Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs

Nanocrystals,a carrier-free colloidal delivery system in nano-sized range,is an interesting approach for poorly soluble drugs.Nanocrystals provide special features including enhancement of saturation solubility,dissolution velocity and adhesiveness to surface/cell membranes.Several strategies are applied for nanocrystals production including precipitation,milling,high pressure homogenization and combination methods such as Nano-Edge^(TM),SmartCrystal and Precipitation-lyophilization-homogenization(PLH)technology.For oral administration,many publications reported useful advantages of nanocrystals to improve in vivo performances i.e.pharmacokinetics,pharmacodynamics,safety and targeted delivery which were discussed in this review.Additionally,transformation of nanocrystals to final formulations and future trends of nanocrystals were also described.

Alginate encapsulated mesoporous silica nanospheres as a sustained drug delivery system for the poorly water-soluble drug indomethacin

We applied a combination of inorganic mesoporous silica material,frequently used as drug carriers,and a natural organic polymer alginate(ALG),to establish a sustained drug delivery system for the poorly water-soluble drug Indomethacin(IND).Mesoporous silica nanospheres(MSNs)were synthesized using an organic template method and then functionalized with aminopropyl groups through postsynthesis.After drug loading into the pores of aninopropyl functionalized MSNs(AP-MSNs),IND loaded AP-MSNs(IND-AP-MSNs)were encapsulated by ALG through the ionic interaction.The effects of surface chemical groups and ALG layer on IND release were systematically studied using scanning electron microscopy(SEM),transmission electron microscopy(TEM),nitrogen adsorption,zetapotential analysis and TGA analysis.The surface structure and surface charge changes of the ALG encapsulated AP-MSNs(ALG-AP-MSNs)were also investigated.The results showed that sustained release of IND from the designed drug delivery system was mainly due to the blockage effect from the coated ALG.We believe that this combination will help designing oral sustained drug delivery systems for poorly water-soluble drugs.

Application of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticles

Nanoparticles are considered to be a powerful approach for the delivery of poorly watersoluble drugs. One of the main challenges is developing an appropriate method for preparation of drug nanoparticles. As a simple, rapid and scalable method, the flash nanoprecipitation(FNP) has been widely used to fabricate these drug nanoparticles, including pure drug nanocrystals, polymeric micelles,polymeric nanoparticles, solid lipid nanoparticles, and polyelectrolyte complexes. This review introduces the application of FNP to produce poorly water-soluble drug nanoparticles by controllable mixing devices, such as confined impinging jets mixer(CIJM), multi-inlet vortex mixer(MIVM) and many other microfluidic mixer systems. The formation mechanisms and processes of drug nanoparticles by FNP are described in detail. Then, the controlling of supersaturation level and mixing rate during the FNP process to tailor the ultrafine drug nanoparticles as well as the influence of drugs, solvent, anti-solvent, stabilizers and temperature on the fabrication are discussed. The ultrafine and uniform nanoparticles of poorly watersoluble drug nanoparticles prepared by CIJM, MIVM and microfluidic mixer systems are reviewed briefly. We believe that the application of microfluidic mixing devices in laboratory with continuous process control and good reproducibility will be benefit for industrial formulation scale-up.

Editor Profiles: Guest Editors of Special Issue on Enhancement of Dissolution and Oral Bioavailability of Poorly Water-soluble Drugs

Dr. Wei Wu is a professor at the Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China. His research interest is in the field of oral drug delivery systems and in vivo fate of drug nanocarriers. He and coworkers invented novel water-quenching ACQ fluorescent dyes to probe the in vivo fate of versatile nanoparticles administered via different routes.

A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

To enhance the dissolution of poorly soluble mefenamic acid,self-emulsifying formulation(SEF),composing of oil,surfactant and co-surfactant,was formulated.Among the oils and surfactants studied,Imwitor■ 742,Tween■ 60,Cremophore■ EL and Transcutol■ HP were selected as they showed maximal solubility to mefenamic acid.The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading.The droplet size after dispersion and drug dissolution of selected formulations were investigated.The results showed that the formulation containing Imwitor■ 742,Tween■ 60 and Transcutol■ HP(10:30:60)can encapsulate high amount of mefenamic acid.The dissolution study demonstrated that,in the medium containing surfactant,nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min.In phosphate buffer(without surfactant),80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min,from the commercial product.The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.

Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer

BACKGROUND Pancreatic cancer is a major cause of cancer-related death,with a 5-year overall survival rate being below 5%.The main causes of poor prognosis in pancreatic cancer include easy metastasis,high recurrence rate,and robust drug resistance.Gemcitabine is a first-line drug for patients with unresectable pancreatic cancer.However,due to drug resistance,the clinical effect is not satisfactory.ADAM28 is reported as a tumor promoter in some cancers,but its role in pancreatic cancer and gemcitabine chemoresistance in pancreatic cancer has not been elucidated.AIM To identify if ADAM28 can act as an important target to reverse the gemcitabine drug resistance in pancreatic cancer.METHODS RNA-sequence analysis was applied to explore the potential targets involved in the gemcitabine of pancreatic cancer.SW1990 pancreatic cancer cells were treated with an increased dose of gemcitabine,and the mRNA levels of ADAM28 were evaluated by RT-PCR.The protein and mRNA levels of ADAM28 were confirmed in the gemcitabine resistant and parallel SW1990 cells.The ADAM28 expression was also assessed in TCGA and GEO databases,and the results were confirmed in the collected tumor and adjacent normal tissues.The overall survival(OS)rate and relapse-free survival(RFS)rate of pancreatic cancer patients with high ADAM28 level and low ADAM28 level in TCGA were evaluated with Kaplan-Meier Plotter.Furthermore,the OS rate was calculated in pancreatic cancer patients with high tumor mutation burden(TMB)and low TMB.CCK-8 assay was used to examine the effect of ADAM28 on the viability of SW1990 cells.The ADAM28 and its co-expressed genes were analyzed in the cBioPortal for cancer genomics and subjected to GSEA pathway analysis.The correlations of ADAM28 with GSTP1,ABCC1,GSTM4,and BCL2 were analyzed based on TCGA data on pancreatic cancer.RESULTS RNA-sequence analysis identified that ADAM28 was overexpressed in gemcitabine-resistant cells,and gemcitabine treatment could induce the expression of ADAM28.The mRNA and protein levels of ADAM28 were elevated in gemcitabine-resistant SW1990 cells compared with parallel cells.Also,the expression of ADAM28 was upregulated in pancreatic tumor tissues against normal pancreatic tissues.Notably,ADAM28 was highly expressed in the classical type than in the basal tumor type.Furthermore,the high expression of ADAM28 was associated with low OS and RFS rates.Interestingly,the high levels of ADAM28 was associated with a significantly lower OS rate in the high TMB patients,but not in the low TMB patients.Moreover,overexpression of ADAM28 could reduce the cell viability inhibition by gemcitabine,and knockdown of ADAM28 could enhance the proliferation inhibition by gemcitabine.The GSEA analysis showed that ADAM28 was related to the regulation of drug metabolism,and ADAM28 was significantly positively correlated with GSTP1,ABCC1,GSTM4,and BCL2.CONCLUSION This study demonstrates that ADAM28 is overexpressed in pancreatic cancer,and closely involved in the regulation of gemcitabine resistance.Overexpression of ADAM28 is a novel prognostic biomarker in pancreatic cancer.

Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration.The particle technology involves several approaches from the conventional size reduction processes to the newer,novel particle technologies that modify the solubility properties of the drugs and produce solid,powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms.This review highlights the solid particle technologies available for improving solubility,dissolution and bioavailability of drugs with poor aqueous solubility.

Special issue on “Formulation strategies and manufacturing technologies to enhance non-invasive drug delivery”

Oral dosage forms including tablets and capsules are themost commonly used drug products. For some poorly water-soluble and poorly permeable drugs injectable dosage formscan be used to circumvent the challenges of poor bioavailabil-ity.

