Evaluation the injectability of injectable microparticle delivery systems on the basis of injection force and discharged rate.

BACKGROUND: Subcutaneous injection of biopharmaceutical agents or microparticles is challenging due to issues with low injection efficiency and high residual amounts. OBJECTIVE: This study aimed to determine the important factors affecting the injectability of microparticle delivery systems, establish a suitable injection system with lower injection force and higher discharge rate, and eventually develop a reliable injectability evaluation system for injectable microparticle delivery systems in vitro and in vivo. METHODS: The effects of various parameters, including particle size, injection speed, concentration of microspheres suspension, vehicle viscosity, needle length and gauge were evaluated by measuring the injection force and discharge rate. The characteristics of microparticles and rheological measurement of the suspension systems were studied. A design of experiment approach was utilized to evaluate the interaction between the microsphere suspension, vehicle viscosity and needle gauges. Both in vitro sieve tests and in vivo tests in rats were conducted to evaluate injectability. RESULTS: The in vitro test results showed that the vehicle viscosity and injection speed have varying effects on discharge rate and injection force, respectively. Particle size and needle gauge have substantial influence on injectability, larger particle size and smaller needle gauges resulting in poor injectability, while the needle gauge was found to have the greatest influence on injectability. Levonorgestrel (LNG) microsphere and glass bead were relatively uniform spherical, the glass bead had extremely smooth surface; while mesoporous silica had irregular shape. The settling rate of glass bead was the fastest, which was about 18 times faster than the LNG microsphere. The CMC-Na had a poor interaction with the LNG microspheres, glass bead and mesoporous silica and showed basically Newtonian behavior in the shear rate range of 0.1 s-1-100 s-1. When shear rate increased to more than 100 s-1, no obvious shear thinning behavior was observed. CMC-Na formed a nodule structure with whether LNG microspheres or the glass beads, which were much lower than that with the mesoporous silica in static state, among which the glass beads were the weakest. The viscosity of the suspension increased with the rising of the volume fraction of particles. Fundamentals of hydrodynamics in capillaries were referenced, such as Navier-Stokes Law equation, Krieger-Dougherty (K-D) equation, Hagen-Poiseuille equation. The best results achieved was using a suspension concentration of 120-240 mg /mL and a viscosity of 60 cP at 20 °C with 23-gauge needles. The optimized conditions were verified in vivo tests. It was proven that the LNG microsphere suspension had a good injectability when injected into subcutaneous tissue of rats. CONCLUSION: The injection system of injectable microparticle delivery system with lower injection force and higher discharge rate was established and the evaluation method was suitable for the injectability evaluation both in vivo and in vitro. Improved injectability would promote the clinical translation of microparticle delivery systems.

Current Progress and Outlook for Agrimonolide: A Promising Bioactive Compound from Agrimonia pilosa Ledeb.

Agrimonolide (AM), which is a derivative of isocoumarins, is found mainly in the herb Agrimonia pilosa Ledeb. This compound is highly lipophilic and readily crosses the blood-brain barrier. In recent years, interest has grown in the use of AM as a multitarget natural treatment for various diseases, such as cancer, inflammation, hepatic injury, myocardial damage, and diabetes mellitus. The potential mechanisms of these pharmacological effects have been clarified at cellular and molecular levels. AM shows no cytotoxicity over a range of concentrations in different types of cells, providing evidence for its good safety profile in vitro. These findings indicate that AM is a promising medicinal agent. However, most studies on AM's pharmacological activities, mechanisms of action, and safety lack substantial animal or human data. Additionally, the pharmacokinetics, metabolism, and disposition of this compound have received little attention. This review highlights the status of current information regarding the sources, properties, pharmacological effects, and safety of AM. Furthermore, potential strategies to resolve problematic issues identified in previous studies are fully discussed. This summary and analysis of the research progress of AM may inspire deeper investigations and more extensive applications of AM in the future.

Physical Characterization and Safety Evaluation of Folic Acid-conjugated Mesoporous Silica Nanoparticles Loaded with Rhodojaponin III.

BACKGROUND: Rhodojaponin III (RJ-III), a characteristic diterpene of Rhododendron molle G. Don, has a wide range of pharmacological activities including anti-inflammatory, antihypertensive, and analgesic effects. However, further research and development have been limited because of its intense acute toxicity and poor pharmacokinetic profile. OBJECTIVE: In this study, we propose the construction of folic acid-conjugated mesoporous silica nanoparticles (FA-MSNs) as carriers to deliver RJ-III in an attempt to reduce acute toxicity and improve biomedical applications by prolonging drug release and targeting delivery. METHODS: FA-MSNs were synthesized and characterized. RJ-III was then loaded into FA-MSNs (RJIII@ FA-MSNs), and the in vitro drug release profile was assessed. Subsequently, the RJ-III@FAMSNs' cytotoxicity and targeting efficiency were explored in lipopolysaccharide-activated RAW 264.7 cells, and their acute toxicity was investigated in mice. RESULTS: Spherical FA-MSNs were approximately 122 nm in size. Importantly, the RJ-III@FA-MSNs showed prolonged RJ-III release in vitro. Moreover, in lipopolysaccharide-activated RAW 264.7 cells, RJ-III@FA-MSNs not only reduced the cytotoxicity of RJ-III (P < 0.01), but also showed a good targeting effect from the results of cellular uptake. Additionally, the acute toxicity results demonstrated that RJ-III@FA-MSNs improved the LD50 value of RJ-III in mice by intraperitoneal injection 10-fold. CONCLUSION: This is the first study to use FA-MSNs as carriers of RJ-III to reduce the acute toxicity of RJ-III. The results confirm the potential for targeted delivery of RJ-III in inflammatory cells to enhance efficacy, as well as providing data for future investigations on anti-inflammatory activity.

