Research progress of in-situ gelling ophthalmic drug delivery system

Blindness and vision impairment are the most devastating global health problems resulting in a substantial economic and social burden.Delivery of drug to particular parts of the anterior or posterior segment has been a major challenge due to various protective barriers and elimination mechanisms associated with the unique anatomical and physiological nature of the ocular system.Drug administration to the eye by conventional delivery systems results in poor ocular bioavailability(<5%).The designing of a novel approach for a safe,simple,and effective ocular drug delivery is a major concern and requires innovative strategies to combat the problem.Over the past decades,several novel approaches involving different strategies have been developed to improve the ocular delivery system.Among these,the ophthalmic in-situ gel has attained a great attention over the past few years.This review discussed and summarized the recent and the promising research progress of in-situ gelling in ocular drug delivery system.

A comprehensive review of in-situ polymer gel simulation for conformance control

Gel treatment has been widely applied in mature oilfields to improve sweep efficiency and control water production.Correct numerical simulation is of major importance to the optimization design and prediction of a successful gel treatment.However,there exist many problems in current simulation studies in published literature.This paper first presents a comprehensive review on the major factors that have been considered at different gelation stages during gel treatment,the models used in the commercial/inhouse simulators,and current numerical simulation studies on both laboratory and field scales.Then we classify the current in-situ gel numerical simulation problems as 1,deficient model problem that has published numerical model but has not been applied in simulator and application studies;2,missing model problem that does not have published quantitative model;and 3,inaccurate application problem that does not consider the major factors of gel performance,based on the reasons from some questionable results of current simulation studies.Finally,we point out the major research efforts that should be made in the future to better simulate in-situ gel treatment process.The review indicates that numerous simulation studies using commercial software packages intend to predigest the gel treatment,many of which,however,ignore important mechanisms and mislead the operation of gel treatment.In fact,a full assessment of simulating in-situ gels cannot be achieved unless the quantitative models can be qualified in terms of transport and plugging mechanisms based on the experimental results.

Disulfiram thermosensitive in-situ gel based on solid dispersion for cataract

To improve the corneal permeability and water-solubility of disulfiram(DSF), which is an ocular drug for cataract, P188 was selected as a matrix to prepare solid dispersion of DSF(DSF SD) by hot melt method. The DSF SD was characterized by DSC, XRD, and IR, and the results suggested that DSF was amorphous in DSF SD. The DSF SD was added to borate buffer solution(BBS) contained 20% poloxamer P407 and 1.2% poloxamer P188 to form in-situ gel. In vitro and in vivo experiments revealed that DSF SD combined with in-situ gel(DSF SD/in-situ gel) increased the residence time and the amount of DSF penetrated through the corneal. The pharmacodynamics studies exhibited DSF SD/in-situ gel delayed the development of selenium-induced cataract at some content. These results investigated that DSF SD/in-situ gel as a drug delivery system can improve DSF ocular permeability.

Molecular Reactivity and Interface Stability Modification in In-Situ Gel Electrolyte for High Performance Quasi-Solid-State Lithium Metal Batteries

Quasi-solid-state lithium metal battery is a promising candidate for next generation high energy density and high safety power supply.Despite intensive efforts on electrolytes,uncontrolled interfacial reactions on lithium with electrolyte and patchy interfacial contacts still hinder its practical process.Herein,we bring in rationally designed F contained groups into polymer skeleton via in-situ gelation for the first time to establish quasi-solid-state battery.This method achieves a capacity retention of 90%after 1000 cycles at 0.5C with LiFePO_(4)cathodes.The interface constructed by polymer skeleton and reaction with–CF_(3)lead to the predicted solid electrolyte interface species with high stability.Furthermore,we optimize molecular reactivity and interface stability with regulating F contained end groups in the polymer.Comparisons on different structures reveal that high performance solid stable lithium metal batteries rely on chemical modification as well as stable polymer skeleton,which is more critical to construct robust and steady SEI with uniform lithium deposition.New approach with functional groups regulation proposes a more stable cycling process with a capacity retention of 94.2%at 0.5C and 87.6%at 1C after 1000 cycles with LiFePO_(4) cathodes,providing new insights for the practical development of quasi-solid-state lithium metal battery.

