Research progress of in vitro-in vivo correlation of injectable polylactide-polyglycolide microspheres / 药学学报

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.

Rhynchophylline nanosuspensions sustained-release tablets: Preparation, optimization and release evaluation in vitro / 中草药

Objective: To prepare the rhynchophylline nanosuspensions and lyophilized powder, and study its sustained-release tablets. Methods: Rhynchophylline nanosuspensions were prepared by microprecipitation combined with high pressure homogenization method, and the particle size and zeta potential were determined. Scanning electron microscopy (SEM) was employed to observe the appearances of nanosuspensions. Nanosuspensions were prepared into lyophilized powder using lactose as freeze-dried protectors. HPMC (hydroxypropyl methyl cellulose) was used as hydrophilic matrix to prepare the sustained-release tablets. Single factor investigation and orthogonal experiments were employed to optimize the formulation of rhynchophylline nanosuspensions sustained-release tablets, and the model fitting was also been studied. Results: The particle size and zeta potential of rhynchophylline nanosuspensions were (153.7 ± 4.9) nm and (-18.54 ± 1.32) mV, respectively. The appearances of rhynchophylline nanosuspensions were spherical or nearly spherical. After orthogonal optimization, the cumulative release rate of rhynchophylline nanosuspensions sustained-release tablets was 92.53% in 12 h. The optimized formulation of hydrogel matrix sustained-release tablets was better accorded with Higuchi model: ln(1-Mt/M∞)=0.286 0 t1/2-0.069 0 (r=0.992 4). The drug release from hydrogel matrix sustained-release tablets were controlled by diffusion and degradation. Conclusion: The obtained rhynchophylline nanosuspensions has small particle size. The prepared hydrogel matrix sustained-release tablets can control the release of rhynchophylline nanosuspensions in a slow characteristic.

Establishment of the quality research method for diclofenac potassium cataplasms and the preparation evaluation / 国际药学研究杂志

Objective: To prepare the new diclofenac potassium cataplasms, establish a quality research method and evaluate the preparation quality by the established method. Methods: A high performance liquid chromatography(HPLC)was performed on an ODS column(the column temperature 35℃)using the methanol-4% glacial acetic acid solution(80: 20, V/V)as mobile phase, and the detection wavelength was set at 276 nm. Diclofenac potassium was extracted with methanol, and the adhesion, content and uniformity of potassium diclofenac were measured. The release of diclofenac potassium from the cataplasms was determined in accordance with the fourth method of the XD release methods in the Appendix of the Chinese Pharmacopoeia. Results: The average maximum number of steel ball stuck in the cataplasms in the initial adhesion test was No. 6. Under the HPLC conditions, potassium diclofenac showed good linearity within the concentration range of 400-800 μg/ml, with the average sample recovery rate 1.33 % and RSD< 1.93%(n=6). The methodological studies for the drug release test for the diclofenac potassium cataplasms showed that the diclofenac potassium showed a good linearity within the range of 1-50 μg/ml in the drug release test, and the precision and recovery well satisfied the requirements of Pharmacopoeia. The content uniformity of the cataplasms was in accordance with the Pharmacopoeia. The release amounts of the cataplasms in 2, 5 and 8 hours were 20%-45%, 40%-80% and more than 70% of the labeled amount, respectively, and the release curve followed the first-order release equation. Conclusion: The established HPLC method is sensitive, accurate, easily operable and reproducible, which could be used for the quality control of diclofenac potassium cataplasms. The prepared diclofenac potassium cataplasms were of uniform content and showed characteristics of the sustained release, which is expected to be developed to a new preparation of diclofenac potassium.

