To optimize the formulation and preparation method of multivesicular liposome of thymopentin and to investigate its pharmacokinetics in rats, the multivesicular liposome of thymopentin was prepared by double emulsification method and the formulation was optimized by orthogonal design. The release characteristics of thymopentin from multivesicular liposome in PBS (pH 7.4) and in plasma were investigated. The multivesicular liposome of thymopentin labeled with fluorescein isothiocyanate was prepared by double emulsification method. Its pharmacokinetics was evaluated following intramuscular injection in rats. The optimal formulation of multivesicular liposome of thymopentin were formulated with 7.5% glucose in aqueous phase and 2.25 mol x L(-1) triolein, 2.68 mol x L(-1) DPPG and 16.96 mol x L(-1) DOPC in organic phase. The entrapment efficiency of the multivesicular liposome of thymopentin was above 85% and the mean particle size was about 22 microm. The in vitro release of thymopentin from multivesicular liposome in PBS (pH 7.4) and in plasma was found to be in a sustained manner. The release curves were fitted to Higuchi equation. The pharmacokinetics following intramuscular injection of the multivesicular liposome of thymopentin labeled with fluorescein isothiocyanate in rats showed that the peak concentration of thymopentin was lower and elimination of it was slower significantly than that of thymopentin labeled with fluorescein isothiocyanate solution in the same dose. The plasma concentration of thymopentin maintained above quantitative limitation at 120 h after administration of multivesicular liposome of thymopentin. The optimized formulation and preparation technology of multivesicular liposome of thymopentin with higher entrapment efficiency are feasible with good reproducibility. Multivesicular liposome of thymopentin showed significant sustained-release property following intramuscular injection in rats.
Adjuvants, Immunologic ; administration & dosage ; pharmacokinetics ; Animals ; Area Under Curve ; Delayed-Action Preparations ; Drug Carriers ; Drug Compounding ; Drug Delivery Systems ; Glucose ; chemistry ; Liposomes ; chemistry ; Male ; Particle Size ; Phosphatidylcholines ; chemistry ; Phosphatidylglycerols ; chemistry ; Rats ; Rats, Sprague-Dawley ; Thymopentin ; administration & dosage ; pharmacokinetics ; Triolein ; chemistry

To prepare cyclosporine A (CyA) loaded block copolymer micelles and observe its release behaviors in vitro and pharmacokinetics in rats, methoxylpoly (ethylene glycol)-poly (D, L-lactide-co-glycolide) (mPEG-PLGA) was synthesized by ring-opening copolymerization of lactide and glycolide in the presence of methoxylpoly (ethylene glycol) (mPEG) as initiator. The structure of the mPEG-PLGA copolymer was confirmed with 1H NMR and FT-IR. The cyclosporine A loaded micelles (CyA-PM) were prepared by solvent evaporation method and their morphology was observed by the transmission electron microscope (TEM). The mean size and size distribution were determined by dynamic light scattering (DLS). The release behaviors in vitro and pharmacokinetics in rats were investigated by HPLC method using cyclosporine A injection commercial agent, sandimmune, as the reference. The obtained CyA-PM showed spherical shape with the core-shell structure, the mean particle sizes are in the range of 136.1-141.9 nm. The drug loading amount and entrapment efficiency were increased and the particle size became smaller with decreasing the ratio of acetone to water. With the increasing of the amount of cyclosporine A fed the drug loading increased, entrapment efficiency decreased and the particle size had no change. CyA-PM showed significant sustained release behave in vitro compared with sandimmune and only 9.7% of encapsulated cyclosporine A was released after 12 hours, the release characteristics was well fitted with Higuchi equation (r = 0.999). The Pharmacokinetics study at equal administration dosage (5 mg x kg(-1)) in rats showed the half-life (t1/2) of CyA-PM extended and the area under concentration-time curve (AUC) increased compared to sandimmune. The results also showed that cyclosporine A concentration-time data were all in accord with two compartment model. Cyclosporine A loaded mPEG-PLGA micelles showed obviously solubility enhancement, sustained release and overcome the side effect and toxicity of sandimmune resulted from solubiling agent-polyoxyethylene castor oil (Cremophor EL) and might be developed as a novel dosage form of cyclosporine A.
Animals ; Area Under Curve ; Cyclosporine ; administration & dosage ; pharmacokinetics ; Delayed-Action Preparations ; Drug Carriers ; administration & dosage ; pharmacokinetics ; Drug Compounding ; Half-Life ; Immunosuppressive Agents ; administration & dosage ; pharmacokinetics ; Male ; Micelles ; Particle Size ; Polyesters ; administration & dosage ; chemical synthesis ; pharmacokinetics ; Polyethylene Glycols ; administration & dosage ; chemical synthesis ; pharmacokinetics ; Polymers ; administration & dosage ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo prepare ligustrazine (TMPZ) ocular sustained-release implant, and investigate its in vitro drug release, pharmacokinetics in rabbit vitreum and in vitro correlation.

