Preparation and evaluation of ophthalmic thermosensitive in situ gels of penciclovir

Aim To develop pluronic F127 （PF127） based formulations of penciclovir （PCV） aimed at enhancing its ocular bioavailability. Methods Thermosensitive in situ gels of penciclovir were prepared through combination of HPMC K4M or carbopol 934P and pluronic F127. Optimized formulations were examined through measuring gelation temperature, rheology speciality, drug release behavior, pharmacokinetics and ocular irritation. Results The gelation temperature was reduced by adding HPMC K4M or carbopol 934P, and the viscosity was enhanced slightly. Either HPMC K4M or carbopol 934P delayed the release of PCV from in situ gel. PCV was released by non-Fickian diffusion. The study of ocular irritation for different PCV formulations did not show any irritation or damage for the cornea. PCV bioavailability from combination of carbopol 934P and pluronic F127 gels was higher than that obtained from any other gels. Conclusion Pluronic F127 formulations of PCV can be used as liquid for administration by instilling into the eye. Facilitated by the appropriate eye temperature, the formulations were transformed to gel phase. On the basis of in vitro and in vivo results, PCV formulations containing HPMC K4M or carbopol 934P and low concentration of pluronic F127 （12%） showed potential for use as a drug delivery system with improved ocular bioavailability.

A stepwise optimization strategy to formulate in situ gelling formulations comprising fluconazole-hydroxypropyl-beta-cyclodextrin complex loaded niosomal vesicles and Eudragit nanoparticles for enhanced antifungal activity and prolonged ocular delivery

Fungal keratitis and endopthalmitis are serious eye diseases.Fluconazole(FL)is indicated for their treatment,but suffers from poor topical ocular availability.This study was intended to improve and prolong its ocular availability.FL niosomal vesicles were prepared using span 60.Also,polymeric nanoparticles were prepared using cationic Eudragit RS100 and Eudragit RL100.The investigated particles had adequate entrapment efficiency(EE%),nanoscale particle size and high zeta potential.Subsequently,formulations were optimized using full factorial design.FL-HP-β-CD complex was encapsulated in selected Eudragit nanoprticles(FL-CD-ERS1)and niosmal vesicles.The niosomes were further coated with cationic and bioadhesive chitosan(FL-CD-Nios-ch).EE%for FL-CD-ERS1 and FL-CD-Niosch formulations were 76.4%and 61.7%;particle sizes were 151.1 and 392 nm;also,they exhibited satisfactory zeta potential+40.1 and+28.5 m V.In situ gels were prepared by poloxamer P407,HPMC and chitosan and evaluated for gelling capacity,rheological behavior and gelling temperature.To increase the precorneal residence time,free drug and selected nano-formulations were incorporated in the selected in situ gel.Release study revealed sustained release within 24 h.Permeation through excised rabbits corneas demonstrated enhanced drug flux and large AUC0-6 h in comparison to plain drug.Corneal permeation of selected formulations labeled with Rhodamine B was visualized by Confocal laser microscopy.Histopathological study and in vivo tolerance test evidenced safety.In vivo susceptibility test using Candida albicans depicted enhanced growth inhibition and sustained effect.In this study the adopted stepwise optimization strategy combined cylodextrin complexation,drug nano-encapsulation and loading within thermosenstive in situ gel.Finally,the developed innovated formulations displayed boosted corneal permeation,enhanced antifungal activity and prolonged action.

Study on Rheology and Release Kinetics of Chuanqi Ophthalmic Microemulsion in situ Gel

[Objectives] To study the rheology and release kinetics of Chuanqi ophthalmic microemulsion in situ gel,so as to provide references for its future study and development. [Methods]The fluid properties and linear viscoelastic regions of this preparation were investigated by MCR 102 rheometer. The release kinetics of Chuanqi ophthalmic microemulsion in situ gel was evaluated by modified Franz diffusion cell method,the ligustrazine and ligustilide were selected as the indictors,and semi-permeable membrane was used as a barrier,sampling time point was 0. 5,1,2,4,6,and 8 h respectively. [Results]Chuanqi ophthalmic microemulsion in situ gel was a pseudoplastic fluid and it had a linear viscoelastic region. Taking the shear stress as the indicator,the linear viscoelastic region was 0-302. 74 Pa; taking the strain as the indicator,the linear viscoelastic region was 0-7. 45%. At the critical point,the storage modulus( G') = the loss modulus( G″) =2 976. 60 Pa,critical shear stress was 302. 74 Pa and critical strain was 7. 45%. The average cumulative release of ligustrazine of 6 samples within 8 h was 33. 71 μg,the average cumulative release rate reached 90. 08%,and the release kinetics followed Higuchi equation. The average cumulative release of ligustilide of 6 samples within 8 h was 68. 46 μg,the average cumulative release rate reached 84. 32%,and the release kinetics followed the zero-order kinetics equation. [Conclusions] Chuanqi ophthalmic microemulsion in situ gel has excellent viscoelasticity and its strain is reversible in a certain range. The release kinetics of ligustrazine is the result from synergistic effect of its physicochemical properties and matrix skeleton,while the release kinetics of ligustilide is mainly affected by its physicochemical properties.