Aluminum phosphate gel reduces early rebleeding in cirrhotic patients with gastric variceal bleeding treated with histoacryl injection therapy

BACKGROUND Esophageal-gastro varices bleeding(EGVB)is the most widely known cause of mortality in individuals with cirrhosis,with an occurrence rate of 5%to 15%.Among them,gastric varices bleeding(GVB)is less frequent than esophageal varices bleeding(EVB),but the former is a more critical illness and has a higher mortality rate.At present,endoscopic variceal histoacryl injection therapy(EVHT)is safe and effective,and it has been recommended by relevant guidelines as the primary method for the treatment of GVB.However,gastric varices after endoscopic treatment still have a high rate of early rebleeding,which is mainly related to complications of its treatment,such as bleeding from drained ulcers,rebleeding of varices etc.Therefore,preventing early postoperative rebleeding is very important to improve the quality of patient survival and outcomes.AIM To assess the efficacy of aluminium phosphate gel(APG)combined with proton pump inhibitor(PPI)in preventing early rebleeding after EVHT in individuals with GVB.METHODS Medical history of 196 individuals with GVB was obtained who were diagnosed using endoscopy and treated with EVHT in Shenzhen People's Hospital from January 2016 to December 2021.Based on the selection criteria,101 patients were sorted into the PPI alone treatment group,and 95 patients were sorted into the PPI combined with the APG treatment group.The incidences of early rebleeding and corresponding complications within 6 wk after treatment were compared between both groups.Statistical methods were performed by two-sample t-test,Wilcoxon rank sum test andχ2 test.RESULTS No major variations were noted between the individuals of the two groups in terms of age,gender,Model for End-Stage Liver Disease score,coagulation function,serum albumin,hemoglobin,type of gastric varices,the dose of tissue glue injection and EV that needed to be treated simultaneously.The early rebleeding rate in PPI+APG group was 3.16%(3/95),which was much lower than that in the PPI group(12.87%,13/101)(P=0.013).Causes of early rebleeding:the incidence of gastric ulcer bleeding in the PPI+APG group was 2.11%(2/95),which was reduced in comparison to that in the PPI group(11.88%,12/101)(P=0.008);the incidence of venous bleeding in PPI+APG group and PPI group was 1.05%(1/95)and 0.99%(1/101),respectively,and there was no significant difference between them(0.999).The early mortality rate was 0 in both groups within 6 wk after the operation,and the low mortality rate was related to the timely hospitalization and active treatment of all patients with rebleeding.The overall incidence of complications in the PPI+APG group was 12.63%(12/95),which was not significantly different from 13.86%(14/101)in the PPI group(P=0.800).of abdominal pain in the PPI+APG group was 3.16%(3/95),which was lower than that in the PPI group(11.88%,12/101)(P=0.022).However,due to aluminum phosphate gel usage,the incidence of constipation in the PPI+APG group was 9.47%(9/95),which was higher than that in the PPI group(1.98%,2/101)(P=0.023),but the health of the patients could be improved by increasing drinking water or oral lactulose.No patients in either group developed spontaneous peritonitis after taking PPI,and none developed hepatic encephalopathy and ectopic embolism within 6 wk of EVHT treatment.CONCLUSION PPI combined with APG can significantly reduce the incidence of early rebleeding and postoperative abdominal pain in cirrhotic patients with GVB after taking EVHT.

