明胶微球/磷酸镁基骨水泥复合药物缓释体系的构建

采用乳化交联法制备出粒径主要分布在100~300 μm的载药明胶微球, 分析了交联剂含量、药物含量和转速对载药率和包封率的影响及药物含量和转速对微球粒径的影响。对载药明胶微球与磷酸镁基骨水泥进行复合, 探讨微球降解过程中复合体系孔隙率的变化及其在体外药物释放的规律, 以期获得一种具有药物缓释性能的多孔磷酸镁基复合骨水泥。结果表明, 随着葡萄糖浓度增加, 载药率和包封率先上升再下降; 随着药物含量的增加, 载药率保持上升, 包封率先上升后下降; 随着转速增加, 载药率和包封率均下降。综合分析, 在转速为400 r/min、葡萄糖浓度为0.5 g/mL、药物与明胶质量比为1:2的条件下制备的载药明胶微球载药量较高, 且粒径合适。将复合不同比例该载药微球的磷酸镁基骨水泥浸泡在Tris-HCl缓冲溶液中进行体外药物释放研究, 结果表明: 在释放前期(0~10 h)药物释放速率较快, 之后药物释放明显减缓。7 d后, 微球几乎降解完全, 药物释放率达到60%~89%, 达到了一定的药物缓释效果。     

掺钕介孔硼硅酸盐生物活性玻璃陶瓷骨水泥的制备与性能表征

骨肉瘤是一种常见的恶性骨肿瘤, 常通过手术切除进行治疗。但术后造成的骨缺损难以自愈, 残余肿瘤细胞还会增加复发可能性。本研究开发了一种用于修复骨缺损和协同治疗骨肉瘤的掺钕介孔硼硅酸盐生物活性玻璃陶瓷骨水泥。首先通过溶胶-凝胶法结合固态反应制备了可作为光热剂和药物载体的掺钕介孔硼硅酸盐生物活性玻璃陶瓷微球(MBGC-xNd), 然后将微球与海藻酸钠(SA)溶液混合制备了可同时进行光热治疗和化学治疗的可注射骨水泥(MBGC-xNd/SA)。结果表明掺Nd³⁺赋予微球可控的光热性能, 负载阿霉素(DOX)的微球显示出持续的药物释放行为。此外, 载药骨水泥的药物释放量随着温度的升高而显著增加, 说明光热疗法产生的热量可促进DOX释放。体外细胞实验结果表明, MBGC-xNd/SA具有良好的促成骨活性, 并且光热-化学联合疗法对MG-63骨肉瘤细胞起到了更显著的杀伤作用, 表现出协同效应。因此,MBGC-xNd/SA作为一种新颖的多功能骨修复材料, 在骨肉瘤的术后治疗方面具有良好的应用前景。     

Three-dimensionally plotted MBG/PHBHHx composite scaffold for antitubercular drug delivery and tissue regeneration

A suitable drug-loaded scaffold that can postoperatively release an antituberculosis drug efficiently in a lesion area and help repair a bone defect is very important in the clinical treatment of bone tuberculosis (TB). In this study, a composite drug-loaded cylindrical scaffold was prepared by using three-dimensional printing technology in combination with the mesoporous confinement range, surface chemical groups, and gradual degradation of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate). This achieves the slow release of a drug for as long as possible. We implanted the drug-loaded compound scaffold into New Zealand rabbits’ femur defect model to study the in vivo drug release performance and osteogenic ability. The in vivo release of isoniazid and rifampicin from the prepared composites could be effectively sustained for 12 weeks in local tissues, whereas these drugs were sustained for just 2 weeks in a control group. The blood drug concentrations were very low and most concentrations were below 5 μg/ml. Therefore, the systemic toxic adverse effect is very low. In addition, the composite exhibits good osteogenic potential in a rabbit bone defect model. The results of this study indicate that this composite has great potential for treating osteoarticular TB.     

