Preparation of indomethacin-nicotinamide cocrystal by hot melt extrusion and its release in vitro / 中国药科大学学报

@#Abstract The indomethacin-nicotinamide cocrystal was prepared by hot melt extrusion(HME)to improve the dissolution of indomethacin in vitro. The optimum preparation conditions were investigated using temperature and rotate speed as variables. Thermogravimetric analysis(TGA), determination of content and determination of related substances were performed to evaluate the thermal stability of indomethacin during the process. Cocrystal was also prepared by solution crystallization from acetonitrile. The products obtained by the two methods were characterized by differential scanning calorimetry(DSC), Fourier transform infrared(FTIR)and powder X-ray diffraction(PXRD). The solubility and dissolution advantages of cocrystal were evaluated. The results showed that the HME method could successfully prepare the indomethacin-nicotinamide cocrystal at 115 °C and eutectic mixture was formed during the process. The cocrystal significantly improved the solubility and dissolution of indomethacin in deionized water, with pH 5. 5 and pH 6. 8 phosphate buffer. The preparation of poorly soluble drug cocrystal by HME can significantly improve its solubility, providing new idea for the development of poorly soluble drugs and HME technology.

Advances of wax matrix tablets / 中国药科大学学报

@#Wax matrix tablets is a special pharmaceutical controlled release preparation. However, it has not yet been fully studied and applied. In this article, the progress in carriers and techniques for the preparation of wax matrix tablets in recent years was reviewed. Analysis and comparison of their advantages and disadvantages can help to promote the application of wax matrix tablets in the future.

Preparation and antitumor activity of mitoxantrone conjugated D-α-tocopherylpolyethylene glycol 1000 succinate prodrug micelle / 中国药科大学学报

@#To improve the theraputic effect of chemotherapeutic drugs, D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)was employed as a carrier of mitoxantrone(MTO). MTO was successfully conjugated to TPGS via succinic anhydride to prepare TPGS-MTO prodrug. The prodrug was then self-assembled into TPGS-MTO micelle, with the particle size of(25. 61±0. 92)nm, the polydispersity of 0. 22±0. 04 and the Zeta potential of -(3. 98±0. 09)mV. The micelle was homogeneous spheres under the observation of transmission electron microscope(TEM). The drug loading capacity(DLC)was(18. 61±0. 24)% by HPLC. Meanwhile, the particle size of TPGS-MTO micelle remained stable in 24 h. TPGS-MTO showed a controlled drug release profile with only 9. 04% MTO being detected in 24 h in neutral conditions, and faster release was achieved by decreasing pH in media. Cellular uptake experiments showed that micelle was 1. 18 times more effective than parent drug after 6 h incubation on MCF-7 cells. The cytotoxicity of micelle on MCF-7 and MCF-7/MDR cells was detected by MTT, both with anti-tumor activity, especially on MCF-7/MDR cells. In conclusion, TPGS-MTO prodrug micelle could be a potential formulation of higher therapeutic effects and fewer side-effects than MTO itself.

Advances of 3D printing technology in advanced pharmaceutical preparations / 中国药科大学学报

@#3D printing is rapidly developing in various areas of science and technology. Owing to its advantages such as simplicity, flexibility, reproducibility and suitability, 3D printing technology is utilized in the field of advanced pharmaceutical preparations. The literatures are mainly related to the formulations with a variety of release mechanism, including conventional-release formulations, controlled-release formulations, implants and compound preparations. Herein the latest 3D printing technology in the advanced preparations is presented and the related developing trends and challenges are also addressed.

