Gegen Qinlian Decoction ameliorates type 2 diabetes osteoporosis via IGFBP3/MAPK/NFATc1 signaling pathway based on cytokine antibody array.

BACKGROUND: Osteoporosis affects more than half the patients with type 2 diabetes mellitus (T2DM). Up to data, there is no effective clinical practice in managing type 2 diabetes osteoporosis (T2DOP) because of its complex pathogenesis. Gegen Qinlian Decoction (GQD) has been used for the long-term management of T2DM. However, the underlying mechanism of GQD in the treatment of T2DOP remains unknown. PURPOSE: To reveal the role of GQD in T2DOP and its potential therapeutic targets in the management of T2DOP. STUDY DESIGN: The effect of GQD on T2DOP was observed in db/db mice in four groups: model group, GQD low-dose group (GQD-L), GQD high-dose group (GQD-H), and metformin (positive control) group. C57BL/6J mice were used as the negative control group. METHODS: Quantitative phytochemical analysis of GQD was performed using high-performance liquid chromatography (HPLC). Micro-CT and hematoxylin-eosin (H&E) staining were used to evaluate bone histomorphometry. To screen for candidate targets of GQD, a cytokine antibody array was used, followed by bioinformatics analysis. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to determine expression levels. RESULTS: The major active components of GQD were confirmed by HPLC. Micro-CT and H&E staining showed that bone mass was significantly increased in the GQD-H group compared with the model group. Antibody arrays revealed that the expression of insulin-like growth factor binding protein 3 (IGFBP3) was elevated in the GQD-H group. The MAPK pathway was identified using bioinformatics analysis. Additionally, the levels of osteoclastogenesis-related genes, including cathepsin K (Ctsk), acid phosphatase 5 (Acp5), matrix metallopeptidase 9 (Mmp9), and ATPase H+ transporting V0 subunit D2 (Atp6v0d2) were significantly decreased in the GQD-H group. Compared with the model group, high-dosage GQD inhibited phosphorylation of extracellular signal-regulated kinases (ERKs) and P38 mitogen-activated protein kinase (MAPK) and the expression of c-Fos and nuclear factor of activated T cells 1 (NFATc1). CONCLUSION: GQD plays a protective role in T2DOP by upregulating IGFBP3 expression and downregulating the IGFBP3/MAPK/NFATc1 signaling pathway. IGFBP3 in serum may also be a novel biomarker in the treatment of T2DOP. Our current findings not only expand the application of GQD, but also provide a theoretical basis and guidance for T2DOP.

Using Acetone/Water Binary Solvent to Enhance the Stability and Bioavailability of Spray Dried Enzalutamide/HPMC-AS Solid Dispersions.

We demonstrated a facile approach, by adjusting the solvent ratio of water/acetone binary mixture, to alter the intermolecular interactions between Enzalutamide (ENZ) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) for spray drying process, which can be readily implemented to produce spray-dried dispersions (SDD) with enhanced stability and bioavailability. The prepared SDD of ENZ/HPMC-AS were examined systematically in terms of particle size, morphology, dissolution, solubility, stability, and bioavailability. Our results show that the introduction of water (up to 30% volume fraction) can effectively reduce the hydrodynamic diameter of HPMC-AS from approximately 220 nm to 160 nm (a reduction of c.a. 20%), which increases the miscibility of the drug and polymer, delaying or inhibiting the crystallization of ENZ during the spray drying process, resulting in a homogeneous amorphous phase. The benefits of using acetone/water binary mixture were subsequently evidenced by an increased specific surface area, improved dissolution profile and relative bioavailability, enhanced stability, and elevated drug release rate. This fundamental finding underpins the great potential of using binary mixture for spray drying process to process active pharmaceutical ingredients (APIs) that are otherwise challenging to handle.

Hot melt extrusion of heat-sensitive and high melting point drug: Inhibit the recrystallization of the prepared amorphous drug during extrusion to improve the bioavailability.

Using tadalafil (TD) as a representative of heat-sensitive drug with high melting point and strong crystallization tendency, we observed that recrystallization of the prepared amorphous materials during extrusion can result in failure of amorphous solid dispersion (ASD) extrusion. Such recrystallization process of amorphous TD during reheating process was investigated systematically. Our results show that spray-dried amorphous TD sample is more prone to recrystallize (occurs from 150 °C) in comparison to the melt-quenched amorphous TD sample (recrystallizes from 190 °C). Poor stability of the spray-dried TD sample is likely due to an excessive amount of available surface area. Co-extruding Soluplus with spray-dried amorphous TD at 160 °C could yield ASD at 10% drug loading and crystalline solid dispersion above 20% drug loading. The method that spray drying 20% TD with 80% Soluplus and then extruding the spray-dried sample can obtain ASD at 20% drug loading at 160 °C, 142 °C lower than the melting point of TD (302 °C). More importantly, the samples prepared by such strategy exhibited a substantially improved bioavailability compared to the samples that were prepared by either spray-dried or hot-melt extruded processes.

Enhancement of the apparent solubility and bioavailability of Tadalafil nanoparticles via antisolvent precipitation.

The ability to increase the bioavailability and dissolution of poorly soluble hydrophobic drugs has been a major challenge for pharmaceutical development. This study shows that the dissolution rate, apparent solubility and oral bioavailability of tadalafil (Td) can be improved by nano-sized amorphous particles prepared by using antisolvent precipitation. Acetone and an acetone-water solution (v:v, 9:1) were selected as solvents, with deionized water as the antisolvent. The antisolvent precipitation process was conducted at a constant drug concentration of 10 mg/ml, at temperatures of 5, 10 and 15 °C and at volume ratios of antisolvent to solvent (AS/S) of 5, 8 and 10. Solid dispersion was achieved by dissolving the polymer in the antisolvent prior to the precipitation and by spray drying the suspension after the antisolvent precipitation process. The selected polymers were HPMC, VA64, and PVPK30 at concentrations of 33, 100 and 300 mg per 100 ml of water (equivalent to weight ratios of drug-to-polymer of 1:3, 1:1 and 3:1, respectively). The solid dispersions were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FT-IR). The improvements in the dissolution rate, equilibrium solubility, apparent solubility and bioavailability were tested and compared with unprocessed Td. Td particles in the suspension (before spray drying) were 200 nm, and the obtained Td solid dispersion had a size of approximately 5-10 µm. The XRPD, DSC and FT-IR analyses confirmed that the prepared Td particles in the solid dispersions were amorphous. The solid dispersion obtained using the optimized process conditions exhibited 8.5 times faster dissolution rates in the first minute of dissolution, 22 times greater apparent solubility at 10 min and a 3.67-fold increase in oral bioavailability than the as-received Td. The present work demonstrated that low temperature antisolvent precipitation technique has excellent potential to prepare nano-sized amorphous particles with a faster release and a higher bioavailability.