Folic acid-functionalized niosomal nanoparticles for selective dual-drug delivery into breast cancer cells: An in-vitro investigation

In this study, a folic acid-functionalized niosome was formulated and loaded with letrozole and curcumin as a promising drug carrier system for chemotherapy of the breast cancer cells. The formulation process was optimized by varying the type of Span 80 and total lipid to drug ratio, where Span 80 and lipid to drug molar ratio of 10 resulted in the niosomes with maximum encapsulation of both drugs but minimum size. The developed niosomal formulation showed a great storage stability up to one month with the small changes in drug encapsulation efficiency and size during the storage. In addition, they showed a pH-dependent release behaviour with slow drug release at physiological pH (7.4) while considerable drug release in acidic conditions (pH = 3), making it a promising candidate for breast cancer treatment. The cytotoxicity study shows the niosomal formulation has high biocompatibility with HEK-293 healthy cells, while having remarkable inhibitory effects on MCF-7 and MDA-MB-231 breast cancer cells due to the presence of folic acid in formulation, and in turn, selective internalization of the as-developed nanocarrier through folate receptor-mediated endocytosis. The double drug-loaded niosomes affect the gene expression by studied breast cancer cell lines; down-regulates the expression of Bcl2, cyclin D, and cyclin E genes while they up-regulate the expression of p53, Bax, caspase-3, and caspase-9 genes. The flow cytometry results showed that letrozole/curcumin-loaded niosomes enhanced the apoptosis rate in both MCF-7 and MDA-MB-231 cells compared to the mixture of letrozole and curcumin, which was due to the synergic effect between the two drugs as well as higher cell uptake by niosomal formulation. The findings of our study show the importance of developing highly biocompatible niosomal formulations in the future of nanomedicine that enables the co-delivery of two hydrophobic drugs into the cancer cells improves the efficiency of chemotherapy due to the synergic effect between the drugs.     

Mesoporous silica nanoparticle-functionalized poly(methyl methacrylate)-based bone cement for effective antibiotics delivery

Poly(methyl methacrylate)-based bone cements are functionalized with mesoporous silica nanoparticles (MSN) to enable a highly efficient and sustained release of antibiotics to reduce the risk of post-operative joint infection. To overcome the limited drug release of 5% for only 1 day with the current commercial-grade bone cements, a 8 wt% MSN-formulated bone cement is able to increase the drug release efficiency by 14-fold and sustain the release for up to 80 days. The loaded MSN is suggested to build up an effective network of rod-shaped silica particles with uniformly arranged nanoporous channels, which is responsible for the effective drug diffusion and extend time-release to the external surfaces. MSN has no detrimental effect on the critical weight-bearing bending modulus and compression strength of bone cement. In vitro assay test results show a much sustained antibacterial effect and low cytotoxicity of MSN demonstrating the potential applicability of MSN-formulated bone cement.     

The application of layered double hydroxide clay (LDH)-poly(lactide-co-glycolic acid) (PLGA) film composites for the controlled release of antibiotics

Many sites of bacterial infection such as in-dwelling catheters and orthopedic surgical sites require local rather than systemic antibiotic administration. However, currently used controlled release vehicles, such as polymeric films, release water-soluble antibiotics too quickly, whereas nonporous bone cement, used in orthopedics, release very little drug. The purpose of this study was to investigate the use of nanoparticulates composed of layered double hydroxide clays to bind various antibiotics and release them in a controlled manner. Mg-Al (carbonate) layered double hydroxides were synthesized and characterized using established methods. These clay particles were suspended in solutions of the antibiotics tetracycline, doxorubicin (DOX), 5-fluorouracil, vancomycin (VAN), sodium fusidate (SF) and antisense oligonucleotides and binding was determined following centrifugation and quantitation of the unbound fraction by UV/Vis absorbance or HPLC analysis. Drug release from layered double hydroxide clay/drug complexes dispersed in polymeric films was measured by incubation in phosphate-buffered saline (pH 7.4) at 37?°C using absorbance or HPLC analysis. Antimicrobial activity of drug released from film composites was determined using zonal inhibition studies against S. epidermidis. All drugs bound to the clay particles to various degrees. Generally, drugs released with a large burst phase of release (except DOX) with little further drug release after 4?days. Dispersion of drug/clay complexes in poly(lactic-co-glycolic acid) films resulted in a reduced burst phase of release and a slow continuous release for many weeks with effective antimicrobial amounts of VAN and SF released at later time points. Layered double hydroxide clays may be useful for controlled release applications at sites requiring long-term antibiotic exposure as they maintain the drug in a non-degraded state and release effective amounts of drug over long time periods. LDH clay/drug complexes are amenable to homogenous dispersion in polymeric films where implant coating may be optimal or required.     

