New strategies to deliver anticancer drugs to brain tumors

Background: Malignant brain tumors are among the most challenging to treat and at present there are no uniformly successful treatment strategies. Standard treatment regimens consist of maximal surgical resection followed by radiotherapy and chemotherapy. The limited survival advantage attributed to chemotherapy is partially due to low CNS penetration of antineoplastic agents across the blood–brain barrier (BBB). Objective: The objective of this paper is to review recent approaches to delivering anticancer drugs into primary brain tumors. Methods: Both preclinical and clinical strategies to circumvent the BBB are considered that include chemical modification and colloidal carriers. Conclusion: Analysis of the available data indicates that new approaches may be useful for CNS delivery, yet an appreciation of pharmacokinetic issues and improved knowledge of tumor biology will be needed to affect significantly drug delivery to the target site.     

Self-emulsifying drug delivery systems: a novel approach to deliver drugs

Self-emulsifying drug delivery systems (SEDDS) are a proven method for poorly soluble substances works by increasing the solubility and bioavailability. SEDDS and isotropic mixtures, are composed of oils, surfactants, and occasionally cosolvents. The ability of these formulations and methods to produce microemulsions or fine oil-in-water (o/w) emulsions after moderate stirring and dilution by water phase along the GI tract might be a promising technique for lipophilic agents with dissolution rate-limited absorption. This review provides an outline of SEDDS''s numerous advances and biopharmaceutical elements, types, manufacturing, characterization, limitations, and future prospects. The evaluation of SEDDS and its applications are also discussed, focusing on the advances of SEDDS''s solid self-emulsifying delivery mechanism and dosage form. By integrating suitable polymer into the formulation, SEDDS may be studied for the creation of a formulation with sustained drug release. This technology''s improvement might lead to a new application in the field of medicine delivery. SEDDS has been demonstrated to be quite efficient in increasing oral bioavailability of lipophilic products. SEDDS is one of the promising methods for controlling the characteristics of medications that are not great choices for oral delivery. It is also worth mentioning that SEDDS may be made in variety of solid dosage forms that are acceptable for both oral and parenteral administration.     

In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery

Microneedles (MNs) system for transdermal drug delivery has the potential to improve therapeutic efficacy, proving an approach that is more convenient and acceptable than traditional medication systems. This study systematically researched dissolving polymer MNs fabricated from various common FDA-approved biocompatible materials, including gelatine, chitosan, hyaluronic acid (HA) and polyvinyl alcohol (PVA). Upon application of MN patches to the porcine cadaver skin, the MNs effectively perforated the skin and delivered drugs to subcutaneous tissue on contact with the interstitial fluid. Both the in vitro and in vivo drug release tests showed the similar trends but different release rates among the prepared MNs. Interestingly, the drug-release kinetics of PVA MNs were able to be altered by changing the molecular weight. To evaluate the feasibility using the proposed MNs for treating diabetes, an in vivo insulin absorption study in diabetic mice was performed. The results showed different insulin release properties of MNs fabricated from various kinds of polymer, leading to different decrease in blood glucose levels. We made a systematic and comprehensive study of some drug-loaded polymer MNs, and anticipated that dissolving polymer MNs have potential to improve therapeutic efficacy through controlled drug release.     

新型透皮给药载体--传递体研究进展

概述新型透皮给药载体——传递体研究的特点、组成及制备方法、穿透动力学以及研发设计中应注意的问题。传递体以其自身的特点与技术，将在不久的将来研发出各种传递体皮肤外用制剂。     

两种用药方法治疗女性生殖器结核效果比较

目的 对比分析临床对于女性生殖器结核患者采用经宫腔注药和全身给药两种治疗方法的疗效以及对预后的影响.方法 选择本院2005年2月～2007年6月收治的60例女性生殖器结核患者为研究对象,根据治疗过程中用药的方式将其分为两组,即治疗组和对照组,每组30例,治疗组患者采用宫腔注药进行治疗,对照组患者采用全身给药治疗,回顾性分析两组患者治疗的效果.结果 治疗组疗效明显好于对照组（P ＜ 0.05）,治疗组患者未出现临床不良反应,对照组部分患者出现一过性轻微的胃肠道反应,未出现其他的不良反应,比较差异具有统计学意义（P ＜ 0.05）.结论 临床对于生殖器结核女性患者采用宫腔注药治疗的效果明显优于全身给药治疗,不良反应发生率极低,同时为临床上采用局部治疗法治疗该类患者提供临床依据,安全、有效、简单、经济的局部治疗促进女性生殖器结核患者尽早的康复,提高患者的生存质量,具有十分重要的临床应用价值和意义.     