德谷门冬双胰岛素注射液治疗口服降糖药物血糖控制不佳2型糖尿病患者的效果及安全性观察

目的 探讨德谷门冬双胰岛素注射液在口服降糖药物血糖控制不佳2型糖尿病(T2DM)患者中的疗效及安全性,为临床提供参考。方法 选取2020年6月至2022年8月太仓市第一人民医院收治的50例口服降糖药物血糖控制不佳T2DM患者为研究对象,按照随机数字表法分为研究组和对照组,各25例。研究组患者给予德谷门冬双胰岛素注射液治疗,对照组患者给予门冬胰岛素30注射液治疗。比较两组患者临床疗效、糖代谢指标[空腹血糖(FPG)、餐后2 h血糖(2 hPG)及糖化血红蛋白(HbA1c)]水平及低血糖发生情况。结果 两组患者整体疗效和总有效率比较,差异无统计学意义(P>0.05)。治疗后,两组患者FPG、2 hPG及HbA1c水平均较治疗前降低(P<0.05),但两组患者间FPG、2 hPG及HbA1c水平比较,差异无统计学意义(P>0.05)。研究组患者低血糖发生率低于对照组(P<0.05)。结论 在口服降糖药物血糖控制不佳的T2DM患者治疗中,应用德谷门冬双胰岛素注射液和门冬胰岛素30注射液的疗效相当,均能够有效控制血糖,且前者的低血糖发生风险较低,用药安全性较高。

Fundamental aspects of solid dispersion technology for poorly soluble drugs

The solid dispersion has become an established solubilization technology for poorly water soluble drugs.Since a solid dispersion is basically a drug-polymer two-component system,the drug-polymer interaction is the determining factor in its design and performance.In this review,we summarize our current understanding of solid dispersions both in the solid state and in dissolution,emphasizing the fundamental aspects of this important technology.

骨科术后切口愈合不良患者分泌物细菌检验结果及耐药分布

目的分析骨科术后发生切口愈合不良的患者切口分泌物细菌鉴定结果以及耐药株分布情况。方法选择2019年1月至2022年5月福州市第二医院骨科术后切口愈合不良的334例患者,收集性别、年龄、细菌生长情况、细菌鉴定结果、耐药分布情况等指标,剔除重复资料后进行回顾性统计分析。结果190例患者分泌物检出细菌,检出率为56.89%。共分离214株菌株:160株革兰阳性球菌(74.77%),52株革兰阴性杆菌(24.29%),2株革兰阳性杆菌(0.94%)。金黄色葡萄球菌占比最高(49.07%),对青霉素类抗生素耐药性高;革兰阴性杆菌多数为多重耐药菌,对碳青霉烯类抗生素较为敏感。结论骨科术后切口愈合不良患者有较大可能发生切口细菌感染,细菌分布广泛,临床医生应当重视细菌的检出以及耐药情况,合理运用抗生素。

Dissolution improvement of fenofibrate by melting inclusion in mesoporous silica

In this study,using mesoporous silica for the solubility enhancement of poorly watersoluble drug was investigated.Although the incorporating drug into mesoporous silica is generally performed through the solvent method,the new melting method was proposed in the present study.Fenofibrate,a poorly water-soluble drug,was incorporated into mesoporous silica by solvent method and melting method.The obtained samples were observed by SEM and their physicochemical properties were evaluated by PXRD and DSC measurement.The dissolution and supersaturated property were also investigated.The results from SEM,PXRD and DSC measurement showed that drug could be loaded into pore via the melting method as well as by the solvent method.The drug loaded quantity depended on the pore volume.Drug up to 33%could be incorporated into mesoporous silica and existed in amorphous state.When drug was overloaded or difficulty in incorporation into pore was found,recrystallization of drug occurred at the outer surface of mesoporous silica.From the dissolution test,samples prepared by solvent method and melting method gave the supersaturated drug concentration which sample from melting method showed superior dissolution to the one from solvent method.From this study,drug was efficiently incorporated into mesoporous silica by the melting method which is a simple and solvent-free process,and the aqueous solubility enhancement of poorly watersoluble drug was achieved.

Characterization of recrystallized itraconazole prepared by cooling and anti-solvent crystallization

The objective of the present study was to alter the crystal habit of itraconazole(ITZ)by cooling and anti-solvent crystallization and characterize its properties.ITZ was recrystallized in different solvents and the effects of each solvent on morphology of crystals,dissolution behavior and solid state of recrystallized drug particles were investigated.The results revealed that ITZ crystals recrystallized by cooling and anti-solvent crystallization showed the different crystal habits from the untreated ITZ.Using cooling crystallization tended to provide needle-shaped crystals while the crystals obtained from anti-solvent crystallization showed more flaky,plate shape.This indicated the importance of preparation method on nucleation and crystal growth.No change in drug polymorphism was observed,according to determination of thermal property and crystalline state by differential scanning calorimetry and powder X-ray diffractometry,respectively.The recrystallized ITZ showed higher drug dissolution than untreated ITZ and the highest drug dissolution was observed from the samples recrystallized in the presence of PEG 200,which provided the small plate-shaped crystals with tremendously increased in surface area.However,the increasing of drug dissolution is relatively small,therefore,further development may be required.