Preparation and characterization of nanostructured lipid carriers with difference in particle size / 中国药科大学学报

@#To construct nanostructured lipid carriers(NLCs)with different particle sizes but the same other physicochemical properties, central composite design was adopted. Coumarin-6(C-6)was selected as the model drug due to its high lipophilicity and high fluorescence intensity. Physicochemical properties of NLCs with 100 nm, 200 nm and 300 nm in particle size could remain stable during certain time in K-R solution and PBS. Release experiments in vitro showed that cumulative release of C-6 in NLCs was less than 7% after 24 h. The MTT assay indicated that both blank NLCs and C-6 loaded NLCs showed low toxicity. To confirm the integrity of NLCs in gastrointestinal tract, DiR-loaded NLCs were prepared and the distribution in vivo was monitored by fluorescence imaging. After 6 h oral administration, intact DiR-loaded NLCs could stiu be found, suggesting that NLCs could be used to characterize the uptake in gastrointestinal tract.

Preparation and in vitro and in vivo evaluation of folate-BSA-coated cationic nanostructure lipid carriers / 中国药科大学学报

@#Folic acid(FA)was conjugated with bovine serum albumin(BSA)to form targeting material. BSA-coated cationic nanostructure lipid carriers(BSA-cNLCs)and folate-BSA-coated cationic nanostructure lipid carriers(FA-BSA-cNLCs)were prepared by film dispersion. The particle sizes of BSA-cNLCs and FA-BSA-cNLCs were 81. 4 nm and 79. 8 nm, while their Zeta potentials were +5. 12 mV and +3. 74 mV. Both nanostructure lipid carriers showed spherical shape. Paclitaxel encapsulation efficiency of them were more than 97%, with drug loading efficiency of about 3. 7%. In vitro experiments confirmed that the uptake of FA-BSA-cNLCs by overexpressed folate receptor SKOV3 cells was significantly higher than that of BSA-cNLCs, demonstrating that FA-BSA-cNLCs were obviously targeted to SKOV3. Blood and tumor pharmacokinetics showed that there was no significant differences between BSA-cNLCs and FA-BSA-cNLCs. This suggested that modified FA on the surface of the preparation had no effect on its in vivo behavior. Tumor inhibition of BSA-cNLCs and FA-BSA-cNLCs were 72. 08% and 80. 75%, repectively, which indicateds that FA-BSA-cNLCs improve anticancer efficacy in vitro and in vivo, and that it could be a potential preparation for the treatment of cancer.

Recent development of natural and reconstituted lipoprotein based nano drug delivery vehicles / 药学学报

Abstract: Lipoproteins are biological lipids carriers. The natural and reconstituted lipoprotein based drug delivery systems have been extensively developed in recent years. This article reviews the development of natural and reconstituted low-density lipoprotein and high-density lipoprotein based vehicles in the antitumor area.

Solidified mPEG-PDLLA micelles as a novel oral delivery system of indomethacin / 药学学报

In this study, indomethacin (IND) loaded solidified-polymeric micelles (IND-SPM) were prepared. Their in vitro characteristics were investigated. Methoxy-poly(ethylene glycol) poly(D, L-lactide) copolymer (mPEG-PDLLA) was used as IND carrier. The preparation of IND-SPM was conducted by solution-absorption method and evaporation by rotary evaporator. Polyplasdone XL-10 was used as adsorbent. The solution-absorption method was conducted by the following procedure; IND and mPEG-PDLLA were dissolved in acetone, followed by addition of polyplasdone XL-10 and stirred to obtain a suspension. The powder of IND-SPM was simply obtained after the organic solvent was completely evaporated. More than 90% (w/w) of IND (20 mg) in the powder was dissolved in 250 mL PBS within 30 min. DSC, 1H NMR and SEM results proved that IND was encapsulated within mPEG-PDLLA. The solubility of IND in the system increased 4.6 times with the highest amount of copolymer. The solidified particles were found to be suitable for the formulation of tablets or capsules.

