The preparation, characterization, and application of porous core-shell composite particles produced with laboratory-scale spray dryer.

OBJECTIVE: To prepare porous core-shell composite particles (PCPs) in order to improve the flowability and compactibility of powder materials for direct compaction (DC), as well as the dissolution of tablets. SIGNIFICANCE: The results obtained are meaningful to boosting the development and further research of PCPs on DC. Methods: In this study, hydroxypropyl methylcellulose (HPMC E3) and polyvinylpyrrolidone (PVP K30) were selected as shell materials, the Xiao Er Xi Shi formulation powder (XEXS) was used as the core materials, ammonium bicarbonate (NH4HCO3), and sodium bicarbonate (NaHCO3) were employed as pore-forming agent. Using co-spray drying method to prepare composite particles (CPs). Then, the physical properties and comparison between different CPs were characterized comprehensively. Finally, the different CPs were directly compacted as tablets to explore the effect on the dissolution behavior of DC tablets, respectively. RESULTS: (i) The XEXS PCPs were prepared successfully by co-spray drying, and the yield of PCPs is almost 80%; (ii) The TS values of PCP-X-P-Na, PCP-X-P-NH4, PCP-X-H-Na and PCP-X-P-Na were 5.70, 7.56, 3.98, and 6.88 times higher than that of raw material (X); (iii) The disintegration time of PCPs tablets decreased 10-25% when compared with CPs tablets; (iv) The values of Carr's index (CI), Hausner ratio (HR), Caking strength (CS), and Cohesion index (CoI) of PCP-X-H-NH4 were 19.16%, 19.29%, 40.14%, and 6.39% lower than that of X, respectively. CONCLUSIONS: The PCPs prepared by co-spray drying did improve the flowability and compactibility of powder, as well as the dissolution of tablets.

Fabrication and Characterization of ß-Cyclodextrin/Mosla Chinensis Essential Oil Inclusion Complexes: Experimental Design and Molecular Modeling.

Essential oils (EOs) are primarily isolated from medicinal plants and possess various biological properties. However, their low water solubility and volatility substantially limit their application potential. Therefore, the aim of the current study was to improve the solubility and stability of the Mosla Chinensis (M. Chinensis) EO by forming an inclusion complex (IC) with ß-cyclodextrin (ß-CD). Furthermore, the IC formation process was investigated using experimental techniques and molecular modeling. The major components of M. Chinensis 'Jiangxiangru' EOs were carvacrol, thymol, o-cymene, and terpinene, and its IC with ß-CD were prepared using the ultrasonication method. Multivariable optimization was studied using a Plackett-Burman design (step 1, identifying key parameters) followed by a central composite design for optimization of the parameters (step 2, optimizing the key parameters). SEM, FT-IR, TGA, and dissolution experiments were performed to analyze the physicochemical properties of the ICs. In addition, the interaction between EO and ß-CD was further investigated using phase solubility, molecular docking, and molecular simulation studies. The results showed that the optimal encapsulation efficiency and loading capacity of EO in the ICs were 86.17% and 8.92%, respectively. Results of physicochemical properties were different after being encapsulated, indicating that the ICs had been successfully fabricated. Additionally, molecular docking and dynamics simulation showed that ß-CD could encapsulate the EO component (carvacrol) via noncovalent interactions. In conclusion, a comprehensive methodology was developed for determining key parameters under multivariate conditions by utilizing two-step optimization experiments to obtain ICs of EO with ß-CD. Furthermore, molecular modeling was used to study the mechanisms involved in molecular inclusion complexation.

Serum PCSK9 is positively correlated with disease activity and Th17 cells, while its short-term decline during treatment reflects desirable outcomes in ankylosing spondylitis patients.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) participates in the autoimmune disease pathology by regulating T helper (Th) cell differentiation, NF-κB pathway, toll-like receptor 4, etc. This study intended to investigate the association of serum PCSK9 with disease activity, Th cells, and treatment response in ankylosing spondylitis (AS) patients. METHODS: Eighty-nine active AS patients were enrolled in this multicenter, prospective study. Serum was collected from AS patients at week (W)0, W4, W8, and W12, as well as from 20 osteoarthritis patients and 20 healthy controls after enrollment to detect PCSK9 by ELISA. Based on the ASAS40 response at W12, AS patients were classified as responders and non-responders. RESULTS: PCSK9 was increased in AS patients versus healthy controls (P < 0.001) and osteoarthritis patients (P = 0.006). In AS patients, PCSK9 was positively linked with C-reactive protein (CRP) (P = 0.003) and ASDAS-CRP (P = 0.017), but not with other clinical properties (P > 0.05). Besides, PCSK9 was negatively correlated with interleukin-4 (P = 0.034), positively associated with Th17 cells (P = 0.005) and interleukin-17A (P = 0.014), but did not relate to Th1 cells, interferon-γ, or Th2 cells (all P > 0.05). Additionally, PCSK9 was decreased from W0 to W12 in general AS patients (P < 0.001) and responders (P < 0.001) but remained unchanged in non-responders (P = 0.129). Moreover, PCSK9 was lower at W4 (P = 0.045), W8 (P = 0.008), and W12 (P = 0.004) in responders versus non-responders. Furthermore, the treatment options did not affect the PCSK9 level (P > 0.05). CONCLUSION: Serum PCSK9 is positively associated with disease activity and Th17 cells, while its short-term decline reflects desirable treatment response in AS patients.