西部贫困地区村卫生室药物使用情况分析

目的了解中国西部38个贫困县村卫生室药物使用情况，为进一步完善村卫生室管理提供基础资料。方法在西部8个省市区选择38个县，每县随机抽取5个乡，每个乡随机抽取3个村进行调查，收集每个村卫生室处方60张，共25870张，进行分类统计分析。结果各贫困县处方使用的西药种类在83～202种之间，其中内蒙古、广西、江西各县西药类基本药物比例较高，分别占95，24％，87．71％和80．73％，宁夏则只有34．73％，青海为53．95％；四川、重庆各县中成药类基本药物比例分别为41．45％和51．77％。处方药的西药使用中，抗感染药使用比例最高，达到44．19％；中成药中的清热剂、解表剂、止咳平喘祛痰剂的使用占50％以上；每次就诊处方药物平均品种数2，52个；药物三联率25．75％；静脉注射给药方式占3．50％。结论应加强村卫生室药物使用的规范化管理以及乡村医生的培训指导，巩固和完善村卫生室预防保健的职能。

偏远贫困地区某基层医疗机构的5年药品不良反应分析

目的:分析偏远贫困地区某基层医疗机构5年以来发生药品不良反应的情况,以指导合理用药。方法:回顾性分析某基层医院2015-2019年发生的药品不良反应病例408例,对其进行分类,并对药品不良反应发生原因进行分析。结果:408例不良反应病例中,导致不良反应最多的药物为抗菌药物(40.0%);累及系统包括皮肤系统、神经系统、消化系统、呼吸系统、免疫系统等,最受影响的身体系统为皮肤系统(31.37%)。结论:偏远贫困地区基层医疗机构在临床用药中常常会发生不良反应,必须强化用药不良反应监测,促进临床合理用药、安全用药,预防或减少不良反应。

1453份贫困地区乡村卫生机构药物处方合格率调查分析

通过对贫困地区乡卫生院和村卫生室的药物处方进行抽查分析，结果表明，贫困地区的农村医疗卫生机构的处方合格率极低，仅有１．７９％处方合格。其中乡镇卫生院处方合格率为２．４２％，村卫生室处方合格率为０．０６％。提示县级卫生管理部门亟待加强基层医疗机构的处方整顿工作．从而有助于杜绝医疗隐患和纠纷。

Improved dissolution of Kaempferia parviflora extract for oral administration by preparing solid dispersion via solvent evaporation

Kaempferia parviflora, a plant in the family Zingiberaceae, has been used in Thai traditional medicines for treating hypertension and promoting longevity with good health and wellbeing. However, its limited aqueous solubility and low dissolution restrict its bioavailability.The aim of the study was therefore to improve the dissolution rate of K. parviflora extracted with dichloromethane(KPD) by solid dispersions. Different water-soluble polymers were applied to improve dissolution of KPD. The solid dispersions in different ratios were prepared by solvent evaporation method. Only hydroxypropyl methylcellulose(HPMC) and polyvinyl alcohol-polyethylene glycol grafted copolymer(PVA-co-PEG) could be used to produce homogeneous, powdered solid dispersions. Physical characterization by scanning electron microscopy, hot stage microscopy, differential scanning calorimetry and powder X-ray diffractometry, in comparison with corresponding physical mixtures, showed the changes in solid state during the formation of solid dispersions. Dissolution of a selected marker,5,7,4′-trimethoxyflavone(TMF), from KPD/HPMC and KPD/PVA-co-PEG solid dispersions was significantly improved, compared with pure KPD. The dissolution enhancement by solid dispersion was influenced by both type and content of polymers. The stability of KPD/HPMC and KPD/PVA-co-PEG solid dispersions was also good after 6-month storage in both longterm and accelerated conditions. These results identified that the KPD/HPMC and KPD/PVAco-PEG solid dispersions were an effective new approach for pharmaceutical application of K. parviflora.

