可降解聚乙交酯-丙交酯缓释微球用于甲状旁腺相关肽的持续释放

采用水包油包水(W1/O/W2)复乳溶剂挥发法制备了包载甲状旁腺激素相关肽(PTHrP)的聚乙交酯-丙交酯(PLGA)微球,通过核磁,红外,GPC,扫描电子显微镜等观察PLGA载药微球的结构,表明载药微球具有良好的球形结构,其平均粒径约为8μm.而体外模拟释放表明,此PLGA载药微球能实现PTHrP1-34长达25天的持续释放.并通过MTT法、碱性磷酸酶活性测定等检测负载PTHrP1-34的PLGA微球缓释系统对小鼠成骨细胞MC3T3-E1增殖及分化的影响,结果表明PTHrP1-34浓度为1×10-9mol/L时对MC3T3-E1增殖促进效应最大,且随着药物作用时间的延长,缓释系统促进细胞增殖、分化的作用越明显.     

载万古霉素PLGA-PEG-PLGA温度敏感水凝胶的体外抗菌性能

利用聚乙二醇（PEG 1500）引发乙交酯和D,L-丙交酯开环共聚合制备聚丙交酯乙交酯（PLGA）三嵌段共聚物（PLGA-PEG-PLGA）温敏水凝胶材料,并通过核磁共振氢谱（¹H NMR）确定产物的结构及组成.应用倒置小瓶法测量得到不同浓度下PLGA-PEG-PLGA水凝胶的溶胶-凝胶相变温度为27~32℃.此外,体外降解实验及细胞毒性实验结果表明,质量分数为25%的水凝胶有满意的降解速度及良好的生物相容性.同时,利用紫外-可见光谱分析了载万古霉素水凝胶的体外药物释放行为,结果表明,万古霉素可以持续释放12 d.抗菌实验结果表明,载万古霉素水凝胶具有良好的抗菌效果.表明PLGA-PEG-PLGA三嵌段温敏水凝胶是一种较理想的万古霉素缓释载体,具有良好的临床应用前景.     

温敏性P(MEO_2 MA-co-OEGMA-co-HMAM)自交联水凝胶的制备和性质

利用原子转移自由基聚合(ATRP)方法合成了新的温度敏感性聚合物聚(2-甲基-2-丙烯酸-2-(2-甲氧基乙氧基)乙酯-co-寡聚乙二醇甲醚甲基丙烯酸酯-co-N-羟甲基丙烯酰胺)[P(MEO2MA-co-OEGMA-coHMAM)]。红外光谱(FTIR)、核磁共振谱(1H NMR)和凝胶渗透色谱(GPC)对其结构进行了表征;利用透光率测定研究了共聚物的温度敏感性以及盐对其低临界溶解温度(LCST)的影响。将共聚物P(MEO2MA-coOEGMA-co-HMAM)链上的羟基分别转化为叠氮基和炔基后,在抗坏血酸钠和Cu SO4的催化条件下,通过温敏性共聚物P(MEO2MA-co-OEGMA-co-HMAM)链间点击自交联反应获得了温敏性水凝胶。凝胶形成流变动力学研究发现凝胶化作用在1 min之内发生,之后体系的储能模量(G')大于损耗模量(G″);通过SEM和溶胀性能分析表明,随着温度的升高水凝胶的孔径减小,导致水凝胶的保水量逐渐减小,证明了合成的凝胶具有温度敏感性;牛血清蛋白(BSA)和茴香脑分别作为亲水和疏水药物模型研究凝胶的药物体外持续释放。结果表明:在37oC时,载药凝胶对BSA释放率较大,释放速度较快。     