Study on Preparation and in vitro Release Property of Diosmin Gel / 中国药房

OBJECTIVE： To optimize the formulation of Diosmin gel and to investigate its in vitro release property. METHODS： Diosmin gel were prepared by using Carbomer 940 as matrix. Using accumulative release rate as index， with the amount of Carbomer 940， ethanol， acetone and pH as factors， L9（34） orthogonal test was conducted. The formulation of Diosmin gel was optimized and validated. Using Diosmin ointment as reference， dialysis bag diffusion method was used to investigate in vitro release property of Diosmin gel prepared by optimal formulation. RESULTS： The optimal formulation of Diosmin gel included Carbomer 940 1.5 g， ethanol 15 mL， glycerol 8 g， pH 6. The gel prepared with optimal formulation was sticky brown-yellow semi solid， and had good coating and spreading properties. The average accumulative release rate （2 h） was （12.67±0.12）％. Results of drug release test showed that Diosmin gel released rapidly within 12 h， then gradually slowed down. The accumulative release rates were （71.93±0.42）％ （12 h） and （80.47±0.54）％ （24 h）， drug release of which were in line with Higuchi equation. Diosmin ointment was released slowly. The accumulative release rates were （41.74±0.18）％ （12 h） and （62.63±0.59）％ （24 h）. Drug release of it were in line with first-order equation. CONCLUSIONS： The formulation of Diosmin gel is optimized successfully. Prepared Diosmin gel has good drug release property.

Investigation in vitro Release Rate and in vivo Pharmacokinetics of Resveratrol/Hydroxypropyl- β-Cyclodextrin/Chitosan Sustained-release Pellets in Rats / 中国药房

OBJECTIVE： To investigate in vitro release rate and in vivo pharmacokinetics of Resveratrol/hydroxypropyl-β- cyclodextrin/chitosan sustained-release pellets （RES/HP-β-CD/Chitosan） in rats. METHODS： In vitro release rate of RES raw materials， RES-HP-β-CD complexes （RES/HP-β-CD） and RES/HP-β-CD/Chitosan in water within 12 h were investigated by paddle method. The pharmacokinetic characteristics of RES raw materials， RES/HP-β-CD and RES/HP-β-CD/Chitosan were compared within 720 min after intragastric administration. RESULTS： Compared with RES raw materials， in vitro release rate of RES/HP-β-CD was increased significantly， and 120 min accumulative release rate reached 87％. Compared with RES/HP-β-CD， in vitro release rate of RES/HP-β-CD/Chitosan were relieved significantly； release time prolonged significantly； 12 h accumulative release rate was 72％. The pharmacokinetic parameters of RES raw materials， RES/HP-β-CD and RES/HP-β-CD/Chitosan included that cmax were 473.3， 2 492.2， 590.5 ng/mL； t1/2 were 2.6， 0.5， 4.6 h； AUC0-12 h were 514.7， 824.6， 2 778.5 ng·h/mL. Compared with RES raw materials， relative bioavailability of RES/HP-β-CD and RES/HP-β-CD/Chitosan were 172.5％ and 540.0％. CONCLUSIONS： RES/HP-β-CD/Chitosan shows good sustained-release effect， and its bioavailability is significantly higher than that of RES raw materials， RES/HP-β-CD.

Method Improvement for Content Determination of Astragaloside Ⅳ in Xiangju Granules and Its Consistency with the Com- ponents of Original Formulation / 中国药房