新兴抗肿瘤靶点EZH2作用机制及研究进展

zeste基因同源蛋白2(enhancer of zeste homolog 2,EZH2)是由EZH2基因编码的一种赖氨酸特异性组蛋白甲基转移酶(histone-lysine N-methyltransferase,HRX),是多梳家族蛋白(polycomb-group proteins,PcGs)家族的重要组分。该基因正常状态下参与胚胎干细胞发育,维持正常细胞分化,在两性发育中驱动女性一个X染色体的沉默,在造血过程中维持B淋巴细胞和T淋巴细胞的未分化状态。病理状态下,EZH2成为一种基因抑制因子,当它过度表达时,组蛋白的三甲基化导致许多正常开启的肿瘤抑制因子被关闭。在多种肿瘤组织中EZH2含量明显高于癌旁组织,预后差的肿瘤中EZH2表达含量明显高于预后良好的肿瘤。因此,抑制EZH2的表达很可能是未来癌症治疗的一个有希望的策略。本文就目前研究状况做一简要综述。

辽北贫困地区急性ST段抬高型心肌梗死二级预防用药情况及对策分析

目的了解辽宁北部贫困地区急性ST段抬高心肌梗死(STEMI)患者的治疗现状及二级预防用药情况,初步探讨可能的改进措施。方法连续入选2014年1月—2016年12月因胸痛就诊于辽北地区7家县医院的STEMI患者635例,详细记录患者的二级预防用药情况及临床资料。结果635例患者中,服用阿司匹林475例(74.8%),氯吡格雷212例(33.4%),血管紧张素转换酶抑制剂/血管紧张素Ⅱ受体拮抗剂(ACEI/ARB)280例(44.1%),β受体阻滞剂178例(28.0%),他汀类药物429例(67.6%),低分子肝素134例(21.1%)。行心脏超声检査116例(18.3%)。院内接受再灌注治疗140例(22.0%),其中溶栓25例(3.9%),院内择期PCI 115例(18.1%);转院接受PCI治疗120例(18.9%),患者住院期间病死率为8.8%(56/635),放弃治疗自行出院134例(21.1%)。患者平均住院费用为8 548.9元,平均住院时长为8.3 d。院内共发生心力衰竭92例(14.5%),急性心肌再梗死68例(10.7%),各种恶性心律失常118例(18.6%),心源性死亡56例(8.8%),脑出血和脑缺血性卒中17例(2.7%),严重消化道出血事件14例(2.2%)。结论辽宁北部贫困地区二级预防用药普遍偏低,接受心脏超声检查比例及再灌注治疗比例极低,应提高基层医院对急性心肌梗死(AMI)的救治能力,提高基于指南的二级预防用药比例,建立合理的AMI救治三级医疗体系,从而提高STEMI救治能力,改善预后。

Polymer-based nanoparticulate solid dispersions prepared by a modified electrospraying process

A modified electrospraying process is exploited to enhance the dissolution profiles of a poorly water-soluble drug. With polyvinylpyrrolidone (PVP) as a hydrophilic polymer matrix and ketoprofen (KET) as a model drug, polymer-drug composites in the form of nanoparticles were prepared and characterized. The surface morphologies, the physical status of the drug, and the drug-polymer interactions were studied using FESEM, DSC, XRD, and ATR-FTIR. FESEM observations demonstrated that the nanoparticles gradually decreased in size from 640 ± 350, to 530 ± 320, 460 ± 200 and 320 ± 160 nm as the KET content increased from 0, to 9.1%, 16.7% and 33.3% w/w, respectively. Results from DSC and XRD suggested that KET was distributed in the PVP matrix in an amorphous manner at the molecular level. This is thought to be due to their compatibility, arising through hydrogen bonding as demonstrated by ATR- FTIR spectra. In vitro dissolution tests showed that the nanoparticles released the incorporated KET within 1 min, evidencing markedly improved dissolution over pure KET and a KET-PVP physical mixture. Electrospraying can hence offer a facile route to develop new polymer composites for biomedical applications, in particular for improving dissolution rate of poorly water-soluble drugs.