Peng-Fei Yue

Process optimization, characterization and evaluation in vivo of oxymatrine-phospholipid complex.

The objective of this study was to prepare oxymatrine-phospholipid complex (OMT-PLC) to enhance oral bioavailability of oxymatrine. A central composite design approach was used for process optimization. The physicochemical properties of the complex obtained by optimal parameters were investigated by means of differential scanning calorimetry (DSC), X-ray diffraction (XRD) and N-octanol/water partition coefficient. Compared with those of the physical mixture or oxymatrine, the hepatocytes permeability of oxymatrine-phospholipid complexes was studied. The concentrations of oxymatrine after oral administration of OMT-PLC at different time in rats were determined by HPCE. Multiple linear regression analysis for process optimization revealed that the acceptable OMT-PLC was obtained wherein the optimal values of X(1), X(2) and X(3) were 3, 60 degrees C and 3 h, respectively. The oxymatrine and phospholipids in the OMT-PLC were combined by non-covalent bond, not forming a new compound. The better hepatocytes permeability was obtained by the OMT-PLC. Pharmacokinetic parameters of the complex in rats were T(max) 2.17 h, C(max) 0.437 microg ml(-1), AUC(0-infinity) 9.43 microg h ml(-1), respectively. The bioavailability of oxymatrine in rats was increased remarkably after oral administration of OMT-PLC (p<0.05), compared with those of oxymatrine or the physical mixture. This was mainly due to an improvement of the solubility of OMT-PLC.

Preparation, characterization, and bioavailability of ursodeoxycholic acid-phospholipid complex in vivo.

The aim of this study was to prepare ursodeoxycholic acid–phospholipid complex (UDCA-PLC) to enhance oral bioavailability of UDCA, and the physicochemical properties of the complex were studied. Compared with those of UDCA tablet after oral administration in rats, the main pharmacokinetic characteristics and bioavailability of UDCA-PLC orally administered were evaluated. Tetrahydrofuran was used as a reaction medium, UDCA and phospholipids were resolved into the medium, and UDCA-PLC was formed after the organic solvent was evaporated off under vacuum condition. The physicochemical properties of the complex were evaluated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction, particle size distribution analysis, and n-octanol/water partition coefficient (P) study. The blood concentrations of UDCA-PLC and UDCA tablet at different time points after oral administration in rats were assayed by high-performance liquid chromatography (HPLC) after derivatization. The pharmacokinetic parameters were computed by software program 3p87. The X-ray diffraction and DSC studies showed that UDCA and phospholipids in the UDCA-PLC were combined by noncovalent bond, not forming a new compound, and n-octanol/water partition coefficient (P) of UDCA-PLC was effectively enhanced. The mean serum concentration–time curves of UDCA after oral administration of UDCA-PLC and UDCA tablet in rats were both in accordance with open two-compartment model. Pharmacokinetic parameters of UDCA tablet and the PLC in rats were Tmax 1.9144 and 1.5610 h, Cmax 0.0576 and 0.1346 μg/mL, and AUC0–∞ 4.736 and 11.437 μg h/mL, respectively. The bioavailability of UDCA in rats was significantly different (p < .05) compared with those of UDCA tablet after administration. The UDCA-PLC would be more prospective formulation in future.

Process optimization by response surface design and characterization study on geniposide pharmacosomes

The objective of this study was to prepare and characterize geniposide-pharmcosomes (GP-PMS) and optimize the process and formulation variables using response surface methodology. Tetrahydrofuran was used as a reaction medium, GP and phospholipids were resolved into the medium, and GP-PMS was formed after the organic solvent was evaporated off under vacuum condition. The process and formulation variables were optimized by central composite design (CCD) of response surface methodology (RSM). The phospholipid-to-drug ratio (X1), reaction temperature (X2) and the drug concentration (X3) were selected as independent variables and the yield (%) of GP ‘present as a complex’ in the PMS was used as the dependent variable. The physico-chemical properties of the complex obtained by optimal parameters were investigated by means of Fourier transform infrared spectrophotometry (FT-IR), differential scanning calorimetry, n-octanol/water partition coefficient (P) and particle size analysis. Multiple linear regression analysis for optimization by CCD revealed that the higher the yield of GP ‘present as a complex’ in the GP-PMS was obtained wherein the optimal settings of X1, X2 and X3 are 3, 50°C and 5.5 mg/mL, respectively. The DSC and IR studies of GP-PMS by the optimal settings demonstrated that GP and phospholipids in the GP-PMS were combined by non-covalent bond, not forming a new compound. GP-PMS could significantly increased the lipophilicify of GP, and P of GP-PMS in n-octanol and water was about 20 multiples more than that of GP material. Pharmacosomes could be an alternative approach to improve the absorption and permeation of biologically active constituents.