High glucose induced HIF-1α/TREK1 expression and myometrium relaxation during pregnancy.

Background: The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM patients have a significantly higher rate of cesarean section and postpartum hemorrhage, suggesting changes in uterine contractility. TWIK-1-related potassium channel (TREK1) expressed in the pregnant uterus and its role in uterine contraction. In this study, we examined the expression of HIF-1α and TREK1 proteins in GDM uterine and investigated whether high glucose levels are involved in the regulation of human uterine smooth muscle cells (HUSMCs) contraction through TREK1, and verified the role of HIF-1α in this process. Methods: Compared the uterine contractility between GDM and normal patients undergoing elective lower segment cesarean section. The HUSMCs were divided into normal glucose group, high glucose group, normal glucose with CoCl2 group, CoCl2 with echinomycin/L-Methionine group, and high glucose with echinomycin/L-Methionine group; Compare the cell contractility of each group. Compared the expression of hypoxia-inducible factor-1α (HIF-1α) and TREK1 protein in each group. Results: The contractility of human uterine strips induced by both KCl and oxytocin was significantly lower in patients with GDM compared with that in normal individuals, with increased TREK1 and HIF-1α protein expression. The contractility of cultured HUSMCs was significantly decreased under high glucose levels, which was consistent with increased expression of HIF-1α and TREK1 proteins. The contractility of HUSMCs was decreased when hypoxia was induced by CoCl2 and increased when hypoxia was inhibited by echinomycin. The TREK1 inhibitor L-methionine also recovered the decreased contractility of HUSMCs under high glucose levels or hypoxia. Discussion: The high glucose levels decreased the contractility of the myometrium, and increased expression of HIF-1a and TREK1 proteins play a role in changes in uterus contractility.

PCSK9 promotes T helper 1 and T helper 17 cell differentiation by activating the nuclear factor-κB pathway in ankylosing spondylitis.

OBJECTIVE: Our previous study reveals that proprotein convertase subtilisin/kexin type 9 (PCSK9) is positively related to inflammatory markers, T helper (Th)-17 cells, and treatment response in ankylosing spondylitis (AS) patients. Subsequently, this study aimed to explore the effect of PCSK9 on Th cell differentiation and its potential molecular mechanism in AS. METHODS: Serum PCSK9 was determined by enzyme-linked immunosorbent assay in 20 AS patients and 20 healthy controls (HCs). Then naïve CD4+ T cells were isolated from AS patients and infected with PCSK9 overexpression or knockdown adenovirus followed by polarization assay. Afterward, PMA (an NF-κB activator) was administrated. RESULTS: PCSK9 was increased in AS patients compared to HCs (p < .001), and it was positively related to Th1 cells (p = .050) and Th17 cells (p = .039) in AS patients. PCSK9 overexpression increased the CD4+ IFN-γ+ cells (p < .05), CD4+ IL-17A+ cells (p < .01), IFN-γ (p < .01), and IL-17A (p < .01), while it exhibited no effect on CD4+ IL-4+ cells or IL-4 (both p > .05); its knockdown displayed the opposite function on them. Moreover, PCSK9 overexpression upregulated the p-NF-κB p65/NF-κB p65 (p < .01), while it had no effect on p-ERK/ERK or p-JNK/JNK (both p > .05); its knockdown decreased p-NF-κB p65/NF-κB p65 (p < .01) and p-JNK/JNK (p < .05). Then, PMA upregulates p-NF-κB p65/NF-κB p65 (p < .001) and increased CD4+ IFN-γ+ cells, CD4+ IL-17A+ cells, IFN-γ, and IL-17A (all p < .01), also it alleviated the effect of PCSK9 knockdown on NF-κB inhibition and Th cell differentiation (all p < .01). CONCLUSION: PCSK9 enhances Th1 and Th17 cell differentiation in an NF-κB-dependent manner in AS, while further validation is necessary.

Surface Modifiers on Composite Particles for Direct Compaction.

Direct compaction (DC) is considered to be the most effective method of tablet production. However, only a small number of the active pharmaceutical ingredients (APIs) can be successfully manufactured into tablets using DC since most APIs lack adequate functional properties to meet DC requirements. The use of suitable modifiers and appropriate co-processing technologies can provide a promising approach for the preparation of composite particles with high functional properties. The purpose of this review is to provide an overview and classification of different modifiers and their multiple combinations that may improve API tableting properties or prepare composite excipients with appropriate co-processed technology, as well as discuss the corresponding modification mechanism. Moreover, it provides solutions for selecting appropriate modifiers and co-processing technologies to prepare composite particles with improved properties.