OBJECTIVE：  To improve the method for the content determination of astragaloside Ⅳ in Xiangju granules， and to evaluate the consistency of relevant preparations with the components of original formulation， so as to provide evidence for the modern preparation of TCM compound. METHODS： HPLC-ELSD method was established for the content determination of astragaloside Ⅳ in Xiangju granules， and compared with original standard TLC scanning. Using critrinin， ferulic acid， calycosin glucoside， liquiritin， glycyrrhizic acid， rosmarinic acid， buddleoside and magnoline as control， HPLC method was used to determine the release components of self-made Xiangju granules， Xiangju capsules， Xiangju tablets in water. Fingerprint characteristics chromatogram of different Xiangju preparations and original formulation extract were compared by using Similarity Evaluation System for Chromatographic Fingerprint of TCM （2012 version）. At the same time， HPLC-ELSD method was used to determine and compare the release rate of astragaloside Ⅳ from different Xiangju preparations and original formulation extract in water. RESULTS： Established HPLC-ELSD method was specific. The linear range of astragaloside Ⅳ was 0.13-2.10 mg/mL. RSDs of precision， repeatability and stability tests were all lower than 3％ （n＝6）， and average recovery was 97.66％ （RSD＝1.01％，n＝6）. Average content of astragaloside Ⅳ by this method was 0.398 mg/g （RSD＝1.01％， n＝3）， which had better reproducibility than TLC scanning. The comparative results of characteristic fingerprints showed that the similarity among Xiangju granules， Xiangju capsules， Xiangju tablets and the original formulation dry extract powder was more than 0.850. Average release rates of astragaloside Ⅳ in Xiangju granules， Xiangju capsules， Xiangju tablets and the original formulation extract were 0.392， 0.358， 0.349， 0.389 mg， respectively. Compared with original formulation extract， there was no statistical significance in release rate of astragaloside Ⅳ in Xiangju granules （P＞0.05）， while there was statistical significance in Xiangju capsules and Xiangju tablets （P＜0.01）. CONCLU- SIONS： Established HPLC-ELSD method is accurate and feasible， and is suitable for the content determination of astragaloside Ⅳ in Xiangju granules. The main components of Xiangju granules are consistent with original formulation.

Study on Release Rate in vitro of Risperidone Sustained-release Tablets and Its Pharmacokinetics in Rabbits / 中国药房

OBJECTIVE： To study release behavior in vitro of Risperidone sustained-release tablets and its pharmacokinetics in rabbits. METHODS： Risperidone sustained-release tablets were prepared by using mesoporous silica as matrix. Release rates in vitro within 12 h （Q12 h） of commercially available Risperidone tablets， Risperidone sustained-release tablets and its physical mixture in 0.1 mol/L HCl fluid were investigated with basket method. The release model of Risperidone sustained-release tablets were fitted. Using clozapine as an internal standard， HPLC method was used to determine blood concentration of risperidone and 9-hydroxyrisperidone in rabbits 48 h （n＝6） after intragastric administration of commercially available Risperidone tablets and Risperidone sustained-release tablets 2 mg. Pharmacokinetic parameters were calculated by using non-compartmental model of Kinetica 4.4 software. RESULTS： Compared with commercially available Risperidone tablets （Q12 h＝97％） and physical mixtures （Q12 h＝95％）， release rate of Risperidone sustained-release tablets （Q12 h＝83.7％） slowed down significantly， and the release of Risperidone sustained-release tablets in 0.1 mol/L HCl fluid was closed to first-order release （R2＝0.998 9）， with diffusion as the main factor and dissolution as the supplement. By risperidone， the pharmacokinetic parameters of commercially available Risperidone tablets and Risperidone sustained-release tablets included that t1/2 were （4.64±0.93），（6.65±0.92） h； cmax were （34.46±7.75） and （8.57±6.91） ng/mL； MRT were （11.48±1.23）， （17.46±2.10） h； AUC0-48 h were （314.39±10.33），（192.98±49.14） ng·h/mL， respectively. By 9-hydroxyrisperidone， the pharmacokinetic parameters of them included that t1/2 were（7.08±0.93），（10.45±0.78） h； cmax were （98.08±5.43），（54.55±4.88） ng/mL； MRT were （11.48±1.23）， （17.46±2.10） h； AUC0-48 h were （894.71±131.15）， （1 227.99±112.12） ng·h/mL （n＝6）， respectively. Compared with commercially available Risperidone tablets， t1/2 and MRT of Risperidone sustained-release tablets prolonged significantly， while cmax decreased significantly （P＜0.05）. CONCLUSIONS： Risperidone loaded in mesoporous silica has sustained release effect and prolong the time of drug efficacy.

Study on Preparation of Triptolide-glycyrrhetic Acid Compound Microemulsion and Its Physicochemical Properties and in vitro Release Characteristics / 中国药房

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.