Incorporation of chitosan in acrylic bone cement: Effect on antibiotic release,bacterial biofilm formation and mechanical properties

Bacterial infection remains a significant problem following total joint replacement. Efforts to prevent recurrent implant infection, including the use of antibiotic-loaded bone cement for implant fixation at the time of revision surgery, are not always successful. In this in vitro study, we investigated whether the addition of chitosan to gentamicin-loaded Palacos R bone cement increased antibiotic release and prevented bacterial adherence and biofilm formation by Staphylococcus spp. clinical isolates. Furthermore, mechanical tests were performed as a function of time post-polymerisation in pseudo-physiological conditions. The addition of chitosan to gentamicin-loaded Palacos R bone cement significantly decreased gentamicin release and did not increase the efficacy of the bone cement at preventing bacterial colonisation and biofilm formation. Moreover, the mechanical performance of cement containing chitosan was significantly reduced after 28 days of saline degradation with the compressive and bending strengths not in compliance with the minimum requirements as stipulated by the ISO standard for PMMA bone cement. Therefore, incorporating chitosan into gentamicin-loaded Palacos R bone cement for use in revision surgery has no clinical antimicrobial benefit and the detrimental effect on mechanical properties could adversely affect the longevity of the prosthetic joint.     

Methotrexate-added acrylic cement: biological and physical properties

Background Previous reports have demonstrated the suitability of adding different chemotherapeutic drugs to acrylic cement for the treatment of bone metastases. The best results so far have been obtained with methotrexate (MTX) for which diffusion from the implanted cement has been demonstrated both in vitro and in vivo. In this study the suitability of adding MTX to acrylic cement as local adjuvant chemotherapy was investigated. Methods Using an in vitro model of human breast cancer cells we demonstrated that the drug is eluted in an active form able to exert a cytotoxic effect over a long period of time. The use of different concentrations of drug on the kinetic of elution and on the mechanical properties of cement was also evaluated. Results The results obtained suggest that the release of MTX is higher at the beginning and progressively decreases over time being affected by the concentration of drug used. Our results also demonstrated that the addition and the subsequent elution of MTX does not alter the compressive properties of the cement. Conclusion These findings confirm the suitability of MTX-supplemented cement and support its use as an effective aid for the management of bone metastases requiring surgical curettage and acrylic cement implantation for structural support.     

Controlled release of local anesthetic from calcium phosphate bone cements

Novel lidocaine containing calcium phosphate bone cements have been developed. Lidocaine release kinetics of these cements have been evaluated.Calcium phosphate cements have a great potential for local drug delivery. Release of local anesthetic, such as lidocaine, at the implant site can be useful for reducing pain immediately after implantation.In this work a local anesthetic – lidocaine hydrochloride – was incorporated into α-tricalcium phosphate cement. Lidocaine release profile was dependent on cement components used. All cements were characterized by an initial burst release, which can be correlated with cement pH values, followed by gradual drug release. Drug release continued for up to 6 days and was slower, if cement pH was higher. Addition of lidocaine hydrochloride accelerated setting and changed microstructure of the set cement.     

Prolonged release from PLGA/HAp scaffolds containing drug-loaded PLGA/gelatin composite microspheres

Porous scaffolds that can prolong the release of bioactive factors are urgently required in bone tissue engineering. In this study, PLGA/gelatin composite microspheres (PGMs) were carefully designed and prepared by entrapping poly(l-lactide-co-glycolide) (PLGA) microspheres (PMs) in gelatin matrix. By mixing PGMs with PLGA solution directly, drug-loaded PLGA/carbonated hydroxyapatite (HAp)/PGMs composite scaffolds were successfully fabricated. In vitro release of fluorescein isothiocyanate-dextran (FD70S) as a model drug from the scaffolds as well as PMs and PGMs was studied by immersing samples in phosphate buffered saline (pH = 7.4) at 37°C for 32 days. Compared with PMs, PGMs and PLGA/HAp/PGMs scaffolds exhibited slow and steady release behavior with constant release rate and insignificantly original burst release. The swelling of PGMs, diffusion of drugs, and degradation of polymer dominated the release behaviors synergistically. The PLGA/HAp/PGMs scaffold offers a novel option for sequential or simultaneous release of several drugs in terms of bone regeneration.     

