Permeation Enhancer-Containing Water-In-Oil Nanoemulsions as Carriers for Intravesical Cisplatin Delivery

Purpose  

In the present work, we developed water-in-oil (w/o) nanoemulsions for the intravesical administration of cisplatin.     

Hyaluronic Acid and Graphene Oxide-incorporated Hyaluronic Acid Hydrogels for Electrically Stimulated Release of Anticancer Tamoxifen Citrate

Transdermal drug delivery is the transport of drug across the skin and into the systemic circulation. Patch is a one of transdermal device that is used to attach on skin and contains drug. The drug matrices from hyaluronic acid (HA) and graphene oxide (GO) incorporated HA hydrogel were fabricated for the release of tamoxifen citrate (TMX) as the anticancer drug under applied electrical field. The pristine HA hydrogels as the matrix and GO as the drug encapsulation host were fabricated for transdermal patch by the solution casting using citric acid as the chemical crosslinker. In vitro drug release experiment was investigated by utilizing the modified Franz-diffusion cell under the effects of crosslinking ratio, electric potential, and GO. The TMX release behaviors from the hydrogels were found to be from the three mechanisms: the pure Fickian diffusion; the anomalous or non-Fickian diffusion; and Super case II transport depending on the crosslinking conditions. The TMX diffusion and release amount from the pristine HA hydrogels were increased with smaller crosslinking ratios. With applied electrical potential, the enhanced TMX diffusion and release amount were observed when compared to that without due to the electro-repulsive force. Furthermore, the TMX diffusion from the HA hydrogel with GO as the drug encapsulation host was higher by two orders of magnitude than without GO.     

透明质酸及其衍生物用作药物载体的研究进展

鉴于透明质酸具有良好的生物相容性、生物可降解性、无免疫原性,以及对肿瘤细胞的高亲和性,透明质酸及其衍生物作为新型药物载体的研究备受瞩目。综述近年来透明质酸及其衍生物作为药物载体的应用研究进展,主要包括纳米粒、凝胶、阳离子聚合物基因载体等方面。     

Pharmacokinetics of Aminolevulinic Acid After Intravesical Administration to Dogs

Purpose. To examine the stability and systemic absorption of aminolevulinic acid (ALA) in dogs during intravesical administration. Methods. Nine dogs received an intravesical dose of ALA either with no prior treatment, after receiving ammonium chloride for urinary acidification, or after receiving sodium bicarbonate for urinary alkalinization. Urine and blood samples collected during and after administration were monitored for ALA using an HPLC assay developed in our laboratories. Concentrations of pyrazine 2,5-dipropionic acid, the major ALA degradation product, and radiolabeled inulin, a nonabsorbable marker for urine volume, were also determined. Results. Less than 0.6% of intravesical ALA doses was absorbed into plasma. Urine concentrations decreased to 37% of the initial concentration during the 2 hour instillation. Decreases in urinary ALA and radiolabeled inulin concentrations were significantly correlated, indicating that urine dilution accounted for over 80% of observed decreases in urinary ALA. ALA conversion to pyrazine 2,5-dipropionic acid was negligible. Conclusions. These studies demonstrate that ALA is stable and poorly absorbed into the systemic circulation during intravesical instillation. Future studies utilizing intravesical ALA for photodiagnosis of bladder cancer should include measures to restrict fluid intake as a means to limit dilution and maximize ALA concentrations during instillation.     

基于poly(N-isopropylacrylamide)的温度敏感性胶束作为抗肿瘤药物载体的研究进展

PNIPAAm广泛应用于温敏敏感性胶束的构建中。文章总结了近年来用于肿瘤药物传递的基于PNIPAAm温敏材料的胶束的结构设计,合成方法以及应用方面的最新研究进展。     