The preparation of Thermosensitive in Situ Gel of Iodine

objective:To Investigate the preparation,dissolution and release in vitro of thermosensitive in situ gel of iodine.Methods:Using orthogonal test method for screening the best prescription;Using the formula of gel accumulative dissolution percentage=(W1-Wt)/(W1-W0)to calculate the dissolution rate of Q by membrane-free;Calculating the accumulative release rate by the standard curve.As time increases,the dissolution rate and the release rate of the gel increased significantly.Conclusion:Thermosensitive in situ gel of iodine has good sustained release effect.

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.

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.

Preparation and Evaluations of Ibuprofen Thermosensitive in situ Gel

[Objectives] To prepare Ibuprofen-β-CD for thermosensitive in situ gel administration to achieve a slow drug release. [Methods]By saturation solution process,the best inclusion technology was screened out with orthogonal design. [Results]The prescription of in situ gel contained ibuprofen-β-CD complex,poloxamer P407,P188,and HPMCK4M( w/v 10%,18%,3%,and 0. 5%). The gelation temperature of ibuprofen gel was 34. 6 ± 0. 3℃. The viscosity of ibuprofen gel increased significantly above 35℃ and showed semi-solid attribute. [Conclusions] The release of ibuprofen from in situ gel was slow and stable in 96 h,demonstrated a proximate zero order release between 24 h and 96 h.

Doxorubicin-loaded zein in situ gel for interstitial chemotherapy of colorectal cancer

The aim of this research was to evaluate doxorubicin(DOX)-loaded zein in situ gels,a new drug delivery system in which a liquid state drug can be transformed into semi-solid after intratumoral injection.In vitro release of DOX-loaded zein was investigated and the pharmacokinetics,biodistribution and therapeutic efficacy of these DOX-loaded zein formulations were investigated using BAI B/c nude tumor-bearing mice.In vitro release of DOX from the gels extended up to 7 days.Efficient accumulation of DOX in the tumor with lower drug concentration in blood and normal organs was obtained resulting in effective inhibition of tumor growth and fewer off-target side effects.In conclusion,a DOX-loaded in situ gel was developed with sustained release,enhanced anti-cancer efficacy for colorectal cancer in vivo,and especially with reduced off-target side effects.

Effect of peritumoral injection of boanmycin hydrochloride within temperature-sensitive in situ gel using Hep-G2 hepatoma nude mice model

Background Boanmycin hydrochloride, a new antitumor agent, has a short half-life and fast clearance speed in vivo. The aim of this research was to investigate the effectiveness of peritumor injection of boanmycin hydrochloride within temperature-sensitive gel in situ using Hep-G2 hepatoma nude mice model. Methods Nude mice with human Hep-G2 tumor in right flank were randomly divided into four groups： normal saline group, in situ gel only group, boanmycin hydrochloride in situ saline group, and boanmycin hydrochloride in situ gel group, and were treated with injection of corresponding agents into peripheral tissue of the tumor. The volume of the tumor and the body weight of the mice were regularly measured, and tumor growth curve was generated. The size, internal echo, and blood flow of the tumors were observed by color Doppler ultrasonography. Histopathologic changes of the tumor after treatment were observed under both optical and transmission electron microscopy. Results The tumor growth was significantly inhibited by peritumoral therapy in boanmycin hydrochloride in situ gel group with the tumor inhibitory rate of 86.76%. The blood flow of the tumor was still seen in both normal saline group and in situ gel only group on color Doppler ultrasound. Punctate calcification and dotted blood flow were seen in boanmycin hydrochloride group; however, there was massive calcification and no blood flow in the tumor in the boanmycin hydrochlodde in situ gel group. Large areas of necrosis and apoptotic cells were shown by microscopic observation in boanmycin hydrochloride in situ gel group. Conclusion Temperature-sensitive boanmycin hydrochloride in situ gel can effectively delay the release of boanmycin hydrochloride and increase its anticancer effects for liver cancer in animal model.