In vitro evaluation of gentamicin release from a bioactive tricalcium silicate bone cement

Tricalcium silicate (Ca₃SiO₅) cement, a novel self-setting biomaterial, has been shown to exhibit good hydraulic properties and excellent bioactivity. In this study, gentamicin sulfate (GS) was integrated into cement pastes and in vitro release of GS from the Ca₃SiO₅ cement was performed in deionized water, phosphate buffer saline (PBS) and HCl solutions with different pH at 37 °C, respectively. The results showed that the initial fast release of GS was restricted to a low level and prolonged release of drugs was achieved in water and PBS. The prolonged GS release is attributed to the interaction of GS with the calcium silicate hydrate network and the formation of unique nano-to-micro porous structure after hydration. Furthermore, GS release from milled powders of the hydrated cement suggested that the constrained GS could be released at low pH environment or during the degradation of the cement. When the samples were soaked in PBS, a nano-structured apatite layer was formed on the surface of the cement, which resulted in a relatively lower GS release rate as compared to that in water. The results suggest that Ca₃SiO₅ cement might be used as bioactive bone implant materials with drug loading and prolonged release properties.     

Influence of ibuprofen addition on the properties of a bioactive bone cement

Bioactive bone cements can promote bone growth and the formation of a strong chemical bond between the implant and bone tissue increasing the lifetime of the prosthesis. This study aims at synthesizing a new bioactive bone cement with different amounts of ibuprofen (5, 10 and 20 wt%) using a low toxicity activator, and investigating its in vitro release profile. The effect of ibuprofen (IB) on the setting parameters, residual monomer and bioactivity in synthetic plasma was also evaluated. It was verified that the different IB contents do not prevent the growth of calcium phosphate aggregates on composite surfaces, confirming that the cements are potentially bioactive. A relevant advantage of these formulations was a significant improvement in their curing parameters with increasing IB amount, associated to a reduction of the peak temperature and an extension of the setting time. The investigated cements released an average of about 20 % of the total incorporated ibuprofen during 30 days test, with IB20 liberating the highest percentage of drug 20.6 %, and IB10 and IB5, respectively 19.1 and 17.6 %. This behavior was attributed to the low solubility of this drug in aqueous media and was also related with the hydrophobic character of the polymer. Regarding the therapeutic concentration sufficient to suppress inflammation, the cement with 10 % of ibuprofen achieved the required release rate for 1 week and the cement with 20 % for 2 weeks.     

Effect of hydroxyapatite nanoparticles on ibuprofen release from carboxymethyl-hexanoyl chitosan/O-hexanoyl chitosan hydrogel

In order to explore the effect of nanofiller on the regulation of the drug release behavior from microsphere-embedded hydrogel prepared by carboxymethyl-hexanoyl chitosan (HNOCC) and O-hexanoyl chitosan (OHC), the release kinetics was investigated in terms of various amounts of calcium-deficient hydroxyapatite (CDHA) nanoparticles incorporated. HNOCC is a novel chitosan-based hydrophilic matrix with a burst release profile in a highly swollen state. The drug release kinetics of the HNOCC hydrogel can be regulated by incorporation of well-dispersed CDHA nanoparticles. It was found that the release duration of ibuprofen (IBU) from HNOCC was prolonged with increasing amounts of CDHA which acts as a crosslink agent and diffusion barrier. On the contrary, the release duration of the IBU from OHC (hydrophobic phase) was shortened through increasing the CDHA amount over 5%, which is due to the hydrophilic nature of the CDHA nanoparticles destroying the intermolecular hydrophobic interaction and accelerating OHC degradation. Thus, water accessibility and molecular relaxation were enhanced, resulting in a higher release rate. In addition, sustained and sequential release behavior was achieved by embedding the OHC microspheres (hydrophobic phase) into the HNOCC (hydrophilic phase) matrix, which could significantly prolong the release duration of the HNOCC drug-loaded implant.     

