Preparation and in vivo pharmacokinetics of nanosuspensions of naringenin phospholipids complex / 中成药

AIM To prepare the nanosuspensions of naringenin phospholipids complex,and to investigate their in vivo pharmacokinetics.METHODS High-pressure homogenization method was applied to preparing the nanosuspensions of phospholipids complex.With stabilizer type,stabilizer-phospholipids complex consumption ratio,homogeneous pressure and homogeneous frequency as influencing factors,particle size,PDI and Zeta potential as evaluation indices,the formulation was optimized by single factor test.The morphology was observed under transmission electron microscope,after which X-ray powder diffraction analysis was performed,solubility,oil-water partition coefficient,dissociation rate of phospholipids complex and accumulative release rate were determined.Twenty-four rats were randomly assigned into four groups and given intragastric administration of the 0.5%CMC-Na suspensions of naringenin and its phospholipids complex,nanosuspensions and nanosuspensions of phospholipids complex(30 mg/kg),respectively,after which blood collection was made at 0,0.25,0.5,1,1.5,2,3,4,5,6,8,10,12 h,HPLC was adopted in the plasma concentration determination of naringenin,and main pharmacokinetic parameters were calculated.RESULTS The optimal formulation was determined to be 50 mg for naringenin consumption,PVP K30+TPGS(1 ∶ 1)as stabilizer,3 ∶ 1 for stabilizer-phospholipids complex consumption ratio,100 MPa for homogeneous pressure,and 10 times for homogeneous frequency,respectively.The obtained spherical-like or oval nanosuspensions of phospholipids complex demonstrated the average particle size,PDI and Zeta potential of(260.53±25.86)nm,0.160±0.024 and(-31.08±1.37)mV,respectively.Naringenin existed in the nanosuspensions of phospholipids complex in an anamorphous state,along with increased solubility,oil-water partition coefficient and dissociation rate of phospholipids complex,and the accumulative release rate reached more than 90%within 4 h.Compared with raw medicine and nanosuspensions,the nanosuspensions of phospholipids complex displayed shortened tmax(P<0.05)and increased Cmax,AUC0-t,AUC0-∞(P<0.05,P<0.01),the relative bioavailability was enhanced to 4.38 times.CONCLUSION The nanosuspensions of phospholipids can enhance naringenin's solubility and dissolution rate,and promote its in vivo absorption.

Aptamer and Peptide-Modified Lipid-Based Drug Delivery Systems in Application of Combined Sequential Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is known as the most common malignancy of the hepatobiliary system with a continued increase in incidence but limited therapeutic options. Nanomedicine has provided a promising strategy through engineered nanocarriers that are capable of targeting therapeutic agents specifically to tumor cells. In this research, two aptamer/peptide-modified lipid-based drug delivery systems (A54-PEG-SLN/OXA and A15-PEG-SLN/SAL) were developed as a sequential therapeutic strategy to conquer specific hepatocellular carcinoma. The nanomedicine A54-PEG-SLN/OXA was able to target specific hepatocellular carcinoma cell BEL-7402 and exhibited a strong targeting ability and antitumor efficiency both in vitro and in vivo. The A15-PEG-SLN/SAL could target and penetrate deeply to the spheroid composed of CD133+ cancer cells. In the study of developing a sequential therapeutic strategy, we demonstrated that A54-PEG-SLN/OXA could kill tumor cells and expose CD133+ cancer cells. After the administration of A15-PEG-SLN/SAL, the growth of the tumors was significantly inhibited. In conclusion, the aptamer/peptide-modified lipid-based drug delivery systems, A54-PEG-SLN/OXA and A15-PEG-SLN/SAL, could specifically target carcinoma cells and had an evident antitumor effect when administrated sequentially.

Use of combined nanocarrier system based on chitosan nanoparticles and phospholipids complex for improved delivery of ferulic acid.