Preparation and evaluation of vinblastine PCL-PEG-PCL nanoparticles / 中国药科大学学报

Aim:To prepare vinblastine-loaded PCL-PEG_(6000)-PCL nanoparticles,and to study their physicochemi-cal properties and in vitro antitumor activity.Methods: PCL-PEG_(6000)-PCL triblock copolymer was prepared by ring-opening polymerization,and vinblastine-loaded PCL-PEG_(6000)-PCL nanoparticles was prepared by coprecipita-tion.The morphous,particle size,polydisperse index,particle yield,the drag-loading content,the encapsulation ef-ficiency and in vitro release rate of these vinblastine-loaded nanoparticles were determined.The cytotoxicity of vinblastine-loaded nanoparticles to K562/A02 leukimia cell line was determined by MTT assay.Results: It was found using transmission electron microscopy(TEM)that the nanoparticles exhibited a spherical shape with core-shell structure.The particle sizes of the nanoparticles obtained by dynamic light scattering were(185 ± 2.7)nm.The drug loading content and the encapsulation efficiency were determined to be 28.83% and 86.52%,re-spectively.In vitro release study revealed that more than 70% of accumulative release of entrapped vinblastine was reached in 9 hr and that nearly complete release was achieved in 24 hr.The inhibition of vinblastine-loaded nanoparticles to K562/A02 cell line was significantly increased as compared with that of the same dose of sulfate vinblastine solution.Conclusions: PCL-PEG-PCL nanoparticles could be used as a carrier of vinblastine,and the prepared nanoparticles exhibited a spherical shape,high encapsulation efficiency,relevant stablity and sustained-release properties.The eytotoxicity of vinblastine to K562/A02 cell line was significantly increased when it was encapsulated in PCL-PEG-PCL nanoparticles.

Microemulsion-based gel of fluorouracil for transdermal delivery / 药学学报

This study is to prepare the microemulsion-based gel based on the W/O microemulsion and fluorouracil (5-Fu) as a model drug to study the transdermal characterization and observe its skin irritation of the microemulsion-based gel in vitro. IPM acted as oil phase, AOT as surfactant, Tween 85 as cosurfactant, water was added dropwise to the oil phase to prepare W/O microemulsion at room temperature using magnetic stirring, then 5-Fu powder was added. The gelatin was used as substrate to prepare 5-Fu microemulsion-based gel. The permeation flux of 5-Fu from 5-Fu microemulsion-based gel across excised mice skin was determined in vitro using Franz diffusion cell to study the influence of the amount of gelatin and the drug loading capacity. Refer to 5-Fu cream, the irritation of microemulsion and microemulsion-based gel on the rat skin was studied. Based on the water/AOT/Tween 85/IPM microemulsion, only the gelatin can form the microemulsion-based gel. At 25 degrees C, 32 degrees C and 40 degrees C, the amount of gelatin required for the formation of microemulsion-based gel were 7%, 14% and more than 17%, respectively. The 12 h transdermal cumulated permeation amount of 5-Fu from microemulsion-based gel containing 14% gelatin and 0.5% drug loading were (876.5 +/- 29.1) microg x cm(-2), 12.3 folds and 4.5 folds more than 0.5% 5-Fu aqueous solution and 2.5% (w/w) 5-Fu cream, respectively. Microemulsion-based gel exhibited some irritation, but could be subsided after drug withdrawal. Microemulsion-based gel may be a promising vehicle for transdermal delivery of 5-Fu and other hydrophilic drug.

Anti-inflammatory Effects of Components in Shuxiong Tablet and Its Possible Formulary Rationality / 中草药·英文版