Study on Preparation Phase Identification and Release Rate in vitro of Inclusion Compound of Indapamide- β-cyclodextrin Inclusion Compound / 中国药房

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.

Effects of the critical quality attribute (cqa) of hypromellose on the release of diclofenac sodium sustained-release tablets in vitro / 中国药学杂志

OBJECTIVE: To investigate the effect of the critical quality attributes of hypromellose (HPMC) on the release profile of diclofenac sodium sustained-release tablets in vitro. METHODS: The characteristics including appearance, particle size, density, compression and specific surface area of HPMC K15M from three manufacturers (A, B and C) were studied and evaluated comprehensively. The compression data of HPMC K15M were non-linear fitted via the pressure-tensile strength curve method, Kawabe equation and Hasano equation. Sustained-release tablets were prepared by using diclofenac sodium as the active ingredient with different HPMC as gel matrix, and the in vitro release behavior of the tablets was determined in order to identify the critical quality attribute of HPMC that affect the in vitro release profile of diclofenac sodium sustained-release tablets. RESULTS: The release rate of diclofenac sodium sustained-release tablets was correlated with the substitution type of HPMC, viscosity, density and specific surface area, but less affected by particle size. CONCLUSION: Substitution, viscosity, density and specific surface area of HPMC are the CQAs factors influencing the release profile of diclofenac sodium sustained- release tablets.

Preparation and in vitro release rate of trichosanthes sustained-release pellets / 国际药学研究杂志

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.

Preparation of long-circulating dihydromyricetinliposomes and its pharmacokinetics in rats / 中草药

Objective To prepare dihydromyricetin (DMY) long-circulating liposomes and evaluate in vitro release dynamics and in vivo pharmacokinetics in rats. Methods Film-ultrasonic method was used to prepare DMY liposomes by single factor experiment and orthogonal test to optimize the formulation and preparation of DMY liposomes. The particle size and zeta potential of liposomes were determined by laser particle size analyzer. The morphological examination of liposomes was performed by using transmission electron microscopy. The liposome release in vitro was studied using dialysis method. DMY concentration in rat plasma was determined by the established LC-MS/MS method. Results The optimal prescription was 75∶20∶5 for soybean phospholipid-cholesterol-mPEG 2000-DSPE, and 1∶12 for DMY-lipid (wt/wt) with the ultrasonic time of 20 min and loading temperature of 60 ℃ in pH 5.0 PBS buffer. Under the optimized conditions, DMY liposomes was sphere with mean particle size of (117.9 ± 5.5) nm and mean zeta potential of (−2.6 ± 1.7) mV, the encapsulation efficiency and drug-loading content was (54.7 ± 3.3) % and (4.3 ± 0.2) %, respectively. The in vitro accumulative release rate of 48 h was 86% in pH 1.2 and pH 6.8 dissolve medium. Compared with free DMY, the t1/2z and AUC0-∞ of DMY liposome were increased by 2.7-fold and 1.8-fold, respectively. Conclusion Compared with free DMY, DMY liposomes released gently and slowly in vitro, eliminated slowly in vivo, and had higher bioavailability of oral administration.

Preparation of microparticles of glycyrrhetinic acid complex TOGA-X4 and in vitro release characteristics / 中草药