Microcrystalline cellulose-carboxymethyl cellulose sodium as an effective dispersant for drug nanocrystals: A case study.

This study is aimed at seeking an alternative dispersant for spray drying of drug nanosuspensions. The ideal dispersant is not only able to prevent the agglomeration of drug nanocrystals in the suspension state, but also it is able to preserve redispersibility of drug nanocrystals after drying. An active pharmaceutical ingredient (API) was used as a model drug. API nanosuspensions were prepared by homogenization and converted into nanocrystals powder (API-NP) with microcrystalline cellulose-carboxymethyl cellulose sodium (MCCS) via spray drying. It was found that MCCS was able to prevent the aggregation of API-NP in the suspension state and the agglomeration during spray-drying process, possibility due to its high Zeta potential and steric barrier from network structure, and reduction of API size at nanoscale and incorporation into MCCS network structure did not affect the solid state of API as evidenced by DSC and XRD analysis. The spray-dried API-NP/MCCS powders exhibited excellent sphere-shape performance, and could easily redispersed to API-NC suspensions state. Dissolution of the spray-dried API-NP was distinctly superior to those of the crude powder and physical mixture, respectively. Within 30 min, approximate 85.87% of API was dissolved from the API-NP/MCCS. MCCS was demonstrated to be an effective dispersant for spray-dried drug nanocrystals and preservation of the nanocrystals associated with excellent redispersibility.

A novel high-pressure precipitation tandem homogenization technology for drug nanocrystals production – a case study with ursodeoxycholic acid

Abstract To overcome the limitations of the conventional particle size reduction technologies, a novel combinative particle size reduction method for the effective production of homogeneous nanosuspensions was investigated. Ursodeoxycholic acid, a poorly soluble drug representative, was tried to prepare nanosuspension by homogenization technology and high-pressure precipitation tandem homogenization technology. It was shown that the combinative approach could significantly improve the particle size reduction effectiveness over conventional homogenization approach. The Box–Behnken design analysis for process optimization revealed that the acceptable UDCA-NS was obtained wherein the optimal values of A, B, C and D were 10%, 500 bar, 0.125 and 600 bar, respectively. SEM results demonstrated that no significant aggregation or crystals growth could be observed in the freeze-dried UDCA nanocrystals. The DSC and XRD results showed that UDCA remained in a crystalline state. Dissolution velocities of the freeze-dried UDCA-NS powder were distinctly superior compared to those of the crude powder and physical mixture. The high-pressure precipitation tandem homogenization technology can be a good choice for nanosuspension preparation of poorly soluble UDCA, due to high efficiency of particle size reduction.

Structural Stabilities and Transformation Mechanism of Rhynchophylline and Isorhynchophylline by Ultra Performance Liquid Chromatography/Time-of-Flight Mass Spectrometry (UPLC/Q-TOF-MS)

To reveal the structural stabilities and transformation mechanism of rhynchophylline (RIN) and isorhynchophylline (IRN), HPLC and UPLC-Q-TOF-MS method were developed for the qualitative and quantitative analysis of the conversion rate. The method was validated for linearity, inter- and intra-day precisions, repeatability and stability. All the quantitative determination method validation results were satisfactory. Under the optimized chromatographic conditions, the effect of various heat temperatures, retention time, and solvent polarities on conversion rate and equilibrium were systematically investigated for the first time. Besides, a model relating the retention yield value and time-temperature was built to predict the t0.5 and Ea of the conversion rate by the Arrhenius equation. The experimental results proved to be in good accordance with the predicted values. Furthermore, UPLC-Q-TOF-MS analysis was performed to verify the transformation mechanism and provide valuable information for stability analysis of the conversion products.