Preparation Process of Plumbagin Nanomicelle In-situ Gel

[Objectives]To prepare plumbagin nanomicelle(PLB-N)in-situ gel,and optimize the formulation and process.[Methods]PLB-N was prepared by self-assembly method,and the optimal formulation of PLB-N in-situ gel was determined by orthogonal experiment design and single factor method.[Results]The optimal preparation process for PLB-N was a drug to lipid ratio of 1:3,a Tween 80 content of 5%,an ethanol content of 7.5%of the hydration medium,a magnetic stirring speed of 2200 rpm,a stirring time of 30 min,and an ultrasound time of 10 min.The optimal formulation of PLB-N in-situ gel was 22%of poloxamer 407,6%of poloxamer 188,and 1:1 of PLB-N to water.The encapsulation efficiency of PLB-N prepared with the optimal formula was(95.8%±0.4%),and the average particle size was(75.19±1.14)nm,and the Zeta potential was(-20.73±1.19)mv.[Conclusions]PLB-N in-situ gel had stable and reliable preparation process,uniform content,and broad application prospects.

A novel profile modification HPF-Co gel satisfied with fractured low permeability reservoirs in high temperature and high salinity

Conformance control and water plugging are a widely used EOR method in mature oilfields.However,majority of conformance control and water plugging agents are unavoidable dehydrated situation in high-temperature and high-salinity low permeability reservoirs.Consequently,a novel conformance control system HPF-Co gel,based on high-temperature stabilizer(CoCl_(2)·H_(2)O,CCH)is developed.The HPF-Co bulk gel has better performances with high temperature(120℃)and high salinity(1×10^(5)mg/L).According to Sydansk coding system,the gel strength of HPF-Co with CCH is increased to code G.The dehydration rate of HPF-Co gel is 32.0%after aging for 150 d at 120℃,showing excellent thermal stability.The rheological properties of HPF gel and HPF-Co gel are also studied.The results show that the storage modulus(G′)of HPF-Co gel is always greater than that of HPF gel.The effect of CCH on the microstructure of the gel is studied.The results show that the HPF-Co gel with CCH has a denser gel network,and the diameter of the three-dimensional network skeleton is 1.5-3.5μm.After 90 d of aging,HPF-Co gel still has a good three-dimensional structure.Infrared spectroscopy results show that CCH forms coordination bonds with N and O atoms in the gel amide group,which can suppress the vibration of cross-linked sites and improve the stability at high temperature.Fractured core plugging test determines the optimized polymer gel injection strategy and injection velocity with HPF-Co bulk gel system,plugging rate exceeding 98%.Moreover,the results of subsequent waterflooding recovery can be improved by 17%.

Determination of Trace Non Rare Earth Elements in High Purity Rare Earth Oxides by ICP－AES with Microcolumn Preconcentration in a Flow Injection System

A new method for the determination of trace non-rare earth elements in high purity rare earth oxides by ICP-AES with preconcentration on an active carbon-silica gel microcolumn in a flow injection system is described in this paper. Experimental parameters such as pH, flow rate,reagent concentration,length of reaction coil,eluent acidity,etc. were optimized. In the buffer solution of NH3. H2O/NH4Cl at pH 4. 6,Al,Cr,Cu,Fe, Pb, V and Zn can be preconcentrated and then eluted with 4. 5 mol/L nitric acid utilizing stop-flow technique. The enrichment factors were in range of 8. 1￣12. 6 with detection limits of μg/m level ,and the RSD with metals at μg/g level were 2. 3￣5. 0% (n= 7). The method proposed can reduce the matrix interference effectively , and has been applied to the determination of non-rare earth metals atμg/g level in high purity Eu2O3 with satisfactory results.