P(γ-PGA-co-NIPAAm)水凝胶对5-氟尿嘧啶药物分子的释放行为

以γ-聚谷氨酸(γ-PGA)、N-异丙基丙烯酰胺(NIPAAm)为单体,通过自由基共聚法制备一种水凝胶缓释材料。采用扫描电镜观察水凝胶的多孔断面形貌,并研究不同温度(25℃和37℃)下水凝胶表面的亲疏水性和不同pH(2.0~10.0)时的溶胀率变化。将该共聚水凝胶用作药物缓释载体,通过紫外分光光度计法研究其对5-氟尿嘧啶(5-FU)药物分子的缓释行为。结果表明:该凝胶在酸性条件下释药速率最快,碱性条件下次之,中性条件下释放最慢,25℃下释放量与γ-PGA含量呈正相关,37℃下结果相反;该凝胶具有温度、pH双敏感性,在弱碱性条件下释放缓慢、释药量小,具有一定的靶向释药能力。     

羧甲基壳聚糖水凝胶制备及其在药物控释中的应用

以戊二醛为交联剂制备了一系列羧甲基壳聚糖pH敏感水凝胶 .研究了合成条件对羧甲基壳聚糖水凝胶溶胀性能的影响 .实验结果表明羧甲基壳聚糖的脱乙酰度、交联剂用量对水凝胶溶胀率的影响较大 .pH=3 0时 ,水凝胶收缩 ,而pH =1 0 ,5 0 ,7 4 ,9 0时 ,水凝胶溶胀 ,且在碱性条件下水凝胶的溶胀率远大于酸性条件下的溶胀率 .包埋在此水凝胶中的水杨酸释放随载药介质的pH值和水凝胶半径大小的变化而显著不同 ,pH =1 0条件下载药的水凝胶的释药率大于pH =7 4 ,12 0条件下的释药率 ,且水凝胶的半径越大 ,释药速度和释药率也越大     

新型羧甲基壳聚糖水凝胶流变性能,药物释放及细胞相容性研究

羧甲基壳聚糖含有丰富的羧基和氨基, 通过1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)共催化交联羧甲基壳聚糖形成新型水凝胶. 调节EDC/NHS用量, 制备不同交联度的羧甲基壳聚糖水凝胶(CMCS hydrogels). 研究水凝胶的流变行为, 结果表明, 高交联度的水凝胶具有较好的弹性形变能力, 较高的储存模量, 这是因为随着交联度的升高, 羧甲基壳聚糖水凝胶化学交联网络结构趋于完善. 以胸腺五肽(TP-5)为模型药物, 初步评价CMCS水凝胶药物释放行为, 结果表明水凝胶交联度越高, 胸腺五肽释放速度越慢. MTT法初步评价了水凝胶细胞毒性, 细胞形态和细胞相对增值速率, 结果表明水凝胶毒性很低. 由此可见, 水凝胶具有良好的生物相容性, 在药物缓释和组织工程领域具有广阔的应用前景.     

超分子水凝胶作为胰岛素缓释体系的研究

利用α-环糊精(α-CD)与含有聚乙二醇(PEG)链段的聚合物Pluronic F127的超分子作用制备水凝胶.该物理交联水凝胶的交联点包括α-CD与PEG链包合物堆积形成的微晶区和聚合物疏水链段聚集区.优化水凝胶组分,得到具有较低固含量和较短凝胶化时间的体系用于胰岛素的负载和释放研究.通过X射线衍射(XRD),扫描显微镜(SEM)对水凝胶结构进行表征.通过紫外分光光度计监测胰岛素的释放过程,结果表明,水凝胶释药时间约为65 h,且释放曲线较为平缓.细胞毒性实验结果表明该水凝胶材料对细胞生长无明显抑制作用.小鼠体内释药实验结果表明该水凝胶载体对延长胰岛素的释药时间有一定效果,可作为多肽类药物的缓释体系.     