Stealth PLA-PEG Nanoparticles as Protein Carriers for Nasal Administration

Purpose. The aim of the study was to encapsulate a model protein antigen, tetanus toxoid (TT), within hydrophobic (PLA) and surface hydrophilic (PLA-PEG) nanoparticles and to evaluate the potential of these colloidal carriers for the transport of proteins through the nasal mucosa. Methods. TT-loaded nanoparticles, prepared by a modified water-in-oil-in-water solvent evaporation technique, were characterized in their size, zeta potential and hydrophobicity. Nanoparticles were also assayed in vitro for their ability to deliver active antigen for extended periods of time. Finally, ¹²⁵I-TT-loaded nanoparticles were administered intranasally to rats and the amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 48 h. Results. PLA and PLA-PEG nanoparticles had a similar particle size (137-156 nm) and negative surface charge, but differed in their surface hydrophobicity: PLA were more hydrophobic than PLA-PEG nanoparticles. PLA-PEG nanoparticles, especially those containing gelatine as an stabilizer, provided extended delivery of the active protein. The transport of the radiolabeled protein through the rat nasal mucosa was highly affected by the surface properties of the nanoparticles: PLA-PEG nanoparticles led to a much greater penetration of TT into the blood circulation and the lymph nodes than PLA nanoparticles. Furthermore, after administration of ¹²⁵I-TT-loaded PLA-PEG nanoparticles, it was found that a high amount of radioactivity persisted in the blood compartment for at least 48 h. Conclusions. A novel nanoparticulate system has been developed with excellent characteristics for the transport of proteins through the nasal mucosa.     

瘤内注射用醋酸奥曲肽温敏凝胶的质量评价

目的:评价自制瘤内注射用醋酸奥曲肽(OA)温敏凝胶的质量。方法:测定醋酸奥曲肽温敏凝胶的胶凝温度、黏度,采用反相高效液相色谱法测定样品中OA含量并考察其体外释放情况。结果:醋酸奥曲肽温敏凝胶的胶凝温度为(37.1±0.2)℃,在此温度下黏度为(4750±13)mPa·s,含量为5.1mg·mL-1,96h在磷酸盐缓冲液释放介质(pH=7.2)中体外累积释药率为(85.7±1.67)%。结论:醋酸奥曲肽温敏凝胶质量合格。     

塞克硝唑温敏性水凝胶的处方设计与含量测定

目的:筛选塞克硝唑温敏性水凝胶的最佳处方,并建立其含量测定方法。方法:以基质泊洛沙姆P407/P188(A)、溶剂乙醇(B)及黏附剂海藻酸钠(C)的用量为因素,以主药塞克硝唑含量为指标,采用正交设计筛选处方;在277nm波长下采用紫外分光光度法测定主药含量。结果:最佳处方为A15g/15g、B20mL、C0.6g。塞克硝唑检测浓度线性范围为4.618～46.18mg·L-(1r=0.9998),平均回收率为98.27%,日内RSD<1.8%,日间RSD<2.1%。结论:该处方设计合理,制备工艺可靠,质量稳定。     

瘤内注射用醋酸奥曲肽温敏凝胶的处方筛选

目的:筛选瘤内注射用醋酸奥曲肽温敏凝胶(OAG)的最佳处方。方法:以泊洛沙姆407、泊洛沙姆188为基质制备OAG,以胶凝温度(T)、黏度(η)及对小鼠腹水型肝癌高淋巴道转移细胞株HCA-F的抑制率(IR)为评价指标,考察泊洛沙姆的不同浓度、渗透压调节剂NaCl的加入及溶液pH等不同因素对OAG的影响,筛选主要处方组成并进行验证。结果:较佳处方组成为0.5%醋酸奥曲肽、18%泊洛沙姆407、12%泊洛沙姆188,0.9%NaCl,溶液pH调至7.2。验证试验中所制OAG的T为37.1℃,η为4750mPa.s,IR为57.6%,符合瘤内注射制剂的要求。结论:制备的OAG可满足瘤内注射给药和在体胶凝的要求,对肿瘤细胞的IR较高,具有较好的应用前景。     

瘤内注射用姜黄素温敏凝胶的处方筛选及pH值的确定

目的:筛选瘤内注射用姜黄素温敏凝胶的最佳处方,并确定其适宜pH值。方法:以胶凝温度、黏度、含药量为评价指标,通过正交试验筛选姜黄素温敏凝胶的最佳处方,并考察pH值对其稳定性的影响。结果:筛选出了姜黄素温敏凝胶的最佳处方为0.2%姜黄素、20%泊洛沙姆407、4%泊洛沙姆188、8%聚乙二醇400、12%1,2-丙二醇,pH值为6.0,其胶凝温度、黏度、含药量分别为(36.5±0.41)℃、(823±6.23)mPa.s和(0.207±0.0021)%。结论:制备的姜黄素温敏凝胶具有适宜的胶凝温度和黏度,含药量大,制剂稳定性好。     