Objective To determine whether the anti-inflammatory properties of Shuxiong Tablet(SXT)and the effective components group of SXT(ECGS)are equivalent and to assess the formulary rationality.Methods ECGS consisted of Panax notoginsen saponion(PNS),hydroxysafflor yellow A,and ferulic acid plus volatile oil of Ligusticum chuanxiong,which was based on the active ingredients and their ratios in SXT.We compared the anti-inflammatory actions of ECGS and SXT using the xylene-induced edema model and the carrageenan-induced edema model,as well as the analgesic activity of them using the acetic acid-induced writhing model.Moreover,cultured macrophages were incubated with media containing serum isolated from SXT-,ECGS-,or every component of ECGS-treated rats,to compare the depress effects on lipopolysaccharide(LPS)-stimulated NO production and inducible nitric oxide synthase(iNOS)expression.Results ECGS and SXT had equivalent anti-inflammatory actions and analgesic effects at an equipotent dosage in a dose-dependent manner.The drug-containing media could inhibit the LPS-stimulated NO production and iNOS expression in cultured macrophages.A 2 × 2 × 2 ANOVA revealed that three effective components could produce synergistic effect on the inhibition of NO production,and PNS was the capital component.Conclusion ECGS and SXT display an equivalent anti-inflammatory effect,and the formula follows traditional Chinese medicine compatibility principle,which shows obvious formulary rationality.

Combined system of sinomenine hydrochloride sustained-release pellets / 中国药科大学学报

Aim: To establish a linear additive model for the predication of in vitro sinomenine hydrochloride release from the combination of immediate release, enteric-coated and sustained-release pellets based on the release profiles of each pellet type. Methods: Immediate release pellets were manufactured by extrusion/spher-onization technology. The operation of bottom-spraying in the fluid-bed equipment was conducted to enteric-coating using Eudragit~(R) L-30D-55 and sustained-release coating using Surelease~(R) . In vitro sinomenine hydrochloride release profiles of both uncoated and coated pellets were fitted to the chosen mathematical equations offered by the curve fitting toolbox of Matlab~(R) before a linear additive model was created based upon the best-to-fitting equations. The proportion of each pellet type in the combined format to generate the desired 24 h sinomenine hydrochloride release profile was solved by Matlab~(R). The predicted and assayed sinomenine hydrochloride release from the polled pellets was compared. Results: It was shown that the actual sinomenine hydrochloride release profiles of each pellet type were approximate to those of predicted ones. A linear additive model of the appropriate mathematical equations of each pellet was proven to be capable of controlling in vitro release of sinomenine hydrochloride multiple-unit pellets. Conclusion: A multiple-unit combined system of the selected pellets, as a novel sustained-release system, was successfully prepared. In vitro release performance of the calculated combination of each pellet type could be guaranteed by this approach in designing sustained-release drug delivery system.

Preparation, dissolution and bioavailability of lycopene-Poloxamer 188 solid dispersion / 中国药科大学学报

Aim: To improve the solubility, dissolution and bioavailability of lycopene by preparing lycopene solid dispersion. Methods: Lycopene solid dispersion was prepared by the solvent method using Poloxamer 188 as car-rier. The physicochemical characteristics of the dispersion were determined by DSC, ultraviolet-visible spectra and the Dissolution Apparatus Ⅱ( Paddle). The oral bioavailability of lycopene was estimated in rat after oral dosing of lycopene solid dispersion or oil preparation. The plasma concentrations of lycopene in rats were determined by HPLC. The pharmacokinetic parameters were estimated by Kinetica software package. Results: In vitro dissolution of lycopene solid dispersion was greater than those of lycopene (raw material), and the physical mixture of lyco-pene and Poloxamer 188, partly due to the existing molecular state of lycopene in the dispersion. It was also found that the relative bioavailability of lycopene solid dispersion to lycopene oil preparation was (312. 2±96. 9) % . The optimal ratio of lycopene to carrier in the dispersion was about 1: 5. Conclusion: Lycopene-Poloxamer 188 solid dispersion could be prepared by the proposed simple, low-costly procedure resulting in improved bioavail-ability of lycopene, which is worthy of further development.

