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As a depot drug delivery system, injectable polylactide-polyglycolide (PLGA) sustained-release microspheres have been successfully used to treat many diseases since the first microsphere product Lupron depot was approved for marketing in the United States in 1989. It has the ability of long-term release in the body for several days to several months, which can not only reduce the times of administration, but also reduce the drug blood concentration fluctuations, significantly improve the safety and patient compliance. In vitro-in vivo correlation (IVIVC) makes the development of microspheres more possible. It can describe the dynamic information of drug release in vivo through the in vitro release behavior of microspheres, and can reduce the workload of each stage and shorten the time span while characterizing the performance of microspheres. IVIVC can provide guidance or support for drug development, production changes, supervision and management. This article summarizes the release mechanism of injectable PLGA sustained-release microspheres, common measurement methods and theories of in vitro and in vivo release. And we also focus on the establishment and application of IVIVC, especially A level IVIVC in the field of microsphere preparations, to provide a reference for further study on in vitro-in vivo correlation of microspheres.
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OBJECTIVE： To establish content determination method of Triptolide-glycyrrhetic acid compound microemulsion， optimize the formula and investigate its physicochemical properties and release rate in vitro. METHODS： The content of Triptolide- glycyrrhetic acid compound microemulsion was determined by UPLC. The determination was performed on ACQUITY UPLC BEH C18 column with mobile phase consisted of 0.1％ formic acid aqueous solution-acetonitrile （gradient elution） at the flow rate of 0.4 mL/min. The column temperature was 40 ℃. The detection wavelength was set at 218 nm， and sample size was 5 μL. Pseudo-ternary phase diagrams were drawn by water titration method. Using oil phase， surfactants and co-surfactants as index， the formula was optimized， and in intro release characteristics was investigated by in vitro release test. RESULTS： The linear range of triptolide and glycyrrhetinic acid were 1-40 μg/mL（r＝0.999 7） and 10-400 μg/mL（r＝0.999 8）， respectively. The limits of quantitation were 0.5 and 0.8 μg/mL； the limits of detection were 0.1 and 0.2 μg/mL. RSDs of precision， stability and reproducibility tests were all less than 2％. Average recoveries were 100.32％-101.15％ （RSD＝0.36％， n＝6）， 99.78％-101.42％ （RSD＝0.59％，n＝6）. The optimal formula included that medium chain triglyceride as oil phase， polyethylene glycol hydroxy stearate as surfactants， ethanol as co-surfactants， water as water phase， the proportion of them was 8 ∶ 28 ∶ 14 ∶ 50. The obtained microemulsion was O/W type， being transparent and clear， with average diameter， average polydispersity index and average viscosity of （62.38±3.44） nm， 0.096±0.001 and （26.84±1.10） mPa·S. Within 24 h， cumulative release rates of triptolide and glycyrrhetinic acid in obtained microemulsion were 99.8％ and 99.7％ （in PBS pH 2.0）， 99.3％ and 99.4％ （in PBS pH 7.4）， 98.9％ and 98.4％ （in PBS pH 9.0）， respectively. Triptolide and glycyrrhetinic acid released faster in the single microemulsion than in the compound microemulsion. CONCLUSIONS： Established content determination method is simple and stable. The optimized formula is stable and feasible. Obtained iriptolide-glycyrrhetinic acid compound microemulsion show better sustained-release effect than sigle microemulsion.
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OBJECTIVE： To establish a method for content determination of indapamide （IDP）-β-cyclodextrin （β-CD） inclusion compound， optimize the preparation technology， carry out phase identification and in vivo release study of it. METHODS： UV spectrophotometry was used to determine the content of IDP in IDP-β-CD inclusion compound. IDP-β-CD inclusion compound was prepared by the solution-stirring method and the preparation technology was optimized by the orthogonal experiment using inclusion rate as index. The inclusion rate and drug-loading rate were compared between different drying methods. Phase identification of IDP-β-CD inclusion compound was verified by IR and DSC. The cumulative release rate of inclusion compound was tested by in vitro experiment. RESULTS： The linear range of concentration of IDP was 2.0-14.0 μg/mL （r＝0.999 7）. The quantitative limit and detection limit were 0.204， 0.067 μg/mL， respectively. RSDs of precision， stability and repeatability tests were all less than 2％. The recoveries range was 98.8％-101.8％（RSD＝1.10％，n＝6）. The optimum technology conditions were as follows the molar ratio of β-CD to IDP was 3 ∶ 1， the inclusion time was 3 h， and the stirring speed was 300 r/min. Average inclusion rate of IDP-β-CD inclusion compound was 72.81％. IR and DSC analysis showed that IDP and β-CD formed inclusion compound through physical interaction. After spray drying， the inclusion rate and drug-loading rate of IDP-β-CD inclusion compound were （60.96±0.25）％ and （4.18±0.12）％. After freeze-drying， the inclusion rate and drug-loading rate of IDP-β-CD inclusion compound were （77.31±0.51）％ and （5.31±0.27）％. Accumulative release rates of IDP， IDP-β-CD inclusion compound （by freeze-drying and spray drying） were 37.2％， 42.5％ and 81.9％ within 12 h， respectively. Compared with IDP raw material， accumulative release rate of IDP-β-CD inclusion compound increased significantly after spray drying. CONCLUSIONS： Established method is simple and accurate. The optimal preparation technology of inclusion compound is stable and feasible. IDP-β-CD inclusion compound is prepared successfully. The inclusion compound prepared by spray drying shows higher release rate.