The Roles of Vitrification of Stabilizers/Matrix Formers for the Redispersibility of Drug Nanocrystals After Solidification: a Case Study

To elucidate the roles of vitrification of stabilizers/matrix formers for the redispersibility of drug nanocrystal powder after solidification at storage stress, the influence of different drying methods and storage stresses on stability of drug nanocrystals was systemically investigated. A poorly soluble drug, baicalin, used as model drug was converted into baicalin nanocrystals (BCN-NC). The residual moisture contents of BCN-NC were applied at two different stress conditions defined as “conservative” (<1%) and “aggressive” (>1%), respectively. The influence of different stabilizers, matrix formers, and storage stresses on the redispersibility of BCN-NC powder was systemically investigated, respectively. The results showed that storage stresses had significantly influence the redispersibility of BCN-NC. Aggressive storage temperature and residual moisture could be unfavorable factors for stability of drug nanocrystals, due to the exacerbation of aggregation of BCN-NC induced by vitrification. It was demonstrated that vitrification of spray-dried BCN-NC was dependent on temperature and time. The polymeric stabilizers hydroxypropylmethylcellulose (HPMC) and sodium carboxymethyl starch (CMS-Na) with high glass transition temperature (Tg) played more important role in protecting the BCN-NC from breakage during storage, compared to the surfactants Tween 80, d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS), or RH 40. Besides, the polyvinylpyrrolidone K30 (PVP K30) and lactose with high Tg were effective matrix formers for preserving the redispersibility of BCN-NC. It was concluded that the vitrification transition of stabilizers/matrix formers could be responsible for aggregation of drug nanocrystals during storage, which was a time-dependent process. The suitable residual moisture contents (RMC) and Tg were very important for preserving the stability of drug nanocrystals during storage.

Enhanced intestinal absorption activity and hepatoprotective effect of herpetrione via preparation of nanosuspensions using pH-dependent dissolving-precipitating/homogenization process.

The main purpose of this study was to enhance the intestinal absorption activity and hepatoprotective effect of herpetrione by drug nanosuspensions.

Process Optimization, Characterization, and Release Study In Vitro of an Intravenous Puerarin Lipid Micropheres Loaded with the Phospholipid Complex

A new formulation of puerarin lipid microspheres with the puerarin–phospholipid complex was prepared. A central composite design approach was used for process optimization in order to obtain the acceptable puerarin–phospholipid complex. The physicochemical properties of the complex obtained by optimal parameters were investigated by Fourier transform infrared spectrophotometry (FTIS). The physicochemical characterizations of puerarin lipid microspheres was evaluated. The release study in vitro of puerarin was studied by using microdialysis and pressure ultrafiltration technology. Multiple linear regression analysis for process optimization revealed that the acceptable puerarin–phospholipid complex was obtained wherein the optimal values of X1, X2, and X3 were 3, 60°C, and 3 hours, respectively. The FTIS studies of the complex demonstrated that puerarin and phospholipids were combined by non-covalent bonds, not form new compounds. The mean diameter and entrapment efficiency (%) were 171.35 and 87.94, respectively. The release of puerarin lipid microspheres could be evaluated by using microdialysis and ultrafiltration, but microdialysis seemed to be more suitable for the release study of puerarin lipid spheres. The drug release at three drug concentrations was initially rapid, but reached a plateau value within 30 minutes. Drug release of puerarin from the lipid microspheres occurred via burst release.

Hydroxypropylcellulose as matrix carrier for novel cage-like microparticles prepared by spray-freeze-drying technology

The objective of this study is to design novel dissolution-enhanced microparticles loaded poorly soluble drug nanocrystals used a low viscosity of hydroxypropylcellulose (HPC) as matrix carrier. An interesting approach combined homogenization and the spray-freeze-drying technique was developed. The results demonstrated that the ratio of HPC to drug played an important role in size-reduction efficiency of drug during homogenization. And the formation of cage-like structure of the composite particles depended on ratio of HPC to drug. The spray-freeze-dried composite particles with HPC ratio of 1:2, 1:1 and 2:1 possessed excellent redispersibility, which attributed to its porous matrix and large surface area (3000m2/g). The dissolution of spray-freeze-dried composite particles with higher ratios of HPC (1:2 and 1:1) was significantly enhanced, which attributed to the particle size reduction of drug. The HPC could immobilize drug nanocrystals in its cage-like structure and prevent it from the subsequent agglomeration during storage. In conclusion, the prepared cage-like microparticles is a promising basis for further formulation development.