Preparation and characterization of diclofenac sodium layered double hydroxide nanohybrids / 中国药科大学学报

Aim: To prepare diclofenac sodium-layered double hydroxide nanohybrids(DS-LDH) and investigate its properties. Methods: The diclofenac sodium anions were hybridized with LDH by co-precipitation. The synthetic nanohybrids were characterized by various methods, such as laser particle sizer, XRD, IR, and TEM. Paddle method according to the Chinese Pharmacopoeia was used to determine the dissolution. The anti-inflammation of nanohybrids and diclofenac sodium were compared by the effect on auricular tumescence induced by xylene in mice. Results: The acidic negative ion of layered double hydroxides were replaced by the diclofenac anion to form DS-LDH. Release studies showed that the nanohybrids could serve as controlled release systems for DS. Zn-Al-NO3-LDH was proved to have character of neutral pH which is more suitable for orphthalmic preparation. The DS-LDH nanohybrids could keep the effect of anti-inflammation. Conclusion: Layered double hydroxide nanohybrids can be used as sustained-release carrier of anionic drugs. A novel type of drug-inorganic nanohybrids was prepared successfully which has a potential value of clinical application.

Effect of constituents combination on pharmacokinetics of Shuxiong tablet / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effect of combination components on pharmacokinetics of Shuxiong tablet to provide evidence for the new recipe.</p><p><b>METHOD</b>Six groups of rats (6 for each group) were orally administered with co-extractum of chuanxiong and honghua (CHE), mixed solution of hydroxysafflor yellow A (HSYA) and ferulic acid (FA) (HFM). Panax notoginseng saponins solution (PNS), mixed solution of PNS and CHE (PCHE), mixed solution of PNS and HFM (PHFM) and mixed emulsion of Chuanxiong volatile oil (CVO) and PHFM (CVO-PHFM), respectively. The concentrations of HSYA, FA, ginsnenoside Rg1 and Rb1 in rat plasma were determined by HPLC. Pharmacokinetic parameters (Ka, Kel, Cmax, Tmax and AUC) were calculated by model simulation. The differences of HSYA, FA, Rg1 and Rb1 in pharmacokinetics parameters after administration of six preparations were demonstrated by statistical analysis.</p><p><b>RESULT</b>After oral administration of six preparations to rats, the concentration-time curve of HSYA and Rg1 fitted to one-compartment model, and that of FA fitted to double-compartment model. After oral administration of CHE, Kel of FA reduced; Cmax decreased; but K12 increased, significantly, compared with oral administration of HFM. Other parameters were not significant differences. After co-administration of PNS and CHE (PCHE) or PNS and HFM (PHFM), Ka of HSYA increased; Tmax reduced, significantly. After oral administration of PNS and HFM (PHFM), Ka of Rg1 improved, Tmax decreased, significantly. However, the parameters of FA and Rb1 were not significantly changed. After co-administration of CVO and PHFM (CVO-PHFM), Cmax of Rb1 decreased, K12 improved, significantly. Meanwhile, the oral bioavailability of HSYA, FA and Rg1 was improved by 6.056, 2.854 and 2.055 folds, respectively.</p><p><b>CONCLUSION</b>After oral administration of different combinations of Shuxiong tablet constituents, some pharmacokinetics parameters of active ingredients are significantly changed, but the bioavailability is improved only when CVO is co-administered.</p>

Fabrication, characterization and drug release characteristics of drug loaded poly (L-lactic acid) fiber / 生物医学工程学杂志

To develop a long-term released and implantable biodegradable fiber carrier for hydrophobic drug incorporation, fibers were fabricated by organic phase separation method. The structure of the fiber was observed by scanning electron microscopy and the state of the drug dispersed in the polymer was measured by differential scanning colorimetry (DSC) and Fouvier transform infrared spectroscopy (FTIR). The drug loading content and release profiles were determined by high performance liquid chromatography (HPLC) and ultra-violet spectrophotometry, respectively. Blank and drug loaded fibers were successfully fabricated and the drug was entirely encapsulated into the fiber. The drug was dispersed in the polymer with minicrystal and noncrystal form. The drug release profile was long-term sustained and could be regulated. The PLLA fibers in micrometer range successfully fabricated by organic phase separation method could be taken as sustained release and implantable drug carrier.