新型温度/pH敏感性ABA型三嵌段共聚物的合成、胶束化及凝胶化行为研究

采用原子转移自由基聚合（ATRP）方法合成了水溶性良好的不同聚合度的三嵌段共聚物P（DEAEMA-co-MEO₂MA-co-HMAM）-b-PEG-b-P（DEAEMA-co-MEO₂MA-co-HMAM）. 利用傅里叶变换红外光谱（FT-IR）、核磁共振氢谱（¹H NMR）以及凝胶渗透色谱（GPC）对聚合物结构及组成进行表征;通过透光率、表面张力的测定以及动态光散射（DLS）、荧光探针和透射电镜（TEM）技术研究了共聚物水溶液的性质及胶束化行为. 通过对不同pH下共聚物的凝胶状态和不同pH下温度诱导的溶胶-凝胶转变过程的观察,研究了温度和pH对共聚物凝胶化行为的影响. 测定了载药凝胶分别在不同温度和不同pH的缓冲溶液中对药物的累积释放率. 结果表明：ABA型三嵌段共聚物具有良好的温敏性和pH敏感性,在温度或pH诱导下可形成核壳胶束和凝胶. 载药凝胶对药物的累积释放率随温度和pH的降低而升高.     

温敏性PCL-PEG-PCL水凝胶的合成、表征及蛋白药物释放

考察了温敏性PCL-PEG-PCL水凝胶中聚乙二醇(PEG)及聚己内酯(PCL)不同嵌段组成对其溶胶-凝胶相转变温度以及亲水性药物(牛血清白蛋白, BSA)释放速率的影响. 采用开环聚合法, 以辛酸亚锡为催化剂、PEG1500/PEG1000为引发剂, 与己内酯单体发生开环共聚, 合成了一系列具有不同PEG和PCL嵌段长度的PCL-PEG-PCL型三嵌段共聚物. 通过核磁共振氢谱及凝胶渗透色谱对其组成、结构及分子量进行了表征. 共聚物的溶胶-凝胶相变温度由翻转试管法测定. 利用透射电镜、核磁共振氢谱及荧光探针技术证实了该材料在水溶液中胶束的形成. 以BSA为模型蛋白药物, 制备载药水凝胶, 利用microBCA法测定药物在释放介质中的浓度, 研究其体外释放行为. 实验结果表明, 共聚物的溶胶-凝胶相变温度与PCL及PEG嵌段长度紧密相关, 即在给定共聚物浓度情况下, 固定PEG嵌段长度而增加PCL嵌段长度, 会导致相变温度降低; 而固定PCL嵌段长度而增加PEG嵌段长度, 其相变温度相应升高. 水凝胶中蛋白药物的释放速率与疏水的PCL嵌段长度无关, 而与亲水的PEG嵌段长度密切相关, 即PEG嵌段越长, 蛋白药物释放越快.     

基于改性多糖交联的生物可降解水凝胶的合成及其释药性

在4-二甲氨基吡啶(DMAP)的催化下,天然高分子海带多糖(Lam)与甲基丙烯酸缩水甘油酯(GMA)发生亲核取代反应,制备出一种新型水溶性生物可降解交联剂——甲基丙烯酸缩水甘油酯接枝海带多糖(Lam-GMA)。以Lam-GMA为交联剂,与丙烯酰胺(AM)单体共聚制备水凝胶。在生理条件与脂肪酶的作用下,对凝胶的溶胀特性和降解行为进行研究。以牛血清白蛋白(BSA)为模型高分子药物,包埋在水凝胶中,研究其降解释药行为。结果表明,GMA接枝到Lam链的反应转化率很高,并且接枝率可控;交联剂用量越大,水凝胶降解所需时间越长;随着水凝胶的降解BSA缓慢释放。     

Design of a rate- and time-programming drug release device using a hydrogel: pulsatile drug release from kappa-carrageenan hydrogel device by surface erosion of the hydrogel