注射用姜黄素温敏凝胶在实体瘤内滞留时间的研究

目的:研究注射用姜黄素温敏凝胶在小鼠实体瘤内的滞留时间。方法:复制小鼠实体瘤模型,以亚甲蓝温敏凝胶和亚甲蓝水溶液为模型药物,直观考察温敏凝胶是否可延长滞留时间,确定所用方法的可行性。通过反相高效液相色谱法测定注射用姜黄素温敏凝胶于不同时间点时在小鼠实体瘤内的剩余量,从而确定其滞留时间,并与同浓度的注射用姜黄素混悬液对比。结果:亚甲蓝水溶液注射进入瘤体后会沿着针孔外渗,而亚甲蓝温敏凝胶无此现象。注射用姜黄素温敏凝胶在实体瘤内的滞留时间为43.02h,显著长于姜黄素混悬液的滞留时间(P<0.01)。结论:注射用姜黄素温敏凝胶在小鼠实体瘤内滞留时间较长,显示其具有一定的缓释作用。     

Hyaluronic Acid Increases Anti-Inflammatory Efficacy of Rectal 5-Amino Salicylic Acid Administration in a Murine Colitis Model

5-amino salicylic acid (5-ASA) is a standard therapy for the treatment of mild to moderate forms of inflammatory bowel diseases (IBD) whereas more severe forms involve the use of steroids and immunosuppressive drugs. Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan that has shown epithelium protective effects in experimental colitis recently. In this study, both 5-ASA (30 mg/kg) and HA (15 mg/kg or 30 mg/kg) were administered rectally and investigated for their potential complementary therapeutic effects in moderate or severe murine colitis models. Intrarectal treatment of moderate and severe colitis with 5-ASA alone or HA alone at a dose of 30 mg/kg led to a significant decrease in clinical activity and histology scores, myeloperoxidase activity (MPO), TNF-α, IL-6 and IL-1β in colitis mice compared to untreated animals. The combination of HA (30 mg/kg) and 5-ASA in severe colitis led to a significant improvement of colitis compared to 5-ASA alone. Combined rectal therapy with HA and 5-ASA could be a treatment alternative for severe cases of IBD as it was the only treatment tested that was not significantly different from the healthy control group. This study further underlines the benefit of searching for yet unexplored drug combinations that show therapeutic potential in IBD without the need of designing completely new drug entities.     

Gliadin Nanoparticles as Carriers for the Oral Administration of Lipophilic Drugs. Relationships Between Bioadhesion and Pharmacokinetics

Purpose. The aim of this work was to evaluate the bioadhesive properties of non-hardened gliadin nanoparticles (NPs) and cross-linked gliadin nanoparticles (CL-NP) in the carbazole pharmacokinetic parameters obtained after the oral administration of these carriers. Methods. A deconvolution model was used to estimate the carbazole absorption when loaded in the different gliadin nanoparticles. In addition, the elimination rates of both adhered and non-adhered nanoparticulate fractions within the stomach were estimated. Results. Nanoparticles dramatically increased the carbazole oral bioavailability up to 49% and provided sustained release properties related to a decrease of the carbazole plasma elimination rate. The carbazole release rates from nanoparticles (NP and CL-NP), calculated by deconvolution, were found to be of the same order as the elimination rates of the adhered fractions of nanoparticles in the stomach mucosa. In addition, good correlation was found between the carbazole plasmatic levels, during the period of time in which the absorption process prevails, and the amount of adhered carriers to the stomach mucosa. Conclusion. Gliadin nanoparticles significantly increased the carbazole bioavailability, providing sustained plasma concentrations of this lipophilic molecule. These pharmacokinetic modifications were directly related to the bioadhesive capacity of these carriers with the stomach mucosa.     