A novel nanocarrier system of phospholipids complex loaded chitosan nanoparticles (FAPLC CNPs) was developed to improve the oral bioavailability and antioxidant potential of FA. FAPLC CNPs were optimized using a Box-Behnken Design (BBD). FAPLC CNPs were characterized using differential scanning calorimetry, Fourier transforms infrared spectroscopy, powder x-ray diffractometry, proton nuclear magnetic resonance, solubility, in vitro dissolution, ex vivo permeation, and in vivo antioxidant activity in carbon tetrachloride (CCl4)-induced albino rat model. The characterization studies indicated a formation of the complex as well as FAPLC CNPs. The FAPLC CNPs exhibited a lower particle size ~123.27 nm, PDI value ~0.31, and positive zeta potential ~32 mV respectively. Functional characterization studies revealed a significant improvement in the aqueous solubility, dissolution, and permeation rate of FAPLC and FAPLC CNPs compared to FA and FA CNPs. The FAPLC CNPs showed significant enhancement of in vivo antioxidant activity of FA by restoring the elevated marker enzymes in the CCl4-intoxicated rat model compared to FA CNPs. Moreover, the pharmacokinetic analysis demonstrated a significant enhancement of oral bioavailability of FA from FAPLC CNPs compared to FA CNPs. These findings show that FAPLC CNPs could be used as an effective nanocarrier for improving the oral delivery of FA.

Different preparations of magnolol: Preparation, characterization and pharmacokinetics comparative study in SD rats / 中草药

Objective: To prepare magnolol solid dispersions (Mag-SD), magnolol phospholipids complex (Mag-PC) and magnolol solid lipid nanoparticles (Mag-SLN), and compare their effects on the pharmacokinetics in vivo. Methods: Solvent evaporation method was used to prepare Mag-SD and Mag-PC. Their existential state of Mag in Mag-SD and Mag-PC were analyzed by X-ray power diffraction (XRPD). High pressure homogenization method was employed to prepare Mag-SLN, its particle size and Zeta potential were also studied. The dissolution in vitro of Mag-SD, Mag-PC and Mag-SLN were also studied compared to magnolol suspension. SD rats in each group were administered intragastrically with magnolol, Mag-SD, Mag-PC and Mag-SLN, respectively. The concentration of magnolol in blood was analyzed by HPLC, and the main pharmacokinetic parameters were obtained. The pharmacokinetic behavior and bioavailability of magnolol, Mag-SD, Mag-PC and Mag-SLN were also compared. Results: The results of XRPD indicated that magnolol showed an amorphous state in Mag-SD and Mag-PC. The average particle size and Zeta potential of Mag-SLN was (161.37 ± 3.77) nm and (-29.16 ± 1.83) mV, respectively. The results of dissolution in vitro indicated that the cumulative dissolution of magnolol was 30.6% within 12 h. Mag-SD, Mag-PC and Mag-SLN enhanced its cumulative dissolution to 96.3%, 76.4% and 45.9%, respectively. The results of pharmacokinetics in vivo showed that Cmax, AUC0-t and AUC0-∞ of Mag-SD, Mag-PC and Mag-SLN were enhanced greatly compared to magnolol suspension. Mag-PC, Mag-SD and Mag-SLN increased its Cmax from (429.67 ± 53.12) ng/mL to (533.62 ± 59.01), (721.73 ± 103.44) and (1 063.21 ± 108.22) ng/mL, respectively. The bioavailability of Mag-SD, Mag-PC and Mag-SLN were enhanced to 1.38, 2.12 and 3.45 times, respectively. Conclusion: Mag-SD, Mag-PC and Mag-SLN could promote the absorption of magnolol in SD rats notably. In addition, Mag-SLN could give a better effect on the bioavailability.