新型钇-羟基磷灰石骨水泥的制备及性能研究

利用高温固相法合成了掺钇的磷酸四钙,将其与无水磷酸氢钙以物质的量比1∶1混合制备了钇-羟基磷灰石骨水泥(Y-HAC)。结果表明:少量钇的掺入不会改变骨水泥的水化产物,骨水泥能正常水化,水化产物为弱结晶羟基磷灰石。与纯羟基磷灰石骨水泥(HAC)相比,Y-HAC的湿态抗压强度提高了120%,干态抗压强度提高了85%。同时,钇的掺入还提高了材料的孔隙率。Y-HAC的微观结构呈现紧密结合的片状羟基磷灰石结晶体。体外释放实验表明,钇的释放量极低,说明钇-羟基磷灰石骨水泥具有较好的稳定性。Y-HAC是一种很有前途的骨组织修复材料,并可用于载药材料和骨组织工程支架材料。     

PEG大分子硅氧烷制备药物缓释杂化纳米纤维膜

采用Jones试剂对聚乙二醇(PEG)进行修饰并合成端基为-Si(OEt)3的PEG大分子硅氧烷,将其与TiO2溶胶进行共水解缩合,制得PEG/SiO2-TiO2杂化纺丝液。在杂化纺丝液中加入头孢唑啉钠,经静电纺丝法制备载药杂化纳米纤维膜。对杂化电纺纤维膜的结构与形态进行了表征,并研究了其药物释放性能。红外光谱(FT-IR)研究了PEG大分子硅氧烷合成机理和产物结构;扫描电镜(SEM)照片显示,纳米纤维的平均直径约为115 nm,载药纳米纤维平均直径约为130 nm;紫外可见光(UV-Vis)光谱分析表明,载药纤维的初期释放速度较快,随时间推移释放速率逐渐降低,具有良好的药物缓释性能。     

In vitro release dynamics of model drugs from psyllium and acrylic acid based hydrogels for the use in colon specific drug delivery

Psyllium is medicinally important gel forming polysaccharides. Keeping in view, the pharmacological importance of psyllium and drug delivery devices based on hydrogels, psyllium, if suitably tailored to prepare the hydrogels, can act as the double potential candidates for the novel drug delivery systems. Therefore, it is an attempt to prepared psyllium and acrylic acid based pH sensitive novel hydrogels by using N,N'-methylenebisacrylamide (N,N-MBAAm) as crosslinker and ammonium persulfate (APS) as initiator for the use in colon specific drug delivery. The present paper discusses the swelling kinetics of the hydrogels and release dynamics of model drugs (tetracycline hydrochloride, insulin and tyrosine) from drug-loaded hydrogels, for the evaluation of the swelling mechanism and drug release mechanism from the polymeric networks .The effect of pH on the swelling kinetics and release pattern of drugs have been studied by varying the pH of the release medium. It has been observed that swelling and release of drugs from the hydrogels occurred through non-Fickian or anomalous diffusion mechanism in distilled water and pH 7.4 buffer. It shows that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable.     

Preparation and properties of calcium phosphate cements incorporated gelatin microspheres and calcium sulfate dihydrate as controlled local drug delivery system

To develop high macroporous and degradable bone cements which can be used as the substitute of bone repairing and drug carriers, cross-linked gelatin microspheres (GMs) and calcium sulfate dihydrate (CSD) powder were incorporated into calcium phosphate bone cement (CPC) to induce macropores, adjust drug release and control setting time of α-TCP–liquid mixtures after degradation of GMs and dissolution of CSD. In this study, CSD was introduced into CPC/10GMs composites to offset the prolonged setting time caused by the incorporation of GMs, and gentamicin sulphate (GS) was chosen as the model drug entrapped within the GMs. The effects of CSD amount on the cement properties, drug release ability and final macroporosity after GMs degradation were studied in comparison with CPC/GMs cements. The resulting cements presented reduced setting time and increased compressive strength as the content of CSD below 5 wt%. Sustained release of GS was obtained on at least 21 days, and release rates were found to be chiefly controlled by the GMs degradation rate. After 4 weeks of degradation study, the resulting composite cements appeared macroporous, degradable and suitable compressive strength, suggesting that they have potential as controlled local drug delivery system and for cancellous bone applications.     