Evaluation of the Intelisite capsule to deliver theophylline and frusemide tablets to the small intestine and colon

The objective of the research was to establish the capability of the Intelisite capsule to deliver the probe drugs, theophylline and frusemide, in the form of split immediate release (IR) tablets, to the small intestine and colon. The two probe drugs were administered together in an open, random, three-way crossover study in eight healthy volunteers, comparing absorption following Intelisite delivery in the small bowel and colon to conventional IR dosing. Gamma scintigraphy was employed to monitor the gastrointestinal transit and activation of the Intelisite capsule. Standard pharmacokinetic parameters, and the percentage remaining in the capsules post defecation were determined. The Intelisite capsule was well tolerated in human volunteers and successfully activated on 15/16 occasions. Pharmacoscintigraphy showed internal marker release from the Intelisite capsule to be approximately 10-fold faster in the small intestine than in the colon. Theophylline and frusemide were both well absorbed following Intelisite activation in the small intestine, whereas complete colonic absorption was only observed in 1/7 subjects for theophylline, and 0/7 subjects for frusemide. The probe drugs were successfully delivered in particulate form from the Intelisite capsule in the small intestine and produced expected pharmacokinetic profiles. However drug release in the colon was incomplete and variable possibly due to: low water content, poor mixing, and a high loading dose.     

Target-specific drug release to the colon

Background: The ability to deliver drugs to the human colon in a specific manner has become feasible over the years. Targeting pharmaceutical drugs to the colon makes it possible to achieve local or systemic drug delivery to this site. Objective: To deliver the compounds in a non-degraded form to the lower part of the gastrointestinal tract, they must first pass through the stomach and the upper part of the intestine before releasing the contents in the colon. Methods: This review provides an overview of the various approaches to targeted drug delivery to the colon using different drug delivery systems, their limitations and the future developments in this field. Results/conclusions: A microbially controlled system, which is a well-accepted approach, based on natural polymers, has the greatest potential for colonic delivery, particularly in terms of site specificity and safety. However, close attention should be paid to the performance of these products in the heterogeneous environment of the human gastrointestinal tract.     

Strategies to optimize siRNA delivery to hepatocellular carcinoma cells

Introduction: hepatocellular carcinoma (hcc) is the predominant form of primary liver cancer and the second leading cause of cancer-associated mortality worldwide. available therapies for hcc have limited efficacy due to often late diagnosis and the general resistance of hcc to anti-cancer agents; therefore, the development of novel therapeutics is urgently required. small-interfering rna (sirna) molecules are short, double-stranded rnas that specifically recognize and bind the mrna of a target gene to inhibit gene expression. despite the great therapeutic potential of sirnas towards many human tumors including hcc, their use is limited by suboptimal delivery.

Areas covered: In this review, we outline the current data regarding the therapeutic potential of siRNAs in HCC and describe the development of effective siRNA delivery systems. We detail the key problems associated with siRNA delivery and discuss the possible solutions. Finally, we provide examples of the various siRNA delivery strategies that have been employed in animal models of HCC and in human patients enrolled in clinical trials.

Expert opinion: Despite the existing difficulties in siRNA delivery for HCC, the increasing scientific attention and breakthrough studies in this field is facilitating the design of novel and efficient technical solutions that may soon find practical applications.     

Genetic Engineering of Protein-Based Polymers: Potential in Controlled Drug Delivery

Pharmaceutical Research -     

Doxycycline delivery from PLGA microspheres prepared by a modified solvent removal method

We report on the development of a modified solvent removal method for the encapsulation of hydrophilic drugs within poly(lactic-co-glycolic acid) (PLGA). Using a water/oil/oil double emulsion, hydrophilic doxycycline was encapsulated within PLGA spheres with particle diameters ranging from approximately 600?nm to 19?µm. Encapsulation efficiencies of up to 74% were achieved for theoretical loadings from 1% to 10% (w/w), with biphasic release over 85 days with nearly complete release at the end of this time course. About 1% salt was added to the formulations to examine its effects on doxycycline release; salt modulated release only by increasing the magnitude of initial release without altering kinetics. Fourier transform infrared spectroscopy indicated no characteristic differences between doxycycline-loaded and control spheres. Differential scanning calorimetry and X-ray diffraction suggest that there may be a molecular dispersion of the doxycycline within the spheres and the doxycycline may be in an amorphous state, which could explain the slow, prolonged release of the drug.     