Preparation, characterization and pharmacokinetics of dihydromyricetin phospholipids complex loaded by nanostructured lipid carriers / 中草药

Objective: To prepare dihydromyricetin (DMY) phospholipids complex (DMY-PC) and its nanostructured lipid carriers (DMY-PC-NLC), and carry out in vitro and in vivo evaluation. Methods: DMY-PC was prepared by solvent evaporation method. High pressure homogenization method was used to prepare DMY-PC-NLC. Orthogonal test was employed to optimize the ratio of solid/liquid lipid, dose of lipids materials, dose of DMY-PC and the concentration of emulsifier of poloxamer. The lyophilized powder of DMY-PC-NLC was prepared with 5% of mannitol as protective agent. The comparation of in vitro release and pharmacokinetics between DMY-PC and DMY-PC-NLC was also studied. Results: DMY was in an amorphous state in DMY-PC. The results of 1HNMR showed that the structure of DMY was not changed. The optimized prescription of DMY-PC-NLC determined by orthogonal test was as follow: The ratio of solid/liquid lipid was 5:1, dose of lipids materials was 325 mg, dose of DMY-PC was 45 mg and the concentration of emulsifier of poloxamer was 0.9%. The average size, Zeta potential, entrapment efficiency and drug loading of DMY- PC-NLC was (197.25 ± 4.42) nm, (-18.2 ± 2.1) mV, (71.68 ± 1.36)% and (3.94 ± 0.24)%, respectively. The in vitro release model was accord with Weibull model and the equation was lnln(1-Mt/M∞)=0.700 1 lnt-1.954 1 (r = 0.971 4). The relative bioavailability of DMY-PC and DMY-PC-NLC were enhanced to 1.63 and 3.22 times compared to DMY, respectively. Conclusion: Compared with DMY-PC, the absorption was promoted by DMY-PC-NLC in further, and the bioavailability of DMY was enhanced effectively.

Comparative study of preparation, characterization and pharmacokinetics of three preparations of osthole / 中草药

Objective: To prepare osthole solid dispersions (Ost-SD), osthole phospholipids complex (Ost-PC), and osthole nanosuspensions (Ost-NS), and compare their effects on the pharmacokinetics in SD rats in vivo. Methods: Solvent evaporation method was used to prepare Ost-SD and Ost-PC. Their existential state of Ost in Ost-SD and Ost-PC were analyzed by X-ray power diffraction (XRPD). High pressure homogenization method was employed to prepare Ost-NS, its particle size and Zeta potential were studied. The dissolution in vitro of Ost-SD, Ost-PC, and Ost-NS were also studied compared to Ost suspension. SD rats in each group were ig administered with Ost, Ost-SD, Ost-PC, and Ost-NS, respectively. The concentration of Ost in blood was analyzed by HPLC, and the main pharmacokinetic parameters were obtained. The pharmacokinetic behavior and bioavailability were also been compared. Results: The results of XRPD indicated that Ost showed an amorphous state in Ost-SD and Ost-PC. The average particle size and Zeta potential of Ost-NS were (161.37 ± 3.77) nm and (-29.16 ± 1.83) mV, respectively. The results of dissolution in vitro indicated that the dissolution of Ost was improved greatly by Ost-SD, Ost-PC, and Ost-NS. The results of pharmacokinetics in vivo showed that Cmax, AUC0~t and AUC0~∞ of Ost-SD, Ost-PC, and Ost-NS were enhanced greatly compared to Ost. The bioavailability of Ost-SD, Ost-PC,and Ost-NS were enhanced to 165.92%, 138.46%, and 259.35%, respectively. Conclusion: Ost-SD, Ost-PC, and Ost-NS can enhance the bioavailability of Ost in SD rats notably. In addition, Ost-NS can give a better effect.

Two kinds of luteolin solid dispersion: Preparation, characterization, and pharmacokinetic behaviors in SD rats in vivo / 中草药