Perspectives on Current Effective Enforcement of Drug Recall Administration in China / 中国药房

OBJECTIVE:To strengthen the implementation of Drug Recall Administration(DRA).METHODS:Based on the study of "DRA" and the analysis of the current drug recall status both in China and abroad,effective measures for the enforcement of the regulation was presented.RESULTS & CONCLUSIONS:In the initial enforcement stage of "DRA",some relative effective measures should be taken from the aspects of drug manufacturing enterprises,consumers and the related supporting regulations to ensure the effective enforcement of the regulation.

Preparation of Stable Solid Lipid Nanoparticles (SLNs) Suspension with Combined Surfactants / 中国药科大学学报

AIM:Surfactants and their blend play important roles in the preparation of solid lipid nanoparticles (SLNs).In this study,four types of surfactant were employed to investigate the influence of the surfactants on properties of SLNs in the absence of model drugs thereby avoiding the interaction between the surfactant and the drug.METHODS:The physicochemical properties of the colloidal systems,such as mean particle size,distribution range and Zeta potential,were investigated by laser diffractometry and the DSC analysis was performed as well.RESULTS:It was found that ionic surfactants,such as sodium deoxycholate, increased the Zeta potential of nanoparticles leading to improve the physical stability of the system.But it showed obviously relative low emulsification efficiency in the preparation.Non-ionic emulsifier,especially Pluronic F-68, offered additional steric stabilization effect avoiding aggregation of the fine particles in the colloidal system.CONCLUSION:The formulation in the study for the first time combined four types of additives including ionic surfactant (sodium deoxycholate),non-ionic emulsifier (Pluronic F-68 and Tween-80),and lecithin to obtain favorably stable nanosuspension,which could stabilize for more than six months without creaming.

TRANSDERMAL DELIVERY OF CYCLOSPORIN A SOLUBILIZED IN MIXED MICELLES THROUGH MICE SKIN / 药学学报

AIM　To investigate the transdermal delivery effects of cyclosporine A solubilized in mixed micelles composed of phospholipid and different surfactants. METHODS　When applied onto the excised abdominal skin of the mice occlusively, the enhancing effects of various mixed micelles on the penetration of cyclosporin A were assessed by an in vitro permeation technique. In vivo study was carried out by topical application of sodium cholate-phospholipid mixed micelles onto the mice skin and drug blood concentration was detected. RESULTS　In vitro, mixed micelles containing different surfactants displayed distinct permeability and corresponded to the following order: sodium cholate > sodium deoxycholate > Trition X-100 > Tween-20. In vivo, peak drug concentration was detected at 5 h and after that the concentration fell down slowly. CONCLUSION　Mixed micelles were shown to be efficient carrier for the transdermal delivery of the lipophilic polypeptide when kept in solution during the application process.

Pharmacological study on the substitution of effective compounds group for Shuxiong Tablet / 中成药

AIM:To compare the difference between Shuxiong Tablet(Radix et Rhizoma notoginseng,Flos Carthami,Rhizoma Chuanxiong)(SXT) and its effective compounds group(SECG) in anti-inflammatory,relieving pain,anticoagulation,anti-thrombus and myocardial protection.METHODS:We adopted experiments of carrageenan-induced paw edema,hot water shrink trail,clotting time in mice,and thrombus in arteriovenous shut,and pituitrin induced acute myocardial ischemia in rats.RESULTS:Both of SXT and SECG could inhibit the tumefaction,decrease PGE_2 and SOD in inflammatory tissue;enhance the pain threshhold of mice;extend clotting time;inhibit the thrombosis;inhibit myocardial ischemia,significantly decrease CK,LDH,MDA and increase SOD in myocardial tissue.CONCLUSION:SXT and SECG have the same effects on anti-inflammatory,relieving pain,anticoagulation,anti-thrombus and myocardial protection.Further more,their dose-response relationship curves were similar,suggesting that SECG having the main effective components of SXT,could take place of SXT in clinical research.