Polymeric networks for controlled release of drugs: a patent review

Introduction: Polymeric networks for controlled drug delivery possess wide pharmaceutical and biomedical applications.

Areas Covered: In this review, we explore the diversity of polymeric networks that exist, from simple to highly complex and ‘smart’ embodiments. The patented delivery systems reviewed reflect this, based on both conventional polymeric networks and stimulus-responsive networks where engineering of a controlled molecular architecture of polymeric networks enables a defined response to external or internal stimuli. Future trends in terms of nano-sized polymeric network patents are also highlighted.

Expert Opinion: A critical analysis of challenges potentially facing extended propulsion of the research and development of polymeric networks is provided. The significant therapeutic potential of polymer networks for controlled drug delivery is highlighted in the patented drug delivery systems examined; however, there needs to be enhanced representation of such systems in the market and thus available to patients. Concerted efforts are therefore necessary to propel these systems from the experimental setting to pilot scale production, and preclinical and clinical testing, for extension of their practicality.     

Potential of Guar Gum Microspheres for Target Specific Drug Release to Colon

Various approaches for colon targeted drug delivery have been studied over the last decade including, pro-drugs, timed-released systems, coating of pH-dependant polymer and the use of polysaccharides. In the present work, a novel formulation consisting of cross-linked microspheres of guar gum has been investigated for colon-targeted delivery of metronidazole. An emulsification method involving the dispersion of aqueous solution of guar gum in castor oil was used to prepare spherical microspheres. Process parameters were analyzed in order to optimize the formulation. Shape and surface morphology of the microspheres were examined using scanning electron microscopy. Placebo microspheres exhibited a smooth surface while the incorporation of drug imparted a slight roughness to the surface texture. Particle size of the microspheres was determined using laser diffraction particle size analyzer. The in vitro drug release studies were performed in simulated gastric fluid for 2 h and intestinal fluid for 3 h, which revealed that the drug was retained comfortably inside the microspheres and that only 15.27±0.56% of the drug was released in 5 h. In vitro release rate studies were also carried out in simulated colonic fluid (SCF) in the presence of rat cecal contents, which showed improved drug release. Moreover, to induce the enzymes that specifically act on guar gum, the rats were treated with 1 ml of 1% w/v dispersion of guar gum for 2, 4 and 6 days and release rate studies were repeated in SCF in the presence of 2 and 4% w/v of cecal matter. A marked improvement in the drug release was observed in presence of cecal matter obtained after induction when compared to those without induction. In vitro release studies exhibited 31.23±1.49% drug release in 24 h in dissolution medium without rat cecal matter. However, the incorporation of 4% w/v cecal matter obtained after 6 days of enzymes induction increased the drug release to 96.24±4.77%.     

Controlled Release of Insulin from Injectable Biodegradable Triblock Copolymer Depot in ZDF Rats

PURPOSE: The purpose of this study was to design sustained release system which provides basal insulin release over a week by one injection in diabetic animals. For an effective injectable formulation and controlled release of insulin, a water soluble biodegradable triblock copolymer of PLGA-PEG-PLGA was used. METHODS: For in vitro release, samples were analyzed by reversed-phase high performance liquid chromatography. Animal studies using ZDF rats have been conducted to demonstrate the bioactivity of the released insulin. Insulin formulation was injected subcutaneously. At designated times, the blood glucose levels and insulin levels of the ZDF rats were measured. RESULTS: The in vitro release of zinc-complexed insulin showed no initial burst and demonstrated constant release rate with the duration of 14 days. Constant steady state plasma levels of exogenous insulin were detected for nearly two weeks indicating constant rate of insulin release in vivo upon single subcutaneous injection. CONCLUSIONS: We conclude that it is feasible to achieve basal insulin levels over a week by a single injection of ReGel formulation. This will provide various advantages, including depot formation without surgery, easy sterilization, straightforward drug loading, simple dose adjustment, system biocompatibility with no inflammatory reaction, and no requirement of using organic solvents.     

Delivery of drugs,growth factors,genes and stem cells via intrapericardial,epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease

Introduction: Local myocardial delivery (LMD) of therapeutic agents is a promising strategy that aims to treat various myocardial pathologies. It is designed to deliver agents directly to the myocardium and minimize their extracardiac concentrations and side effects. LMD aims to enhance outcomes of existing therapies by broadening their therapeutic window and to utilize new agents that could not be otherwise be implemented systemically.