Objective To prepare TOGA-X4 microparticles with uniform size and good rehydration property and to obtain the stable and reliable preparation process, and evaluate the in vitro release characteristics. Methods With the average particle size, polydispersity index and rehydration as indexes, optimizing the process of antitumor active substance TOGA-X4 microparticles by stainless steel rapid film emulsification method through single factor investigation to investigate the factors influencing the size and dispersion of the drug microparticles and observe the morphology of the particles by scanning electron microscopy. With the cumulative release degree of TOGA-X4 as index, direct drug release method was adopted to determine the cumulative release rate of TOGA-X4 and the size of TOGA-X4 microparticles. The curve of in vitro drug release was fitted with different release model to estimate the in vitro release characteristics of TOGA-X4 raw powders and TOGA-X4 microparticles. Results The optimized preparation technology contained TOGA-X4 mass concentration of 5 mg/mL in oil phase, PVA mass concentration of 30 mg/mL in for aqueous phase, the ratio of oil to water was 1:1, transmembrane pressure at 0.4 MPa, sucrose aqueous solution of 50 mg/mL as freeze-drying protective agent, curing temperature at 70 ℃; Compared with other in vitro release models, the logistic equation was the fittest model to TOGA-X4 microparticles, zero order equation was the fittest model to TOGA-X4. Conclusion The preparation of microparticles by stainless steel rapid film emulsification is simple, stable and reliable, which can improve the dissolution rate of insoluble drugs and has advantages in the preparation of microparticles of poorly water-soluble drugs.

Preparation and evaluation of progesterone injection with different particle size / 国际药学研究杂志

Objective To compare the release rate and bioavailability of progesterone injection with different particle sizes. Methods The preparation of progesterone nano sized injection and micron sized injection were performed by power X-ray diffraction (PXRD)and Fourier trensform infrared spectooscory(FTIR). The dissolution rate of two preparations and progesterone was compared by dialysis Method. HPLC-MS method was used to determine the progesterone concentration of plasma in rats after intramuscular injec-tion of different preparations,and the main pharmacokinetic parameters were calculated and analyzed statistically. Results Based on the analysis of PXRD and FTIR,there were no crystal structure changes between the two preparations and progesterone. The complete release of progesterone nano sized injection and micron sized injection required 2 and 4 h in the PBS solution,respectively,while the release of progesterone required nearly 40 h. In the pharmacokinetic experiment,compared with progesterone injection,the Cmax of pro-gesterone nano sized injection and micron sized injection were increased by 1.8 and 1.7 times,respectively;the AUC0-t were increased by 2.95 and 1.63 times,respectively. The bioavailability of both was higher than that of progesterone injection. Conclusion The re-lease rate bioavailability of progesterone nano sized injection and micron sized injection is higher than that of progesterone and proges-terone injection. Bioavailability of progesterone nano sized injection is higher than that of progesterone micron sized injection.

Preparation of Ibuprofen Lysine Sustained-release Liquid Suppository and Its Evaluation in vivo and in vi-tro / 中国药房

OBJECTIVE:To prepare Ibuprofen lysine sustained-release liquid suppository,and conduct the evaluation in vivo and in vitro. METHODS:Ibuprofen lysine sustained-release liquid suppository was prepared by using Poloxamer solution as main matrix,carbomer as bioadhesive agent,laurocapram as penetrant. The ratios of poloxamer 407(P407)-poloxamer 188(P188)and carbomer content were screened by using gel temperature,gel intensity,biological adhesion and release rate in vitro as indexes, and the concentration-time curves and pharmacokinetic parameters of prepared liquid suppository and common solid suppository af-ter rectal administration in Beagle dogs in vivo were compared. RESULTS:When the P407-P188 ratio was 1:1.2,the gel tempera-ture of sustained-release liquid suppository was 30.4-38.1 ℃,which was the nearest to the rectal temperature;when the content of carbomer was 0.8%,the in vitro release of sustained-release liquid suppository was in zero-order model,with favorable correlation (R2=0.996). The tmax of common solid suppository was 3.206 h,then plasma concentration decreased significantly,release time did not exceed 12 h,AUC0-∞ was 501.826 mg·h/L;tmax of sustained-release liquid suppository was 8.814 h,then plasma concentration decreased,release time exceeded 24 h,AUC0-∞ was 715.489 mg·h/L. CONCLUSIONS:Ibuprofen lysine sustained-release liquid suppository is successfully prepared,which shows better sustained-release effect and excellent correlation in vivo and in vitro than common solid suppository.