We have found that a repetitive pulsatile drug release with a certain time interval is observed from a monolithic hydrogel device by surface erosion of the hydrogel. As a model system of pulsatile drug release, dibucaine hydrochloride and kappa-carrageenan hydrogel were chosen as a drug and a device, respectively. Electrostatic interactions between dibucaine hydrochloride and kappa-carrageenan polymer segments are strong, since dibucaine hydrochloride is positively charged and each disaccharide repeating unit of kappa-carrageenan chains has one sulfate group. Dibucaine hydrochloride was loaded into the hydrogel by immersing dry kappa-carrageenan hydrogel disks in a dibucaine hydrochloride solution for 24 h. The pulsed release of dibucaine hydrochloride from the device was observed every 50 min between 30 and 250 min after the release starts. The weight of kappa-carrageenan hydrogel decreases in an oscillatory manner with time in distilled water. The oscillatory changes observed in the hydrogel weight in distilled water are considered to be caused by influx and efflux of water molecules into and from the surface and core of the hydrogel and by polymer liberation from the hydrogel. This phenomenon was well explained by our kinetic model [Colloids and Surfaces B 8 (1996) 93-100]. The time interval between pulses observed in drug release coincides with that observed in the oscillatory weight change of the hydrogel. From these, it was concluded that the pulsatile release of dibucaine hydrochloride from the device was caused by the pulsatile liberation of swollen kappa-carrageenan hydrogel from the surface of the device.     

Design of a rate- and time-programming drug release device using a hydrogel: pulsatile drug release from κ-carrageenan hydrogel device by surface erosion of the hydrogel

We have found that a repetitive pulsatile drug release with a certain time interval is observed from a monolithic hydrogel device by surface erosion of the hydrogel. As a model system of pulsatile drug release, dibucaine hydrochloride and κ-carrageenan hydrogel were chosen as a drug and a device, respectively. Electrostatic interactions between dibucaine hydrochloride and κ-carrageenan polymer segments are strong, since dibucaine hydrochloride is positively charged and each disaccharide repeating unit of κ-carrageenan chains has one sulfate group. Dibucaine hydrochloride was loaded into the hydrogel by immersing dry κ-carrageenan hydrogel disks in a dibucaine hydrochloride solution for 24 h. The pulsed release of dibucaine hydrochloride from the device was observed every 50 min between 30 and 250 min after the release starts. The weight of κ-carrageenan hydrogel decreases in an oscillatory manner with time in distilled water. The oscillatory changes observed in the hydrogel weight in distilled water are considered to be caused by influx and efflux of water molecules into and from the surface and core of the hydrogel and by polymer liberation from the hydrogel. This phenomenon was well explained by our kinetic model [Colloids and Surfaces B 8 (1996) 93–100]. The time interval between pulses observed in drug release coincides with that observed in the oscillatory weight change of the hydrogel. From these, it was concluded that the pulsatile release of dibucaine hydrochloride from the device was caused by the pulsatile liberation of swollen κ-carrageenan hydrogel from the surface of the device.     

Synthesis and characterization of a novel controlled release nitrogen-phosphorus fertilizer hybrid nanocomposite based on banana peel cellulose and layered double hydroxides nanosheets

In the present study, a novel environment-friendly hybrid nanocomposite of Banana Peel Cellulose-g-poly(acrylic acid)/PVA (BPC-g-PAA/PVA) hydrogel and Layered double hydroxides (LDH) nanosheets was developed using in situ graft polymerization for slow release of NP (nitrogen, phosphorous) fertilizers and water retention. The hybrid nanocomposite hydrogel containing NP fertilizers was characterized using FTIR, and SEM. The effects of pH changes and different saline solutions on the swelling behavior, fertilizer release and water retention properties of the nanocomposite were investigated.The nanocomposite hydrogel showed a pH dependent swelling, as in the pH range of 7–10, the hydrogel had higher water absorbency. However, pH had opposite effects on the release of fertilizers. Phosphorus release had an increasing trend from pH 2 to 7 and it reached its maximum value at normal pH while nitrogen had a higher release rate at acidic pH and by increasing pH from 2 to 7, the release of nitrogen decreased gradually. Water absorption and fertilizer release of hydrogel was influenced by different cations in the order of Ca²⁺ < K⁺ < Na⁺. Water retention study in loamy sand soil showed that the nanocomposite hydrogel significantly improved the water retention of the soil for a longer period of time, compared to neat BPC-gPAA. This result indicated that incorporation of LDH nanosheets in hydrogel matrix improved its water retention property. The obtained results revealed that the nanocomposite of BPC-g-PAA/PVA hydrogel and LDH nanosheets can be a promising controlled release fertilizer formulation with enhanced water retention properties for agricultural applications.     