Pharmacokinetic incompatibility of the Huanglian-Gancao herb pair.

BACKGROUND: Pharmacokinetic interaction is one of the most important indices for the evaluation of the compatibility of herbal medicines. Both Gancao (Glycyrrhizae Radix et Rhizoma) and Huanglian (Coptidis Rhizoma) are commonly used traditional Chinese medicines (TCMs). In this study, the influence of Gancao on the pharmacokinetics of Huanglian was systematically studied by using berberine as a pharmacokinetic marker. METHODS: Extracts of the herbal pieces of Huanglian and the herb pair (Huanglian plus Gancao) were prepared with boiling water. The concentration of berberine in the samples was analyzed using liquid chromatography-mass spectrometry. The total amounts of berberine in all extract samples were compared. Comparative pharmacokinetic studies of Huanglian and the herb pair were conducted in ICR mice. In vitro berberine absorption and efflux were studied using mice gut sacs. The equilibrium solubility of berberine in the extracts was determined. The in vitro dissolution of berberine was comparatively studied using a rotating basket method. RESULTS: Gancao significantly reduced berberine exposure in the portal circulation (425.8 ng·h/mL vs. 270.4 ng·h/mL) and the liver (29,500.8 ng·h/mL vs. 15,422.4 ng·h/mL) of the mice. In addition, Gancao decreased the peak concentration (Cmax) of berberine in the portal circulation (104.3 ng·h/mL vs. 76.5 ng·h/mL) and liver (4926.1 ng·h/mL vs. 2642.8 ng·h/mL) of mice. Significant influences of Gancao on the amount of berberine extracted (32% reduction), the solubility of berberine (34.7% compared with the control group), and dissolution (88.7% vs. 66.1% at 15 min in acid buffer and 68% vs. 51.8% at 15 min in phosphate buffer) were also revealed. Comparative pharmacokinetic studies in ICR mice indicated that the formation of sediment was unfavorable in terms of berberine absorption (345.3 ng·h/mL vs. 119.8 ng·h/mL). CONCLUSIONS: Gancao was able to reduce intestinal absorption and in vivo exposure of berberine in Huanglian via the formation of sediment, which caused reductions in the extracted amount, solubility, and dissolution of berberine.

Pharmacokinetics, bioavailability and tissue distribution studies of rhodojaponin III in mice using QTRAP LC-MS/MS.

Rhodojaponin III is a bioactive diterpenoid isolated from the medicinal plant Rhododendron molle G. Don. Quantitative analysis of rhodojaponin III was challenging and the pharmacokinetics of oral rhodojaponin III remained to be investigated. Here, a rapid and sensitive liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated. The calibration curve was linear over the concentration range of 1-200 ng/mL (r = 0.992). The method was further validated following internationally approved guidelines and all the issues including intra- and inter-day precision, accuracy, carryover, extraction recovery, matrix effects and stability met the recommended limits. The method was then applied to study the pharmacokinetics of rhodojaponin III in mice after intravenous (0.06 mg/kg) or oral (0.24 mg/kg) administration. The results showed that rhodojaponin III had fast oral absorption (time to peak concentration, 0.08 h) and good oral bioavailability (73.6%). In addition, rhodojaponin III was quickly eliminated after it was intravenously or orally administered, with half-life values of 0.19 and 0.76 h, respectively. After oral administration, it was widely distributed in tissues including kidney, lung, heart, spleen and thymus, but had extremely low concentrations in liver and brain. The data presented in this study is beneficial for the further study of rhodojaponin III.

Zhujie Hewei Granules Ameliorated Reflux Esophagitis in Rats.

BACKGROUND: Gastroesophageal reflux disease (GERDs) is a common chronic digestive system disease, in which the symptoms of reflux esophagitis (RE) seriously affect the quality of life. AIMS: We aimed to study the therapeutic effect of Zhujie Hewei granules (ZHG) on reflux esophagitis in model rats. MATERIALS AND METHODS: A rat model of RE was established with the steps of half pylorus ligation, cardiotomy, and hydrochloric acid perfusion. The rats in treatment groups were orally administered with 1.30, 2.60, or 5.20 g/kg ZHG once daily for 28 days. Histopathological changes of the esophagus were observed with hematoxylin-eosin staining. The content of total bilirubin and pH in gastric juice was determined. Esophageal mucosal injury was assessed by macroscopic observation scores, mucosal injury index scores, and esophageal inflammation scores. The levels of gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) in serum were evaluated by using ELISA kits. RESULTS: After treatment with ZHG, the body weight of RE rats tended to increase drastically, the macroscopic observation scores of the esophagus mucous membrane decreased (P < 0.05), the mucosal injury index scores decreased (P < 0.05), the gastric pH values increased (P < 0.05), and the levels of serum MTL and VIP decreased (P < 0.05). In addition, the high dose of the ZHG-treated group showed lower serum GAS (P < 0.05), while the high and middle doses of the ZHG-treated groups showed lower esophageal inflammation scores (P < 0.05). CONCLUSIONS: ZHG was effective in treating RE in rats due using mechanisms including improving the pH value of gastric contents, decreasing the gastrointestinal hormones (including GAS, MTL, and VIP), and improving the inflammatory damage.