Inulin Hydrogels as Carriers for Colonic Drug Targeting: I. Synthesis and Characterization of Methacrylated Inulin and Hydrogel Formation

Purpose. Vinyl groups were introduced in inulin chains in order to form hydrogels of this sugar polymer by free radical polymerization. Methods. Inulin was reacted with glycidyl methacrylate in N,N-dimethylformamide in the presence of 4-dimethylaminopyridine as catalyst. ¹H and ¹³C NMR spectroscopy were used for the characterization of the obtained reaction product. Solid state ¹³C NMR spectroscopy revealed the conversion of the incorporated vinyl groups into covalent cross-links upon free radical polymerization of aqueous solutions of the derivatized inulin. Results. During reaction of inulin with glycidyl methacrylate, transesterification occurred, leading to the direct attachment of the methacryloyl group to inulin. Consequently, the obtained reaction product is methacrylated inulin. The extent of chemical modification of inulin could be tuned by varying the molar ratio of glycidyl methacrylate to inulin in the reaction mixture. Aqueous solutions of methacrylated inulin were converted into cross-linked hydrogels by free radical polymerization using ammonium persulphate and N,N,N,N-tetramethylethylenediamine as initiating system. Conclusions. Inulin hydrogels can be formed by free radical polymerization of aqueous solutions of methacrylated inulin.     

A composite System Combining Self-Targeted Carbon Dots and Thermosensitive Hydrogels for Challenging Ocular Drug Delivery

We developed a composite system combining self-targeted carbon dots and thermosensitive in situ hydrogels for ocular drug delivery of diclofenac sodium (DS). DS-CD_C-HP nanoparticles were prepared by loading DS on the surface of CD_C-HP via electrostatic interactions. An orthogonal experimental design was selected to screen the optimal thermosensitive hydrogel matrices and then DS-CD_C-HP nanoparticles were embedded to form the composite system. The physicochemical properties and release behavior of this system were characterized, and in vivo fluorescence imaging was carried out. Corneal penetrability and in vitro cellular studies (cytotoxicity, cell imaging and cell uptake) were performed to test the feasibility and potential of this ocular delivery system. Finally, the optimal gel matrix consisting of Poloxamer 407: Poloxamer 188: HPMC E50 was 21:1:1 (w/v %), and the gelation temperature before adding artificial tear fluid was 26.67°C and 34.29°C, respectively. This system has the characteristics of biphasic drug release. In addition, the corneal penetrability and in vivo fluorescence study indicated that corneal transmittance was enhanced and drug retention time was extended. Cellular studies revealed that the DS-CD_C-HP-Gel has good cytocompatibility and CD44 targeting. In summary, this composite system combines carbon dots with hydrogels, offering new potential for ocular drug delivery.     

Modeling of Caffeine Release from Crosslinked Water-Swellable Gelatin and Gelatin-Maltodextrin Hydrogels

Research from this group has recently led to the development of a genipin-crosslinked gelatin gel that may be used as a controlled release matrix for bioactive compounds. This study presents a model that simulates the release of entrapped caffeine from the hydrogel and the ingress of water into these gels. Fick's second law of diffusion is used to describe the water penetration and bioactive release in the system. To validate the model, caffeine release experiments from the gel were carried out. The predicted bioactive release profiles are in very good agreement with experimental data at different gel compositions. The model may also be used for a wide range of bioactive molecules and hydrogels with different cylindrical dimensions.     

Chemical Modification of Hyaluronic Acid for Intraoral Application

This study was aimed to investigate chemical preactivated thiomers for their potential use in mucosal drug delivery. Thiomers—thiolated polymers—are mucoadhesive polymers with sulfhydryl group-bearing side chains. Thiomers are synthesized by covalent attachment of low molecular mass compounds bearing sulfhydryl group to the polymeric backbone of well-established polymers. Hyaluronic acid–cysteine ethyl ester–mercaptonicotinamide conjugates (HA–CYS–MNA) were synthesized by the oxidative S–S coupling of HA–CYS with 6-MNA. Conjugates were compressed into test discs to investigate cohesive properties, cytotoxicity assays, and mucoadhesion studies. Because of the immobilization of MNA, the HA–CYS-MNA conjugates exhibit comparatively higher swelling properties and cohesive properties corresponding unmodified HA. On the rotating cylinder, discs based on HA–CYS–MNA conjugates displayed fourfold improved mucoadhesion time compared with thiolated polymers. Tensile study results were found in good agreement with rotating cylinder results. Moreover, preactivated thiomers showed higher stability. All polymers were found nontoxic over Caco-2 cells. On the basis of achieved results, the preactivated thiomeric therapeutic agent seems to represent a promising generation of mucoadhesive polymers that are safe to use for a prolonged residence time to target the mucosa requested for intraoral application. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2414–2423, 2014     