Mathematical model for the prediction of the overall profile of in vitro solute release from polymer networks

The loading of solutes onto and their release from hydrogel-based devices can be better understood when they are treated as a partition phenomenon. Partition activity (alpha) is a parameter that determines the existence of partition phenomena. It expresses the physical chemical affinities of the solute between the solvent and hydrogel phases. When alpha=0, there is no release of the solute from the hydrogel; however, if alpha>0, there is partitioning of the solute between the solvent and the hydrogel phases, and release of the solute from the hydrogel can be observed. The mathematic model proposed here predicts the overall release profile of vitamin B(12), methylene blue (MB), and acid orange 7 (AO) from semi-interpenetrating network (semi-IPN) hydrogels composed of PNIPAAm and PAAm. Experimental release tests demonstrated that alterations on variables of the system change both the released fraction and the release rate of such solutes, confirmed by the changes on values of alpha (an equilibrium parameter) and k(R) (an kinetic parameter). The modeling of solute release describes the alpha effects on release of the solute from polymer networks. The solute release mechanism is viewed here as a diffusional transport process and as a partition phenomenon. The partitioning of the solutes occurs between the solvent phase and the hydrogel phase, and the possible physical chemical affinities of the solute between hydrogel and solvent are considered.     

Design of polyvinyl alcohol hydrogel as a controlled-release vehicle for rectal administration of dl-propranolol-HCl and atenolol

Preparations of beta-blockers, propranolol-HCl and atenolol, in poly(vinyl alcohol) (PVA) hydrogel were designed for the therapeutic treatment of hypertension by transrectal delivery. In vitro release characteristics and plasma drug concentration profiles after rectal administration in rats and dogs were examined. The PVA hydrogels containing beta-blockers were prepared by a low-temperature crystallization method. The release of beta-blockers from hydrogel preparations was consistent with Fickian diffusion (Higuchi model); the drug release versus the square root of release time profile gave a straight line over 60% of the total release process. The release of beta-blockers from hydrogel preparations increased at higher concentrations of PVA in the hydrogel preparations and was not affected by the pH of hydrogel preparations. Plasma concentrations of beta-blockers after rectal administration of hydrogels were higher than those after administration of suppositories (Witepsol H-15) in rats and dogs. The drug plasma concentrations increased at higher concentrations of PVA in hydrogel preparations. In the case of propranolol, which is a hepatic high-clearance drug, area under the blood concentration curve, 0-8 h after rectal administration of a hydrogel preparation (20% w/w PVA, pH 7.0) was 2.16 times and 5.26 times higher than those obtained with Witepsol H-15 suppository and oral administration, respectively. Rectal administration with PVA hydrogels is a favorable route for a hepatic high-clearance drug such as propranolol.     

麦饭石含量对载药复合凝胶小球释药性能的影响

以瓜尔胶-g-聚丙烯酸/麦饭石复合水凝胶(GG-g-PAA/MS)和海藻酸钠(SA)为原料,双氯芬酸钠(DS)为模拟药物,采用离子凝胶法制备了载药复合凝胶小球,考察了pH敏感性以及MS含量对复合凝胶小球的包封率、载药率、溶胀性和药物释放行为的影响.结果表明:凝胶小球具有明显的pH敏感性,在不同pH介质中溶胀率和释放速率...     