Objective To prepare luteolin solid dispersions (Lut-SD) and luteolin phospholipids complex solid dispersions (Lut-PC-SD), and compare the effects of two kinds of solid dispersions on the bioavailability in vivo. Methods PVP K30 was employed as carrier, and solvent evaporation method was used to prepare Lut-SD and Lut-PC-SD. Their existential state of luteolin in solid dispersions was analyzed by X-ray power diffraction (XRPD). The solubility and dissolution rate were also studied. SD rats in each group were administered intragastrically with Lut, Lut-SD, and Lut-PC-SD, respectively. Their blood samples were collected at different time intervals. Diosmetin was used as internal standard, the concentration of Lut in blood was analyzed by HPLC, and the main pharmacokinetic parameters were obtained. Results The results of XRPD indicated that Lut showed an amorphous state in Lut-SD and Lut-PC-SD. The solubility of Lut was enhanced from (61.09 ± 0.09) μg/mL to (365.33 ± 0.38) μg/mL and (401.14 ± 0.19) μg/mL by Lut-SD and Lut-PC-SD, repectively. The dissolution of Lut was also improved greatly by the two kinds of solid dispersions. Compared to Lut, the bioavailability of Lut-SD and Lut-PC-SD was enhanced to 150.10% and 204.52%, repectively. Conclusion Lut-SD and Lut-PC-SD both could enhance the bioavailability of Lut in SD rats notably. In addition, Lut-PC-SD could give a better effect.

The absorption of baicalin phospholipid complex in rat stomach and intestine / 中国药学杂志

OBJECTIVE: To study the absorption kinetics of baicalin phospholipid complex in rats stomach and intestine. METHODS: Using rats in vivo stomach and intestinal absorption mode, the drug concentration by in situpefusion in rats were determined by HPLC to comparise the stomach, whole intestine absorption and metabolism characteristics among baicalin, baicalin phospholipid complex and physical mixture, and the sub-bowel absorption and metabolism characteristics of baicalin phospholipid complex. RESULTS: The percentage of per hour absorpion in the stomach of baicalin, baicalin phospholipid complex and physical mixture shows little difference among them. The whole intestine absorption of baicalin phospholipid complex was better than the baicalin and physical mixture, which is (2 940.87±1.45) μg,(1 373.23±3.21) μg, (992.66±3.65) μg, respectively. Baicalin phospholipid complex has extensive absorption window in the whole intestine and duodenum is the best. The absorption percentage of duodenum, jejunum, ileum and colon is 51.81%, 32.29%, 29.56%, 11.80%,respectively. CONCLUSION: Baicalin phospholipid complex can significantly enchance absorption of baicalin in rat gastrointestinal tract.

Preparation and characterization of cucurbitacin B phospholipids complex and its in vitro antitumor activity / 中草药

Objective: To prepare cucurbitacin B phospholipids complex (CuB-PLC) and evaluate its physicochemical properties and in vitro antitumor activity. Methods: CuB-PLC was prepared using solvent evaporation method and optimized by Box-Behnken design. The oil-water partition coefficient, particle size, and morphology of CuB-PLC were investigated; X-ray diffraction (XRD) spectroscopy and infrared (IR) spectroscopy were used to analyze the formation machenism of CuB-PLC. MTT method was used to determine the in vitro antitumor activity of CuB-PLC. Results: The optimal formulation protocol for CuB-PLC was as follows: Tetrahydrofuran was taken as the reaction medium, phospholipids-cucurbitacin B molar ratio, reaction concentration of cucurbitacin B, reaction temperature and time were 1:1, 1.5 mg/mL, 60℃, and 3 h, respectively. The complex rate and particle size for the optimized CuB-PLC was 97.15% and (521.30 ± 10.50) nm, and the polydispersity index (PDI) was 0.133 2 ± 0.024 0. MTT experiments showed that the half of the HepG-2 cell proliferation inhibition concentration (IC50) values of CuB and CuB-PLC were 42.55 and 27.61 μmol/L. Conclusion: CuB-PLC is successfully developed under the optimized protocol, possessing high complex rate, and enhanced solubility in water, and the inhibition on HepG-2 cell proliferation is significantly enhanced, which provides the reference for the further research of CuB.