Role of clove oil in solvent exchange-induced doxycycline hyclate-loaded Eudragit RS in situ forming gel

Solvent exchange induced in situ forming gel(ISG) is the promising drug delivery system for periodontitis treatment owing to the prospect of maintaining an effective high drug level in the gingival crevicular fluid. In the present study, the influence of clove oil(CO) on the characteristics of doxycycline hyclate(DH)-loaded ISG comprising Eudragit RS(ERS) was investigated including viscosity/rheology, syringeability, in vitro gel formation/drug release, matrix formation/solvent diffusion and antimicrobial activities. CO could dissolve ERS and increase the viscosity of ISG and its hydrophobicity could also retard the diffusion of solvent and hinder the drug diffusion; thus, the minimization of burst effect and sustained drug release were achieved effectively. All the prepared ISGs comprising CO could expel through the 27-gauge needle for administration by injection and transform into matrix depot after exposure to the simulated gingival crevicular fluid. The antimicrobial activities against Staphylococcus aureus, Escherichia coli, Streptococcus mutans and Porphyromonas gingivalis were increased when the ratio of CO and N-methyl pyrrolidone(NMP) was decreased from 1:1 to 1:10 owing to higher diffusion of DH except that for C. albicans was increased as CO amount was higher.Therefore, CO could minimize the burst while prolonging the drug release of DH-loaded ERS ISG for use as a local drug delivery system for periodontitis treatment.

In-Situ Synthesis of Terbium Complex with Salicylic Acid in Silica Matrix by a Two-Step Sol-Gel Process

A process for in situ synthesis of terbium complex with salicylic acid by a two-step solgel method in silica matrix has been proposed. The luminescence properties of the silica gelscodoped with terbium and salicylic acid have also been discussed with respect to that of the geldoped with terbium and that of pure terbium complex with salicylic acid.

星点设计-效应面法优化白及多糖pH-离子敏感原位凝胶的处方

目的优化白及多糖pH-离子敏感原位凝胶的处方。方法以去乙酰结冷胶用量、海藻酸钠用量、氯化钙用量、枸橼酸钠与氯化钙的质量比为考察变量,采用单因素实验初步确定各变量的范围。以25℃凝胶前体溶液黏度和37℃胶凝黏度为考察指标,采用星点设计-效应面法优选白及多糖pH-离子敏感原位凝胶的处方工艺,并进行预测分析。结果白及多糖pH敏感原位凝胶的最优处方为:去乙酰结冷胶用量为0.50%,海藻酸钠用量为1.10%,氯化钙用量为0.07%,枸橼酸钠与氯化钙的质量比为4∶1。该处方条件下,25℃前体溶液黏度为(704.00±3.00)mPa·s,37℃胶凝黏度为(12544.70±47.33)mPa·s。结论白及多糖pH-离子敏感原位凝胶稳定性好,前体溶液在25℃流动性良好,凝胶强度良好,可为基于白及多糖原位凝胶的后续研究提供实验基础。

Sol-Gel与在位聚合联用制备分散良好的纳米杂化材料

采用 Sol- Gel法与在位聚合相结合的方法 ,使正硅酸乙酯在聚合物单体中进行水解、缩聚 ,然后再加入引发剂使单体聚合 ,制得了稳定分散的纳米粒子杂化的聚合物材料 ,该材料性能优良 ,具有很好的透明度。在保持树脂光学性能的前提下 ,材料的抗冲击性能有所改善。