Magnetic Resonance Methods as a Prognostic Tool for the Biorelevant Behavior of Xanthan Tablets

Hydrophilic matrix tablets with controlled drug release have been used extensively as one of the most successful oral drug delivery systems for optimizing therapeutic efficacy. In this work, magnetic resonance imaging (MRI) is used to study the influence of various pHs and mechanical stresses caused by medium flow (at rest, 80, or 150 mL/min) on swelling and on pentoxifylline release from xanthan (Xan) tablets. Moreover, a bimodal MRI system with simultaneous release testing enables measurements of hydrogel thickness and drug release, both under the same experimental conditions and at the same time. The results show that in water, the hydrogel structure is weaker and less resistant to erosion than the Xan structure in the acid medium. Different hydrogel structures affect drug release with erosion controlled release in water and diffusion controlled release in the acid medium. Mechanical stress simulating gastrointestinal contraction has no effect on the hard hydrogel in the acid medium where the release is independent of the tested stress, while it affects the release from the weak hydrogel in water with faster release under high stress. Our findings suggest that simultaneous MR imaging and drug release from matrix tablets together provide a valuable prognostic tool for prolonged drug delivery design.     

A bioinspired 4D printed hydrogel capsule for smart controlled drug release

With the ever-increasing demands for personalized drugs, disease-specific and condition-dependent drug delivery systems, four-dimensional (4D) printing can be used as a new approach to develop drug capsules that display unique advantages of self-changing drug release behavior according to the actual physiological circumstances. Herein, a plant stomata-inspired smart hydrogel capsule was developed using an extrusion-based 4D printing method, which featured with UV cross-linked poly(N-isopropylacrylamide) (PNIPAM) hydrogel as the capsule shell. The lower critical solution temperature (LCST) of the PNIPAM hydrogels was approximately 34.9 °C and macroporous PNIPAM hydrogels were prepared with higher molecular weight polyethylene glycols (PEGs) as the pore-forming agents. Owing to the LCST-induced shrinking/swelling properties, the prepared PNIPAM hydrogel capsules exhibited temperature-responsive drug release along with the microstructure changes in the PNIPAM hydrogels. The in vitro drug release test confirmed that the PNIPAM hydrogel capsules can autonomously control their drug release behaviors on the basis of ambient temperature changes. Moreover, the increased PEG molecular weights in the macroporous PNIPAM hydrogel capsules caused an obvious improvement of drug release rate, distinctly indicating that the drug release profiles can be well programmed by adjusting the internal pore size of the hydrogel capsules. In vitro biocompatibility studies confirmed that the PNIPAM hydrogel capsules have great potential for biomedical applications. The bioinspired 4D printed hydrogel capsules pioneer the paradigm of smart controlled drug release.     

Radiation preparation and thermo-response swelling of interpenetrating polymer network hydrogel composed of PNIPAAm and PMMA

Interpenetrating polymer network (IPN) hydrogel composed of hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) and hydrophobic poly(methyl methacrylate) (PMMA) were synthesized by sequential IPN method using γ-rays from ⁶⁰Co source. Compared with pure PNIPAAm hydrogel, PNIPAAm/ PMMA IPN hydrogel not only behaved with obvious temperature sensitivity, but also had higher mechanical strength. The shrinking rate of the prepared IPN hydogel was slower than that of PNIPAAm hydrogel and the relative shrinkage was higher than that of PNIPAAm hydrogel. The IPN hydrogel with less PMMA was not stable while with more PMMA it was quite stable. In addition, the release of Methylene Blue (MB) from the IPN hydrogel was slower than that from PNIPAAm hydrogel as well.     

Layered hydrogel of poly(γ-glutamic acid), sodium alginate, and chitosan: fluorescence observation of structure and cytocompatibility

In this study, a novel layered hydrogel composing of poly (γ-glutamic acid) (PGA), chitosan (CS), and alginate (AL) were prepared. Furthermore, PGA, CS, and AL were labeled with different fluorescent dyes. The bilayer structure of hydrogel was then revealed using these fluorescent labeled polymers. To mimic the stability of these hydrogels in physiological fluids, the dissolution of PGA and the release of Ca2+ from these hydrogels in normal saline were also monitored. The results showed that by adding CS to the hydrogel, the dissolution of PGA was decreased by 67%, and the release of Ca2+ was reduced by 40%. In addition, the hydrogel exhibited no cytotoxicity for L929 fibroblasts.