-sized curcumin to fabricate core-shell nanoparticles. The developed CNs@EPO@L100 exhibited programmed pH-responsive drug release behavior, improved in vitro anti-inflammatory ability, and enhanced accumulation at the site of inflammation in the colon. Furthermore, after oral administration, CNs@EPO@L100 significantly ameliorated the inflammatory symptoms in mice. Taken together, this study provides insights into programmed release through the rational application of pH-sensitive materials and offers strategies for a precisely targeted therapy of UC using core-shell nanoparticles.

Visualization of HOCl in the brains of Alzheimer's disease models using an easily available two-photon fluorogenic probe.

As an inflammatory signaling molecule, hypochlorous acid (HOCl), which is generated by myeloperoxidase (MPO) catalysis, is associated with neuronal cell death during neuroinflammation and the etiology of Alzheimer's disease (AD). Thus, it is significant to employ effective tools for the in vivo mapping of HOCl during the early pathology of AD. In this study, we propose the use of an easily available two-photon fluorogenic probe, named Q-HOCl, for the specific and sensitive detection of HOCl in AD brains. The Q-HOCl probe displayed favorable selectivity and rapid response (20 s) to HOCl with a limit of detection of 12.5 nM. In addition, the Q-HOCl probe manifested splendid ability to penetrate the blood-brain barrier. Subsequently, it was utilized to visualize HOCl fluctuation induced by LPS in PC12 cells via two-photon imaging. Importantly, we monitored the elevated level of HOCl in AD brains compared to normal brains. Ultimately, based on the two-photon imaging of the hippocampus of brain slices and Morris water maze test, the cognitive ability of the AD model mice was effectually ameliorated by treatment with an MPO inhibitor. Thus, we expect that the Q-HOCl probe can be applied to reveal the capacity of HOCl in AD pathology and develop efficacious MPO inhibitor drugs for the treatment of AD.

Positive association between weight-adjusted-waist index and hyperuricemia in patients with hypertension: The China H-type hypertension registry study.

Background and aims: The relationship between the new obesity index weight-adjusted-waist index (WWI) and hyperuricemia is unclear. We aimed to explore the association of the WWI and hyperuricemia among the hypertensive population. Methods: A total of 14,078 hypertension participants with complete data were included in our study. WWI was calculated by waist circumference divided by the square root of weight. Specifically, men with 420 µmol/L and women with 360 µmol/L were considered to have hyperuricemia. Results: The prevalence of hyperuricemia was 61.1% in men and 51.4% in women. On the whole, multivariate logistic regression analyses found that there was a linear positive correlation of WWI with hyperuricemia in both men (OR: 1.37; 95%CI: 1.25, 1.49) and women (OR: 1.35; 95%CI: 1.26, 1.45). Subgroup analysis found that the relationship between WWI and hyperuricemia was stable in stratified subgroups (all P-interactions >.05). Conclusion: WWI showed a positive association with hyperuricemia among hypertension patients.

Revealing the roles of polymers in supersaturation stabilization from the perspective of crystallization behaviors: A case of nimodipine.

Formulating drugs into amorphous solid dispersions (ASDs) represents an attractive means to enhance the aqueous solubility of drugs. Furthermore, water-soluble polymers have proven highly advantageous for stabilizing supersaturated solutions of ASDs. However, the performance and mechanism of various polymers in stabilizing supersaturated drug solutions have not been well-studied. The aim of this study was to investigate the effects of different commercial polymers on the dissolution behaviors and supersaturation stabilization of the ASDs and to further explore the mechanism of polymer mediated supersaturation maintenance by studying the crystallization behaviors of the ASDs. In this study, nimodipine (NMD) was used as a model drug because of its poor water-solubility and fast crystallization rate in aqueous solution, and three polymers polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (PVP VA), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) was selected as the drug carriers to form the ASDs with NMD. Solid-state characterizations of the ASDs confirmed the amorphous state of the ASD systems. ASDPVP VA demonstrated superior supersaturation maintenance in dissolution experiments compared to the other two ASD systems. Among the polymers tested, PVP VA most efficiently maintained dissolution of NMD and prevented its crystallization from the supersaturated solution. The ability of PVP VA to most-effectively maintain supersaturation of the drug was manifested by inhibition of crystal nucleation rather than inhibition of crystal growth following nucleation. These results suggest that nucleation inhibition was instrumental in enabling the polymer-mediated supersaturation maintenance, at least with NMD.