Calcium Alginate Beads as Core Carriers of 5-Aminosalicylic Acid

The utilization of calcium alginate beads as core carriers for delayed dissolution followed by burst release as a potential method of intestinal site specific drug delivery was investigated. 5-Aminosalicylic acid was spray-coated on dried calcium alginate beads and then coated with different percentages of enteric coating polymer and/or sustained-release polymer. Beads coated with more than 6% (w/w) methacrylic copolymer plastisized with dibutyl sebacate and triethyl citrate resisted release in 2-hr acid fluid challenge and allowed immediate dissolution upon transfer to simulated intestinal fluid. With 6% (w/w) methacrylic copolymer on top of 4% (w/w) ethylcellulose polymer, the major portion of drug did not release in 2 hr of acid treatment or the next 3 hr of simulated intestinal fluid treatment. This dosage form provides the possibility to deliver drug to the lower intestinal tract with minimal early release, followed by sustained release in the colon.     

Hyaluronic Acid Derivative-Based Self-Assembled Nanoparticles for the Treatment of Melanoma

Purpose

Hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs) were developed for the targeted delivery of doxorubicin (DOX), and their antitumor efficacy for melanoma was evaluated.

Methods

DOX-loaded HACE-based self-assembled NPs were prepared and their physicochemical properties were characterized. The in vitro cytotoxicity of HACE was measured using an MTS-based assay. The cellular uptake efficiency of DOX into mouse melanoma B16F10 cells was assessed by confocal laser scanning microscopy and flow cytometry. Tumor growth and body weight were monitored after the intratumoral and intravenous injection of DOX-loaded NPs into a B16F10 tumor-bearing mouse model.

Results

DOX-loaded NPs, with a mean diameter of ~110?nm, a narrow size distribution, and high drug entrapment efficiency, were prepared. A sustained DOX release pattern was shown, and drug release was enhanced at pH 5.5 compared with pH 7.4. The cytotoxicity of HACE to B16F10 cells was negligible. It was assumed that DOX was taken up into the B16F10 cells through receptor-mediated endocytosis. A significant inhibitory effect was observed on tumor growth, without any serious changes in body weight, after the injection of DOX-loaded NPs into the B16F10 tumor-bearing mouse model.

Conclusions

DOX-loaded HACE-based NPs were successfully developed and their antitumor efficacy against B16F10 tumors was demonstrated.     

RP-HPLC法测定姜黄素温敏凝胶的含量及体外释放度

目的:建立姜黄素温敏凝胶中姜黄素的含量测定方法并研究其体外释放行为。方法:以泊洛沙姆407、泊洛沙姆188为基质制备姜黄素温敏凝胶;采用反相高效液相色谱(RP-HPLC)法测定姜黄素温敏凝胶的含量和体外释放度,色谱柱为Kromasil C18(250mm×4.6mm,5μm),流动相为乙腈-2%冰醋酸溶液(58∶42),检测波长为430nm。结果:回归方程为A=113.2c+82.177(r=0.9993),姜黄素检测浓度在4～128μg·mL-1范围内与峰面积积分值线性关系良好,平均回收率为(100.23±0.75)%,低、中、高浓度标准品溶液日内精密度的RSD分别为1.99%、1.86%、1.96%,日间精密度的RSD分别为1.04%、1.74%、1.98%。样品于120h在释放介质中的累积释放率为(81.54±1.07)%,药物释放遵循Higuchi方程释放动力学模型。结论:本方法准确、可靠,可用于姜黄素温敏凝胶中姜黄素的含量测定。姜黄素温敏凝胶具有一定的缓释作用。