Optimization of Mirabegron Sustained-release Tablets by Central Composite Design-response Surface Meth-od / 中国药房

OBJECTIVE:To optimize the formulation of Mirabegron sustained-release tablets. METHODS:Using polyethylene oxide(PEO)and hydroxypropylmethyl cellulose(HPMC K4M)as the sustained release matrix,Mirabegron sustained-release tab-lets were prepared by powder direct compression technology. Using 1,3,5,7 h accumulative release rate as indexes,the amounts of PEO,HPMC K4M and OPADRY? were optimized by composite design-response surface method,and then validated. Accumula-tive release rates of sustained-release tablet and original tablet (MyrbetriqTM) were compared in different pH mediums (water,pH 1.0 simulated gastric fluid,pH 4.5 acetate buffer solution,pH 6.8 phosphate buffer solution) at different rotation rates (100,50 r/min),and similiar factor f2 was calculated to fit drug release model of sustained-release tablet. RESULTS:In the optimized firmu-lation each Mirabegron sustained-release tablet contained mirabegron 25 mg,PEO 108.02 mg,HPMC K4M 21.69 mg,OPADRY? 2.27%. Relative error of accumulative release rates at 1,3,5,7 h to predicted value were 4.78%,3.48%,0.69% and -1.41%, respectively. f2 of release curves of sustained-release tablet and original tablet were higher than 65 in different pH medium at differ-ent rotation rates. The drug release of sustained-release tablet was fitted to zero-order release equation. CONCLUSIONS:Mirabe-gron sustained-release tablet by optimized technology is similar to original tablet in drug release behavior.

In vivo pharmacokinetics of tectorigenin floating sustained-release tablets in rabbits and evaluation of in vitro-in vivo correlation / 中草药

Objective: To evaluate therelease characteristicsin vitro, pharmacokinetics in rabbits and in vivo-in vitro correlation of tectorigenin floating sustained-release tablets (TFSRT). Methods: The release characteristics of TFSRTin vitro was detected with HPLC in the artificial gastric fluid. Six Japanese Giant Ear Rabbits as self crossover control, which were given TFSRT and suspension liquid (200mg). The concentration of tectorigenin in plasma was determined with HPLC and the data were processed with PKsolver 2.0 software. Results:The cumulative releaserate of TFSRTin vitro was over 70% in 10 h.The pharmacokineticsin rabbits showed that TFSRT and tectorigenin suspension liquid conformed to the single compartment model and the pharmacokinetic parameters were obtained: tmax: (2.809±0.371) and (0.442±0.138)h, Cmax: (6.317±1.337) and (9.662±2.759) μg/mL, AUC0-t: (74.156±10.420) and (57.059±13.309) μg∙h/mL. The relative bioavailability of TFSRT was (134.63±27.94)%, so there was significant difference between them. Conclusion: TFSRT can release slowly, so it increase the relative bioavailability significantly. The correlation between the absorption in vivo and release in vitro is fine (r=0.9879), so the release rate in vitro can control the quality of TFSRT.

Preparation and pharmacokinetics of honokiol long-circulating liposomes / 中草药

Objective To optimize the preparation process of honokiol long-circulating liposomes (HLCL) and study the in vitro and in vivo release. Methods An orthogonal experiment was designed to optimize the composition of HLCL using entrapment efficiency as evaluation indicator. The liposome surface morphology was observed by transmission electron microscope (TEM), and the liposome release in vitro was studied by dialysis method. The concentration of honokiol in rat plasma was determined by the established LC-MS/MS method, and the differences in pharmacokinetic parameters were compared after honokiol and HLCL (20 mg/kg) were orally administered to SD male rats, respectively. Results The optimal composition of HLCL was 8:1:1 for soya phosphatidyl choline-cholesterol-mPEG2000-DSPE, and 1:10 for honokiol-liposome materials with the ultrasonic time of 12 min. Under the optimized conditions, HLCL was sphere with mean particle size of 121.5 nm and mean Zeta potential of -30.8 mV, the encapsulation efficiency and drug-loading content was 84.7% and 10.4%, respectively. In vitro release results showed that the liposomes could be gently and slowly release with the 24 h cumulative release rate at pH 1.2 and pH 6.9 dissolve medium of 80% and 71%, respectively. Based on the pharmacokinetic results, Cmax, tmax, and t1/2 were (23.29 ± 11.76) ng/mL, (0.13 ± 0.05) h and (10.59 ± 5.72) h for HLCL, and (79.34 ± 56.32) ng/mL, (0.30 ± 0.07) h and (4.44 ± 3.14) h for honokiol, respectively. There was no significant difference about the AUC0-∞ following oral administration of honokiol and HLCL at isodose honokiol (20 mg/kg). Conclusion Compared with honokiol, HLCL was released gently and slowly in vitro, absorpted rapidly and eliminated slowly in vivo.