METHODLigustrazine ocular sustained-release implants were prepared by micro-twin conical screw mixers with hot-melting extrusion method, with polyactic-co-glycolic acid (PLGA) as the matrix. HPLC was adopted to determine the concentration in vitreum after ligustrazine was implanted in rabbit eyes, in order to examine its in vivo sustained-release behavior, and study the correlation between in vitro and in vivo.

RESULTLigustrazine implants were prepared with a drug-loading rate between 10% and 30%, which was in conformity to the pharmacopoeia in terms of the content uniformity. Its in vitro release was in conformity to the zero-order release model. With PLGA 5050, 2. 5A as a vector, ligustrazine implants with a drug-loading rate of 30% could slowly release drug for more than 3 weeks, indicating a good correlation between in vitro and in vivo release.

CONCLUSIONLigustrazine ocular implants prepared with hot-melting extrusion method is practicable. Ligustrazine ocular implants release drug smoothly in rabbit vitreous vitreums, suggesting good sustained-release effect.

Animals ; Biological Availability ; Drug Implants ; Eye ; Female ; Male ; Polyglycolic Acid ; chemistry ; Pyrazines ; administration & dosage ; chemistry ; pharmacokinetics ; Rabbits ; Vitreous Body

AIMTo prepare diclofenac sodium liposomes and observe its ocular pharmacokinetics in rabbits.

METHODSThe diclofenac sodium cationic liposomes were prepared by reverse-phase evaporation methods and the formula of liposome was optimized with uniform design. HPLC method was established and validated for the determination of diclofenac sodium in precornea, cornea and aqueous humor of rabbit eye. Liposome and eyedrop solution 50 microL with total 50 microg diclofenac sodium were instilled to eyes of rabbits, separately. Samples of tear, cornea and aqueous humor were collected at different time intervals after rabbits were sacrificed. The ocular pharmacokinetics was investigated by the concentration-time data of tear, cornea and aqueous humor.

RESULTSThe mean particle size of the diclofenac sodium liposomes was 226.5 nm with zeta potential of + 18. 1 mV. The entrapment efficiency reached 63%. Compared with solution, liposome was characterized by slower clearance in precornea. The concentration of diclotenac in cornea and aqueous humor instilled with liposome were higher than that with eye-drop solution. Cmax of diclofenac sodium in aqueous humor instilled with liposome and eye-drop solution were (0.69 +/- 0.25) and (0.48 +/- 0.19) microg x mL(-1) and (36.68 +/- 11.7) and (21.82 +/- 8.6) microg x g(-1) in cornea, respectively. But no significant difference were found to Tmax in aqueous humor and cornea between liposome and eyedrop, T(1/2) of diclofenac in aqueous humor and cornea with liposoine were longer than that with eye-drop solution. The ocular bioavailability of liposome in aqueous humor was 211% compared with that of eyedrop.

CONCLUSIONDiclofenac sodium cationic liposomes can increase the corneal contact time, enhance the corneal permeability of diclofenac sodium and improve its ocular bioavailability.

Animals ; Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; chemistry ; pharmacokinetics ; Aqueous Humor ; metabolism ; Area Under Curve ; Biological Availability ; Chromatography, High Pressure Liquid ; Cornea ; metabolism ; Diclofenac ; administration & dosage ; chemistry ; pharmacokinetics ; Drug Compounding ; Liposomes ; Microscopy, Electron, Transmission ; Particle Size ; Rabbits ; Random Allocation

In this study, physical fingerprint and multivariate statistical analysis was applied to characterize the quality consistency of different sources of carboxymethylcellulose sodium, and the visualization of R language was used to explore the intrinsic correlation on its performances, and we drew contour maps between independent variables and flowability of powder to find the design space. Through the physical fingerprint and multivariate statistical analysis, it was found that there were differences in the powder properties of carboxymethylcellulose sodium from different sources, and its moisture content, bulk density and tapped density have a great influence on the fluidity. The fillibility was positively correlated with flowability, both negatively correlated with compressibility by R intelligent visualization analysis, which was statistically significant (P < 0.01). When the angle of repose is 30° - 40°, the appropriate design space was found as 5.092 2% < moisture content < 7.006 7%, 0.560 2 g·cm^-3 < bulk density < 0.579 9 g·cm^-3, and 0.646 3 g·cm^-3 < tapped density < 0.816 5 g·cm^-3. The results show that it is scientific and feasible to evaluate the quality consistency of pharmaceutical excipients by using the physical fingerprint, multivariate statistical analysis and visualization methods, which provides new ideas for the production and quality evaluation of excipients and the development of generic prescriptions.