Liver targeting anti-tumor activity of pH-sensitive liposomes loaded with lactosyl-norcantharitin phospholipids complex / 中草药

Objective: To investigate the antitumor activity of pH-sensitive liposomes (pH-LPC-lips) loaded with lactosyl-norcantharitin (Lac-NCTD) phospholipids complex in vitro and in vivo, and the liver targeting in mice. Methods: Using blank liposomes (blank-lips and blank-pH-lips) as control, the MTT assay was used to study the cytotoxic effects of Lac-NCTD and its liposomes (Lac-lips and pH-LPC-lips) on human hepatoma carcinoma cells HepG2. HPLC assay was used to evaluate the uptake of Lac-NCTD and its liposomes in HepG2. In vivo antitumor activity of Lac-NCTD and its liposomes were evaluated in mice bearing H22 liver tumors. The hepatocyte specificity of near-infrared fluorescence dye (Cy7)-labeled pH-LPC-lips in H22 tumor-bearing mice was monitored through NIR fluorescence real-time tumor imaging instrument. Results: The pH-LPC-lips demonstrated stronger cytotoxicity against tumor cells HepG2 and easily permeated the cell membrane, compared with Lac-NCTD and Lac-lips. The results of antitumor activity in vivo showed that pH-LPC-lips displayed best tumor inhibitory effect. The optical imaging results indicated that Cy7-labeled pH-LPC-lips showed excellent hepatocyte specificity in H22 tumor-bearing mice, which could reduced the side effect, and increased the antitumor activity. Conclusion: The pH-LPC-lips could take the initiative to release at the tumor site and showed the liver-targeting. As a result, the preparation could be regarded as novel liver-targeting agent which has better antitumor effect.

Preparation technology for phospholipids complex of total flavonoids from leaves of Diospyros kaki / 中草药

Objective: To study the influence factors in the preparation process for phospholipids complex of total flavonoids from the leaves of Diospyros kaki (PC-TF-LDK) and to optimize the conditions for the formation. Methods: The solvent method was used to prepare the PC-TF-LDK, and the optimized conditions were obtained by means of single factor test and orthogonal design test with the complex ratio as evaluation criterion. The formation of the complex was analyzed by the X-ray diffraction and differential scanning calorimetry. Results: The formation of the PC-TF-LDK was greatly influenced by the ratio of solvents, TF-LDK, and soybean phospholipid. The optimized preparation conditions for the PC-TF-LDK were obtained as follows: the solvent was anhydrous ethanol, the ratio of TF-LDK to soybean phospholipid was 1:2, the mass of reaction concentration was 30 mg/mL, temperature was 30°C, and reaction time was 1 h. Under this condition, 96.95% complex ratio was achieved. Conclusion: The preparation technology for PC-TF-LDK is reliable, stable, and available for industrial production.

Preparation, characterization and in vitro anti-tumor activities of evodiamine phospholipids complex / 中国药学杂志

OBJECTIVE: To prepare evodiamine phospholipids complex, investigate its physicochemical properties and study its anti-tumor activities in vitro. METHODS: Evodiamine phospholipids complex was prepared and optimized by solvent evaporation method and central composite design, physicochemical characteristics of the complex were investigated by means of apparent solubility studies, Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) ,the Particle size and zeta-potential were also investigated. MTT assay was employed to evaluate the anti-tumor activities of the complex in vitro. RESULTS: The optimal formulation protocol for evodiamine phospholipids complex were as follows: mixture (1:1, v/v) of ethanol and tetrahydrofuran was taken as the reaction medium, phospholipids-to-evodiamine molar ratio, reaction concentration of evodiamine, reaction temperature and time were 2:1, 2.5 mg · mL-1, 60°C and 3 h, respectively. The complex rate, particle size and Zeta potential for the optimized EVO-PLC was 94.15%, 243.4 nm and -44.21 mV, respectively. IR and DSC analysis indicated that evodiamine might interact with phospholipids by apolar interactions. MTT assay showed that the anti-tumor activities of evodiamine phospholipids complex on LLC cells was less effective than evodiamine in vitro. CONCLUSION: Evodiamine phospholipids complex was successfully developed under the optimized protocol, possessing high complex rate and enhanced solubility in water, which was a fundamental formulation for the further research of evodiamine. Copyright 2012 by the Chinese Pharmaceutical Association.