Therapeutic aerosol bioengineering of targeted, inhalable microparticle formulations to treat Mycobacterium tuberculosis (MTb)

Therapeutic aerosol bioengineering (TAB) of Mycobacterium tuberculosis (MTb) therapies using inhalable microparticles offers a unique opportunity to target drugs to the site of infection in the alveolar macrophages, thereby increasing dosing in the lungs and limiting systemic exposure to often toxic drugs. Previous work by us used sophisticated, high content analysis to design the optimal poly(lactide-co-glycolic) acid (PLGA) microparticle for delivery of drugs to alveolar macrophages. Herein, we applied this technology to three different anti-MTb drugs. These formulations were then tested for encapsulation efficiency, drug-release, in vitro killing against MTb and aerosol performance. Methods for encapsulating each of the drugs in the PLGA microparticles were successfully developed and found to be capable of controlling the release of the drug for up to 4 days. The efficacy of each of the encapsulated anti-MTb drugs was maintained and in some cases enhanced post-encapsulation. A method of processing these drug-loaded microparticles for inhalation using standard dry powder inhaler devices was successfully developed that enabled a very high respirable dose of the drug to be delivered from a simple dry powder inhaler device. Overall, TAB offers unique opportunities to more effectively treat MTb with many potential clinical and economic benefits resulting.     

骨碎补载入对磷酸钙骨水泥性能的影响及体外生物学评价

通过在湿法合成的二水磷酸氢钙膏体中加入中药骨碎补的提取物, 作为磷酸钙骨水泥(Calcium Phosphate Cement,CPC)原料之一, 分别制备0、5wt%、10wt%和15wt%的载骨碎补磷酸钙骨水泥. 采用Gilmore针、X射线衍射仪、红外光谱仪、万能材料试验机、扫描电子显微镜和紫外分光光度计研究载骨碎补CPC的理化性能和药物释放; 体外培养MC-3T3成骨细胞, 进行Alamar Blue和碱性磷酸酶检测, 研究载骨碎补CPC对成骨细胞增殖和分化的影响, 扫描电子显微镜观察细胞形貌. 结果表明: 随骨碎补浓度的增加, CPC凝结时间明显延长, 其抗压强度显著提高; 骨碎补促进初期CPC的水化, 却阻碍了α-磷酸三钙的转化, 且随骨碎补浓度增大作用愈明显, 骨碎补不影响CPC水化后的相成分; 含骨碎补CPC的微观形貌中出现片状和针状晶体, 结构较空白CPC更加致密; 药物释放分为突释和缓释两个阶段, 符合Higuchi基质扩散释放模型; 载骨碎补CPC对成骨细胞的作用呈剂量和时间依赖关系, 培养5d时浓度为5wt%和10wt%的CPC较明显地促进细胞增殖, 7d时载骨碎补CPC的细胞增殖较稳定, 细胞分化能力无显著性差异; 成骨细胞在载骨碎补CPC表面生长形态良好, 表明该材料具有较好的生物相容性.     

Evaluation of silicone-based pressure-sensitive adhesives for transdermal drug delivery [II] effect of penetrant lipophilicitv

Abstract

An adhesive polymer drug dispersion-type transdermal drug delivery (a-TDD) system, consisting of a single drug-loaded adhesive polymer layer sandwitched between a drug-impermeable backing membrane and a detachable release liner, was developed from two silicone-based pressure-sensitive adhesive polymers for the controlled administration of drugs. The effect of variation in penetrant lipophilicity, using a series of testosterone derivatives with an increasing number of methyl groups in the steroid skeleton, on the release kinetics from the a-TDD system and skin permeation rate profiles was investigated. Absence of a methyl group at the 19th position of testosterone increased the flexibility of the steroid molecule and thus yeilded higher diffusivity and greater skin permeation rate. Addition of esters at the 17 ß-position resulted in a reduction in diffusivity with an increase in the alkyl chain length of the ester. These esters were found to be bioconverted to testosterone during permeation through the intact hairless rat skin.