黄芪甲苷脂质体原位凝胶眼部给药系统的研究

目的制备黄芪甲苷(ASⅣ)脂质体原位凝胶(ASⅣlips gel),对ASⅣlips gel进行制剂学表征及细胞学评价,探讨ASⅣlips gel在眼部给药系统的应用潜力。方法采用乙醇注入法制备黄芪甲苷脂质体(ASⅣlips),以包封率为考察指标进行ASⅣlips处方及制备工艺优化,对最优处方及工艺制得的ASⅣlips进行表征;以壳聚糖(CS)和甘油磷酸钠(GP)为凝胶基质,通过物理交联制备CS/GP凝胶,对CS/GP凝胶进行表征;将ASⅣlips载入CS/GP凝胶构建ASⅣlips gel,并对ASⅣlips gel进行稳定性研究、体外释放研究、细胞毒性及细胞摄取考察。结果最优处方及工艺制得的ASⅣlips平均粒径为(75.09±0.65)nm,与透射电镜观察到的粒子大小接近,且粒径分布均匀;包封率可达71.68%,对ASⅣ具有较好的包载效率。红外光谱与X射线衍射分析可知已成功制得CS/GP凝胶;CS/GP凝胶在扫描电镜下呈明显的三维网状结构,35℃下胶凝时间为3 min。ASⅣlips gel连续7 d粒径基本无明显变化,稳定性良好;体外释放结果表明,与黄芪甲苷滴眼液相比,ASⅣlips gel有明显的缓释作用。细胞毒性结果显示ASⅣlips gel对人视网膜色素上皮细胞毒性较低,细胞相容性较好。分别用荧光显微镜定性观察、流式细胞仪定量分析制剂的细胞摄取情况,结果表明,脂质体原位凝胶制剂比滴眼液更易被人视网膜色素上皮细胞摄取。结论制备的ASⅣlips gel在眼部温度下可自发成胶,具有明显的缓释作用,更易被人视网膜色素上皮细胞摄取,有作为眼部给药系统的潜力。

用于伤口镇痛及愈合的PLGA-PEG-PLGA热敏凝胶的制备

目的构建一种由PLGA-PEG-PLGA/甘油组成的温敏凝胶系统,用以负载盐酸布比卡因和多聚脱氧核糖核苷酸复方药物。方法以胶凝温度作为关键响应参数,单因素法初步筛选凝胶基质浓度、药物装载量以及甘油添加量。随后,采用正交实验设计,并引入渗透压作为优化参数,以深化配方的优化过程。最后,对优选的配方进行质量评估。结果优选配方包含16%PLGA-PEG-PLGA、5%甘油、2%盐酸布比卡因,0.4%多聚脱氧核糖核苷酸。常温下配方呈均一透明溶液态,胶凝温度33.83℃,胶凝时间100 s,pH值3.11,渗透压836 mOsm,可注射性及黏附性良好。药物体外释放符合Ritger-peppas方程。开放型伤口模型证实了该样品能够有效促进伤口的愈合,达到镇痛的效果。结论优选配方制备工艺简单,各项质量指标均符合要求,有望在临床中得到应用。

注射用原位凝胶的分类与基质材料

注射用原位凝胶作为一种较新的剂型,具有能够长效释放、病灶局部给药、防止药物滥用和误用等优势,具有广阔的应用前景。注射用原位凝胶在注射前具有较低黏度,易通过注射器,并在注射后由于体内环境因素影响在注射部位形成药物贮库。本文综述了注射用原位凝胶的4种主要类型,并对其基质材料方面的进展进行了总结,旨在为此类制剂的设计和优化提供参考。

基于ZrO_(2)-SiO_(2)和介孔SiO_(2)凝胶膜制备可见光区双层减反射膜

采用溶胶-凝胶法,以正丙醇锆、正硅酸四乙酯为原料,在乙醇体系中以原位混合方式成功制备ZrO_(2)-SiO_(2)混合溶胶,Zr摩尔分数为20%~80%。在熔融石英基底上镀制混合凝胶膜,所得ZrO_(2)-SiO_(2)薄膜折射率在1.55~1.75之间可调。以有序介孔SiO_(2)薄膜为外层,选择与之匹配的ZrO_(2)-SiO_(2)薄膜为内层,构建λ/4~λ/2双层宽谱带减反射涂层。根据实际膜层的光学常数进行双层膜的优化设计,成功制备出在可见光区平均透射率达到99.17%的双层减反射薄膜。