颗粒脂肪与Nanofat及SVF-gel联合分层注射在面部年轻化中的应用

目的:评价颗粒脂肪、纳米脂肪(Nanofat)及脂肪干细胞胶(SVF-gel)联合分层注射在面部年轻化中的应用效果。方法:以2017年6月-2018年6月在笔者医院进行面部年轻化诊治的42例患者为研究对象,所有患者均采用自体颗粒脂肪、Nanofat及SVF-gel联合分层注射行面部整形。随访观察,通过VISIA皮肤检测仪检测患者面部皮肤质地,包括斑点、皱纹、毛孔、纹理、紫外线色斑、红色分布、棕色斑、紫质等皮肤特征相关数值,并评价治疗后美学效果。结果:治疗后美学效果优良率为90.48%(38/42)。治疗后,VISIA检测纹理、皱纹、棕色斑均较治疗前有明显改善,差异有统计学意义(P<0.05)。医生评价:面部轮廓及皮肤质地改善的总有效率分别为97.62%、88.10%;患者对面部轮廓、肤质及术后并发症的自我满意度分别为90.48%、78.57%、92.86%。结论:颗粒脂肪、Nanofat及SVF-gel联合分层注射在面部年轻化中的美学效果显著,安全性高,值得临床推广。

Development of re-crosslinkable dispersed particle gels for conformance improvement in extremely high-temperature reservoirs

Micro-scale and nano-scale dispersed gel particles(DPG)are capable of deep migration in oil reservoirs due to their deformability,viscoelasticity,and suitable particle size.Therefore,it has been widely studied and applied in reservoir conformance control in recent years.However,for highly permeable channels,their plugging performance is still limited.In addition,conventional in situ cross-linked polymer gels(ISCPGs)have fast gelation time under extremely high-temperature conditions,which often causes problems such as difficulty in pumping.Therefore,a re-cross linkable dispersed particle gel(RDPG)system applied for conformance control in highly permeable channels of extremely high-temperature petroleum reservoirs was investigated.The particle size distribution,gelation time,gel strength,injection performance,and perfo rmance strength in po rous media were investigated using a laser particle size meter,the Sydansk bottle test method,rheometer,and core displacement experiments,respectively.Results show that the RDPG suspension can be stable for more than 6 months at room temperature with storage modulus G’much lower than 10 Pa.It can pass through the pore throat by elastic deformation effect and does not cause strong blockage.Moreover,it can undergo re-crosslinking reaction at 150℃to form a strong bulk gel.The gel strength G’of re-crosslinked RDPG can be as high as 69.3 Pa,which meets the strength requirement of conformance control.The RDPG suspension has the properties of easy injection,and it also has strong plugging,and high-temperature resistance after re-crosslinked in the core,which can be a very promising material for conformance improvement in extremely high-temperature reservoirs.

Design of wear-out-failure in-situ repair parts by environment-friendly nanocopper additive

Oleic acid surface-modified Cu nanoparticles with an average size of 20 nm were prepared by liquid phase reducing reaction. The tribological performance and mechanism of nanocopper as additive were studied by means of tribotester, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and nanoindentation instrument. The results indicate that the modified nanocopper additive can significantly improve the wear resistance and reduce friction coefficient of base oil. A copper protective film is formed and contributes to the excellent tribological properties of nanocopper additive. On the basis of the film forming mechanism, a new in-situ repair method was designed and used to repair wear-out-failure injection pump plunger and barrel. Furthermore, the current research progress of nanoparticles as green energy-saving lubricating oil additives were presented.

TSK-GEL色谱柱测定注射用氟氯西林钠聚合物的研究

目的:建立以TSK-GEL色谱柱测定注射用氟氯西林钠聚合物的方法,并进行方法适用性试验。方法:用球状蛋白色谱以亲水硅胶(分子量适用范围为1 000~10 000)为填充剂,TSK-GEL柱(300 mm×7.8 mm,5 μm);以磷酸盐缓冲液(pH 7.0)[0.04 mol/L磷酸氢二钠溶液-0.04 mol/L磷酸二氢钠溶液(61∶39)]-乙腈(95∶5)为流动相,流速为0.8 ml/min,检测波长为215 nm。结果:氟氯西林主峰能与其相邻聚合物峰达到有效分离。对照品溶液的线性范围为 0.195 9~ 97.970 8 μg/ml时,溶液浓度与聚合物峰的峰面积呈良好的线性关系(r =1.000 0),最低检测浓度为0.049 μg/ml 。结论:该方法可以准确、快速、高效地测定注射用氟氯西林钠中的聚合物含量,专属性强,重复性好。