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Objective: To prepare Trichosanthes sustained-release pellets and investigate its in vitro release. Methods: Trichosanthes sustained-release pellets were prepared by fluid-bed coating technique.The preparation process of its drug loading layer was optimized by orthogonal experiment with binder, solvent, drug loading and creeping speed of peristaltic pump as the factors of investigation and the yield as the investigation index. The optimum prescription and preparation of the pellets were optimized by single factor test with the content of coating material EC, the amount of poreforming agent PEG4000, the amount of talc powder, the coating weight and the curing time as the factors of investigation and the in vitro release as the investigation index. The in vitro release of the pellets was investigated by high performance liquid chromatography with 3, 29-Diphenyl of Trichosanthes Kirilowii Triol(3, 29-DK)as the detection index. Results: The optimum preparation technology of the drug loading layer was 5% binder, 60% ethanol, 35% drug loading and 0.3 r/min peristaltic velocity of fluid-bed peristaltic pump. The optimum preparation technology of sustained-release layer was 5% EC, 1.5% PEG 4000, 1.25% talc powder, 10% weight gain of coating and 6 h curing. Conclusion: The Tricho- santhes sustained-release pellets prepared in this study were released smoothly. Its production method was simple and easy for operation.
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Objective:To screen the best formula of tegafur temperature-sensitive gel for intratumor injection and investigate the in vitro drug release behavior. Methods:The drug dose was determined by cytotoxicity experiment. The thermo-sensitive gel was prepared with PLGA-PEG-PLGA and HPMC as the matrix. With the in vitro release as the index, the effects of PLGA-PEG-PLGA and HPMC at different concentrations on gel were investigated. The gelation temperature, viscosity and pH were detected. Results:The best formula was as follows:25% PLGA-PEG-PLGA, 1% HPMC, and tegafur dose of 1 mg·ml-1 . The average gelation temperature was 36. 7℃, the average viscosity was 7550 mPa·s, and the average pH was 7. 2. Conclusion:Tegafur thermo-sensitive gel for intratumor in-jection shows temperature sensitivity and obvious sustained-release property, which provides experimental basis for the further clinical research.
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By developing a rapid gelation chitosan (CS) /β-glycerophosphate (β-GP) thermosensitive hydrogel containing Kuijiean, to decrease the loss of drug and confirm the capabilities of the drug delivery. Thermosensitive hydrogel was a carrier, gel time was chosen in this study as the index to investigate the effect of β-GP concentration, pH value, and temperature on the thermosensitive hydrogel by single factor experiments. The properties of the hydrogel were characterized regarding shape and surface morphology by using scaning electron microscopy (SEM); The chemical structure diversification of hydrogels upon gelation was charactered by FTIR spectrometer. By the experiments of the drug loaded thermosensitive hydrogel to deliver drug in vitro, the diversification of the capabilities of the drug delivery was evaluated. The temperature of Kuijiean thermosensitive hydrogel was (37.0 ± 4.5) ℃, by which the sol gel could transform into semi-solid gel at (6.00 ± 0.82) min, the drug release rate slowed down obviously, and the cumulative release rate was only (67.78 ± 0.35)% (n = 3) by 24 h, while the cumulative release rate of the equal quantity of raw material drug was (90.43 ± 0.62)% (n = 3) by 24 h. The release behavior was close to the Weibull model, the drug release mechanism was a double mechanism combining drug diffusion and gel erosion. It is true that achieves the transformation of Kuijiean from sol to semi-solid gel at 37.0 ℃. The CS/β-GP gel system allows the sustained release of the Kuijiean.