原位溶胶-凝胶法制备光固化3D打印大豆油基杂化材料及其性能分析

以2.7官能度大豆油多元醇(SBOP)与甲基丙烯酸乙酯二异氰酸酯(MOI)为原料,成功制备了2.7官能度可自由基光固化的大豆油基光敏树脂SBO-2.7A。将SBO-2.7A作为基体树脂,通过添加一定比例活性稀释剂丙烯酸羟乙酯(HEA),制备出了3D打印大豆油基光敏树脂。通过原位溶胶-凝胶法,将不同正硅酸乙酯(TEOS)添加量的大豆油基打印树脂配方进行3D打印成型,优选出最佳的酸性蒸汽后处理条件后,最终制备出具有机械性能提高的打印大豆油基材料。通过红外光谱仪、电子显微镜、哈克旋转流变仪、拉伸试验机等对3D打印树脂的黏度、光固化行为及其对3D打印样品的热力学性能、机械性能等的影响进行分析,结果表明,原位溶胶-凝胶法生成纳米SiO2使得3D打印制品拉伸性能、储能模量均得到提高,其中拉伸强度由起始的9.96 MPa增加到了14.14 MPa,提高了42%;储能模量由293 MPa提高至567 MPa,提高了93.5%。

纳米复合凝胶AgNPs@Gel的制备及催化性能研究

以2-丙烯酰胺基-2-甲基丙磺酸(AMPS)、N,N-二甲基丙烯酰胺(DMAA)为单体,通过水溶液聚合法制备P(AMPS-co-DMAA)凝胶.再以该凝胶为模板,通过原位还原法成功制备了纳米复合凝胶AgNPs@Gel,并对AgNPs@Gel进行结构表征和催化性能测试.SEM和XRD分析表明,纳米银粒子在AgNPs@Gel中分散较均匀,粒径尺寸在100~200 nm之间.AgNO_(3)浓度、凝胶用量、电场、反应温度均能影响AgNPs@Gel的催化性能,当AgNO_(3)浓度为0.03 mol/L,凝胶用量为50 mg,电压为0 V,反应温度为20℃时,AgNPs@Gel对4-NP的催化反应平衡时间为120 min,催化转化率为96.30%,催化速率常数值为2.75×10^(-2) min^(-1).AgNPs@Gel具有较好的重复使用性能,在第5次催化转化率仍达到86.62%.

适用植物根系生长观察的半固态凝胶配方筛选

【目的】植物根系是植物吸收土壤水分和养分的重要器官,研究植物根系有助于了解植物根系与地上部相互作用以及植物对环境变化的响应机制。本研究分析高分子吸水树脂(SAP)和卡波姆U20(U20)单配和复配的稳定性和植物生长安全性,尝试建立植物根系生长观察的半固态凝胶开放培养方法。【方法】借助根箱试验,以草本植物黑叶芋(Alocasia longiloba)和灌木鹅掌藤(Schefflera actinopylla)为试验对象,基于营养液和SAP与U20复配半凝胶配方,分析1/4 Hoagland’s营养液(CK)、0.3%SAP凝胶营养液(T1)、0.5%U20凝胶营养液(T2)、0.4%U20+0.3%SAP凝胶营养液(T3)和0.5%U20+0.2%SAP凝胶营养液(T4)的稳定性以及在这些培养介质中植物生长、叶片叶绿素、根系形态变化和养分吸收差异。【结果】放置5周后,各处理培养介质均没有观察霉变和长菌现象,T1、T2和T3出现水化或絮凝分层,T4与CK一样性质稳定且澄清透明。动态观察叶片叶绿素变化发现,同一时间内,鹅掌藤各处理SPAD值和总叶绿素含量均与CK无显著差异,黑叶芋各处理SPAD值也均与CK无显著差异(P>0.05)。与CK相比,T1和T2均对鹅掌藤和黑叶芋根系生长产生抑制作用,T1和T2处理鹅掌藤总根长分别显著降低了51.59%和47.48%(P<0.05),根表面积分别显著降低了30.59%和32.27%(P<0.05);黑叶芋总根长分别显著降低了44.72%和45.86%(P<0.05),根表面积分别显著降低了29.23%和27.75%(P<0.05)。T1和T2处理的鹅掌藤和黑叶芋的生物量累积以及氮磷钾吸收也显著低于CK。T3和T4中两种植物的总根长、根表面积、氮磷钾吸收和生物量累积均与CK无显著差异(P>0.05);与CK中根系多下垂于营养液不同,T4中根系舒展自然,侧根和细根均呈一定角度展开在半固态凝胶中,较好的模拟了根系在土壤介质的生长状态。【结论】0.5%U20+0.2%SAP凝胶营养液可在较长时间内保持稳定的半固态凝胶状态,较好满足了模拟植物根系在土壤中生长的要求,并且短时间内在该营养液中植物生长、叶片叶绿素、根系形态变化和养分吸收与纯营养液无显著差异,可考虑选择该凝胶配方来建立植物根系生长观察的半固态凝胶开放培养方法。