刻录机中HOLDER-GEL零件的注射模设计

分析了刻录机中HOLDER-GEL零件的注射成型原理、注射工艺和其相关的工艺参数,论述了HOLDER-GEL零件的生产工艺,论证HOLDER-GEL零件的注射成型技术,阐述了该零件质量检验的意义和方法。

延迟成胶弹性硅酸凝胶堵水剂及其性能研究

针对现有硅酸凝胶堵水剂普遍存在成胶时间短、成胶后脆性大的问题,结合L油田油藏条件,通过考察活化剂类型及用量,弹性改善剂类型及用量,以及水玻璃用量对成胶时间和弹性模量的影响,得出了一种延迟成胶弹性硅酸凝胶堵水剂。其配方为:6%水玻璃+0.85%活化剂三元弱酸一铵GL-1+0.1%弹性改善剂正电胶,该配方在油藏温度65℃下,成胶强度达到E级的时间为72 h,成胶后的弹性模量为589.46 Pa。采用填砂管实验评价了堵水剂的注入性及封堵性,结果表明堵水剂在L油田中具有良好的注入性及封堵性,在渗透率为1168.06×10^(-3)~5061.57×10^(-3)μm^(2)的填砂管中,注入0.8 PV的最高注入压力仅有0.72 MPa,封堵率均>96%。该堵水剂可用于L油田的油井堵水。

高效凝胶色谱联用质谱法快速鉴定盐酸头孢吡肟中的聚合物

目的:采用高效凝胶色谱法联用质谱法推断注射用盐酸头孢吡肟中聚合物的结构。方法:采用TSK gel G2000SWxl高效分子排阻色谱柱,以5 mM甲酸铵溶液-乙腈(95∶5)为流动相,流速为0.8 mL·min^(-1),检测波长为254 nm,柱温为25℃。在正离子模式下获取各聚合物杂质的质谱数据,结合头孢类抗生素聚合物的质谱裂解规律、降解反应原理,解析相关聚合物的结构。结果:推断出4种聚合物的化学结构,其中2个是头孢吡肟二聚体杂质,另外2个是三聚体杂质,其中三聚体杂质为首次报道。结论:采用高效凝胶色谱法联用质谱技术,可快速推断出注射用盐酸头孢吡肟中的聚合物的化学结构,可为其他头孢菌素聚合物的分离、鉴定及产品质量提高提供参考。

注射用单磷酸阿糖腺苷细菌内毒素检查方法研究

目的:建立注射用单磷酸阿糖腺苷的细菌内毒素检测方法并进行方法学验证,以期对该品种的质量控制标准进行统一规范。方法:按照《中国药典》2020年版四部通则1143“细菌内毒素检查法”,确定细菌内毒素的限值,进行干扰试验,并进行内毒素检查。结果:按经验拟定的限值标准(每1mg单磷酸阿糖腺苷中含内毒素的量应小于0.06EU)对15个厂家提供的25个批次的供试品进行细菌内毒素检查,结果均符合规定。结论:本文建立的细菌内毒素检查法检查,可用于注射用单磷酸阿糖腺苷的质量控制。

Preparation and evaluation of a phospholipid-based injectable gel for the long term delivery of leuprolide acetaterrh

A phospholipid-based injectable gel was developed for the sustained delivery of leuprolide acetate(LA). The gel system was prepared using biocompatible materials(SPME), including soya phosphatidyl choline(SPC), medium chain triglyceride(MCT) and ethanol. The system displayed a sol state with low viscosity in vitro and underwent in situ gelation in vivo after subcutaneous injection. An in vitro release study was performed using a dialysis setup with different release media containing different percentages of ethanol. The stability of LA in the SPME system was investigated under different temperatures and in the presence of various antioxidants. In vivo studies in male rats were performed to elucidate the pharmacokinetic profiles and pharmacodynamic efficacy. A sustained release of LA for 28 days was observed without obvious initial burst in vivo. The pharmacodynamic study showed that once-amonth injection of LA-loaded SPME(SPME-LA) led to comparable suppression effects on the serum testosterone level as observed in LA solution except for the onset time. These findings demonstrate excellent potential for this novel SPME system as a sustained release delivery system for LA.