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Objective: To prepare the nepeta oil-oxymatrine (OMT) lipidosome pro vagina thermosensitive gel, and to investigate its in vitro drug release behavior. Methods: P-407 and P-188 were used as gel matrix to prepare the gel, and gelatinization temperature was applied as a target to optimize the prescription. The OMT lipidosome was prepared based on the multiple emulsion method, and the nepeta oil-OMT lipidosome pro vagina thermosensitive gel was obtained by cold-dissolving method. The content of OMT was determined by HPLC, and in vitro release properties of nepeta oil-OMT lipidosome thermosensitive in situ gel was investigated by dialysis method. Results: After optimization, the gel prescription was finally confirmed as 18% P-407, 5% P-188, and 0.2% hydroxy-propyl methyl cellulose (HPMC). The gelatination temperature for nepeta oil-OMT lipidosome thermosensitive gel was (36.8 ± 0.2)°C, and the in vitro accumulating release ratio of sinomenine in the nepeta oil-OMT lipidosome gel system was (58.89 ± 0.34)% and (66.38 ± 0.12)% after 48 h. Conclusion: The prepared nepeta oil-OMT lipidosome thermosensitive gel has the temperature sensitivity and sustained release effect, can effectively delay the release of the drug in vagina and improve the residence time in the vagina.
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Objective: To prepare the solid lipid nanoparticle (SLN) thermosensitive gel of sinomenine hydrochloride (SH) for intra-articular injection and to investigate its in vitro drug release behavior. Methods: Poloxamer 407 (P-407) and Poloxamer 188 (P-188) were used as gel matrix to prepare the gel, and the gelatinization temperature was applied as a target to optimize the prescription. The SH-SLN was prepared based on the microemulsion technique, and the gel system containing SH-SLN was obtained by cold-dissolving methods. The content of SH was determined by HPLC, in vitro release characteristics of SH-SLN thermosensitive gel were investigated by dialysis method. Results: The optimal gel prescription was finally confirmed as 18% P-407, 5% P-188, and 0.6% HPMC. The gelatination temperature for SH-SLN thermosensitive gel was (34.5 ± 0.2)°C, and the in vitro accumulated release rates of SH in the SLN thermosensitive gel system were (57.79 ± 0.36)% after 24 h and (75.16 ± 0.12)% after 48 h. Conclusion: The SH-SLN thermosensitive gel has the temperature sensitivity and obvious sustained-release effect. The combination of nanoparticle thermosensitive gel will be used as a new drug delivery for intra-articular injection.
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OBJECTIVE: To study the factors affecting the in vitro release rate of doxorubicin hydrochloride sustained release implants for glioma to provide information for pharmacodynamic evaluation in animals. METHODS: The implants were prepared by incorporating doxorubicin hydrochloride into poly(lactide-co-glycolide) (PLGA) matrix. The in vitro release rate of the implants was determined by UV. The copolymer ratio and molecular weight (Mw) of PLGA, and the drug loading were examined to study their effects on the in vitro release rate of the implants. RESULTS: The release rate of 10% drug-loaded implants was greater than that of 5% drug-loaded ones, and it was enhanced by an increase in the proportion of copolymerized glycollic acid in PLGA. The cumulative release rate of the implants with LA-GA ratio of 50: 50 was 90% at 35 d, while that of the implants with LA-GA ratio of 75: 25 was only about 60%. The molecular weight of PLGA was inversely proportional to the release rate of the implants. The release rate of the implants with Mw of 20748 was greater than that with Mw of 30834. CONCLUSION: The factors affecting the in vitro release rate of the implants include the copolymer ratio of PLGA, the molecular weight of PLGA and the drug loading, among which the copolymer ratio and molecular weight of PLGA are the major factors. The drug release rate of the implants can be well controlled by regulating the copolymer ratio and molecular weight of PLGA matrix. Copyright 2012 by the Chinese Pharmaceutical Association.
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OBJECTIVE: To prepare Buserelin acetate nanoparticles(BA-NP) and to investigate its release property in vitro.METHODS: The BA-NP was prepared using double emulsion method.The content determination of BA-NP was performed using HPLC,and encapsulation efficiency and drug-loading rate of BA-NP were calculated.In vitro drug release property of nanoparticles was investigated by bag filter method.RESULTS: Prepared nanoparticles were even and regular in appearance.The linear range of buserelin acetate was 0.1～8.0 ?g?mL-1(r=0.999 9) with an average recovery of 105.38%.The RSD of intra-day and inter-day were lower than 1.78% and 0.93% respectively.The encapsulation efficiency of nanoparticles was(63.37?0.29)% and drug-loading rate of(1.03?0.09)%.The accumulative release rate of nanoparticles in phosphate buffer(pH=7.4) at 72 h was 62.35%.CONCLUSION: The preparation process of BA-NP is simple and particle with ideal release effect.
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AIM:To study release rate in-vitro of the panax notoginoside micro-porous osmotic pump(MPOP) tablets.METHODS:To investigate the effects of different dissolution methods,paddle stirring rate and dissolved mediums on the release rate in-vitro of the panax notoginoside MPOP tablets.RESULTS:The delivery rate was not influenced by the dissolution methods,paddle stirring rate and when the pH of dissolution medium was between(3.5)-7.6,the delivery rate was not influenced,too.However,when the pH of dissolved medium was at 1.0,the release rate was decreased severely.CONCLUSION:Panax notoginoside MPOP tablets have a stable release curve except for in the condition of the acid dissolved medium.