Formulation Screening of 5-fluorouracil Polylactic Acid Sustained-release Tablet and Study on Its in vitro Drug-release Mechanism / 中国药房

OBJECTIVE:To screen the formulation of 5-fluorouracil (5-FU) polylactic acid (PLA) sustained-release discs (5-FU-PLA-DS),and study its in vitro drug-release mechanism. METHODS:UV spectrophotometry was used to determine the 5-FU content in the release medium. Using simulate body fluid as release medium,in vitro drug-release test was conducted under 37℃water bath. Using PLA with molecular weight of 3000,6000,10000,15000,20000,15 species of round 5-FU-PLA-DS with drug containing of 1.5,2.5,3.0 mg/piece and 3.0 mm in diameter and 1.0 mm in thickness were prepared. Using effective con-centration sustained release time and cumulative release rate as indexes, the optimal formulation was screened. The form of 5-FU-PLA-DS was observed by scanning electron microscopy after release,and its release mechanism was evaluated. RESULTS:In the optimal formulation, the PLA molecular weight was 20000 and drug containing was 3.0 mg/piece. The prepared 5-FU-PLA-DS can release for 119 d,with cumulative release degree of 100.63% and effective concentration sustained for 91 d. Scanning electron microscopy showed that the microspheres at the surface were degraded to the release medium first,and then the microspheres of inner layer exposed and release drug gradually after PLA degraded. The main mechanism of drug-release was melt-ing and diffusion. CONCLUSIONS:5-FU-PLA-DS is successfully prepared,with long release time in effective concentration,can be degraded step by step from outside to inside and achieve non-synchronous drug-release of microspheres at different layers.

Formulation Screening of 5-fluorouracil Polylactic Acid Sustained-release Tablet and Study on Its in vitro Drug-release Mechanism / 中国药房

OBJECTIVE:To screen the formulation of 5-fluorouracil (5-FU) polylactic acid (PLA) sustained-release discs (5-FU-PLA-DS),and study its in vitro drug-release mechanism. METHODS:UV spectrophotometry was used to determine the 5-FU content in the release medium. Using simulate body fluid as release medium,in vitro drug-release test was conducted under 37℃water bath. Using PLA with molecular weight of 3000,6000,10000,15000,20000,15 species of round 5-FU-PLA-DS with drug containing of 1.5,2.5,3.0 mg/piece and 3.0 mm in diameter and 1.0 mm in thickness were prepared. Using effective con-centration sustained release time and cumulative release rate as indexes, the optimal formulation was screened. The form of 5-FU-PLA-DS was observed by scanning electron microscopy after release,and its release mechanism was evaluated. RESULTS:In the optimal formulation, the PLA molecular weight was 20000 and drug containing was 3.0 mg/piece. The prepared 5-FU-PLA-DS can release for 119 d,with cumulative release degree of 100.63% and effective concentration sustained for 91 d. Scanning electron microscopy showed that the microspheres at the surface were degraded to the release medium first,and then the microspheres of inner layer exposed and release drug gradually after PLA degraded. The main mechanism of drug-release was melt-ing and diffusion. CONCLUSIONS:5-FU-PLA-DS is successfully prepared,with long release time in effective concentration,can be degraded step by step from outside to inside and achieve non-synchronous drug-release of microspheres at different layers.