内镜下组织胶注射联合套扎术、奥曲肽对EGVB凝血功能和再出血的影响

目的探讨内镜下组织胶注射与套扎术结合奥曲肽治疗食管胃底静脉曲张破裂出血(EGVB)对凝血功能及再出血率的影响。方法选取2020年1月至2023年1月符合纳入和排除标准的226例EGVB患者作为研究对象,根据随机数字表将患者分为研究组和对照组,每组113例。对照组患者接受套扎术联合奥曲肽治疗,而研究组患者则接受内镜下组织胶注射联合套扎术及奥曲肽治疗。比较两组的治疗效果、输血量、止血时间、呕血改善时间、凝血功能指标[活化部分凝血酶原时间(APTT)、凝血酶原时间(PT)、凝血时间(TT)]、门静脉血流动力学参数[门静脉压(PVP)、门静脉血流量(PVF)、门静脉血流速度(PVV)]、胃肠激素水平[胃泌素-17(GAS-17)、胃蛋白酶原Ⅰ(PG-Ⅰ)、胃蛋白酶原Ⅱ(PG-Ⅱ)]以及再出血率。结果研究组的总有效率为97.35%(110/113),显著高于对照组的90.27%(102/113),差异有统计学意义(P<0.05)。与对照组相比,研究组的输血量较少,止血时间和呕血改善时间较短,差异均有统计学意义(P<0.001)。治疗后,两组患者的APTT、PT、TT均较治疗前有所缩短,且研究组的缩短程度大于对照组,差异有统计学意义(P<0.001)。同样,治疗后两组患者的PVP、PVF、PVV均较治疗前有所降低,研究组的降低程度亦大于对照组,差异有统计学意义(P<0.001)。治疗后,两组患者的GAS-17、PG-Ⅰ、PG-Ⅱ水平均较治疗前有所下降,研究组的下降程度亦大于对照组,差异有统计学意义(P<0.001)。在治疗后1个月和3个月,研究组的再出血率分别为0和5.31%(6/113),均低于对照组的7.96%(9/113)和13.27%(15/113),差异有统计学意义(P<0.05或0.01)。结论内镜下组织胶注射联合套扎术及奥曲肽治疗EGVB具有确切的疗效,能够改善凝血功能和出血症状,优化门静脉血流动力学,降低再出血率,并减轻胃肠功能损伤。

Injectable bio-responsive hydrogel for therapy of inflammation related eyelid diseases

Eyelid plays a vital role in protecting the eye from injury or infection.Inflammation related eyelid diseases,such as blepharitis,are the most common ocular disorders that affect human’s vision and quality of life.Due to the physiological barriers and anatomical structures of the eye,the bioavailability of topical administrated therapeutics is typically less than 5%.Herein,we developed a bio-responsive hydrogel drug delivery system using a generally recognized as safe compound,triglycerol monostearate(TG-18),for in-situ eyelid injection with sustained therapeutics release.In vitro,drug release and disassembly time of Rosiglitazone loaded hydrogel(Rosi-hydrogel)were estimated in the presence or absence of MMP-9,respectively.Moreover,the disassembly of TG-18 hydrogel was evaluated with 9-month-old and 12-month-old mice in vivo.Owing to the bio-responsive nature of Rosi-hydrogel,the on-demand Rosiglitazone release is achieved in response to local enzymes.These findings are proved by further evaluation in the age-related meibomian gland dysfunction mice model,and the bio-responsive hydrogel is used as an in-situ injection to treat eyelid diseases.Taken together,the in-situ eyelid injection with sustained drug release opens a window for the therapy of inflammation related eyelid diseases.