Areas covered: This article provides a historical overview of six decades LMD evolution in terms of the approaches, including intrapericardial, epicardial, and intramyocardial delivery, and the wide array of classes of agents used to treat myocardial pathologies. We examines delivery of pharmaceutical compounds, targeted gene transfection and cell implantation techniques to produce therapeutic effects locally. We outline therapeutic indications, successes and failures as well as technical approaches for LMD.

Expert opinion: While LMD is more complicated than conventional oral or intravenous administration, given recent advances in interventional cardiology, it is safe and may provide better therapeutic outcomes. LMD is complex as many factors impact pharmacokinetics and biologic result. The choice between routes of LMD is largely driven not only by the myocardial pathology but also by the nature and physicochemical properties of the therapeutic agents.     

柠檬酸递送药物的研究进展

柠檬酸因价廉易得,具有良好的生物相容性、生物可降解性和多功能性受到了广泛关注,已经发展出了众多的柠檬酸基生物材料,并在药物递送系统取得实际进展。总结了柠檬酸在递送基因治疗药物、蛋白质治疗药物、免疫治疗药物、化学治疗药物中的研究进展,希望柠檬酸在药物递送系统得到进一步的研究发展。     

Ocular drug delivery system: a reference to natural polymers

Introduction: Ocular drug delivery is a very challenging endeavor due to the unique anatomical and physiological barriers. The low ocular bioavailability (<10%) obtained from conventional formulations has forced the scientists to develop new formulations to deliver drugs to ocular tissues at a controlled rate to reduce frequent instillations. The natural polymers have represented the potential to deliver drugs topically through the limited precorneal area and release over a prolonged time period.

Areas covered: The important points to be considered during the fabrication of ophthalmic formulations for example, properties of drug molecule and polymer which affect the release rate are discussed. Novel polymers, like arabinogalactan, xyloglucan, gum cordia, locust bean gum, carrageenan and Bletilla striata polysaccharide, besides the conventional polymers like chitosan, starch, sodium alginate, sodium hyaluronate, xanthan gum, gelatin, gellan gum, guar gum, collagen and albumin, have demonstrated the potential to safely deliver drugs at a controlled rate in different ophthalmic formulations.

Expert opinion: The limitations of topical delivery of genes and chemotherapeutic drugs can be overcome by using natural polymers with characteristic properties. Despite the wide applicability, tremendous efforts are required to establish natural polymers in novel formulations on a commercial scale.     

Mesoporous particle-based microcontainers for intranasal delivery of imidazopyridine drugs

Abstract

The aim of this study was to develop mesoporous containers for entrapment of imidazopyridines, such as sedative–hypnotic medicine zolpidem, anxiolytic agent alpidem and their derivatives. For this purpose, calcium carbonate (size 1.2?µm (PDI: 0.6), zeta potential: ?10?mV), manganese carbonate (2.5?µm (PDI: 0.5), zeta potential: ?12?mV) and titanium dioxide particles (3.7?µm (PDI: 0.4), zeta potential: ?15?mV) were used. The compounds were encapsulated applying two techniques: adsorption on the preformed particles and co-precipitation during the synthesis of the particles. The polymer shell of the containers was formed by electrostatic adsorption of polyelectrolytes on the surface of the particles. The best encapsulation efficacy was shown for zolpidem incorporated into calcium carbonate (5.4%) and manganese carbonate (4.6%) by adsorption. Release of the compounds from the containers based on the proposed particles were characterised by the short time burst effect (<10?min) followed by desorption prolongation by formation of polymer shell. X-ray microtomography results demonstrate the prolonged retention of the containers with the mucoadhesive shell in the nasal cavity.     

Targeting anticancer drugs to the brain: II. Physiological pharmacokinetic model of oxantrazole following intraarterial administration to rat glioma-2 (RG-2) bearing rats

The disposition of the anticancer drug oxantrazole (OX) was characterized in rats bearing the rat glioma-2 (RG-2) brain tumor. Following intraarterial administration of 3 mg/kg of OX, serial sacrifices were completed from 5 min to 5 hr after administration. Blood and tissue samples collected at the time of sacrifice were processed and measured for OX concentrations by HPLC. The kidney had the greatest affinity for OX with the C_max being 40.6 g/mlat 15 min after administration. OX concentrations in brain tumor were higher than in normal right and left brain hemispheres, and consistent with enhanced drug blood-tumor barrier (BTB) permeability seen in experimental models for brain tumors. Observed heart, liver, lung, and spleen OX concentrations were similar, ranging from approximately 2 g/mlto 20 g/ml. A unique technique was used to develop a global physiological pharmacokinetic model for OX. A hybrid or forcing function method was used to estimate individual tissue compartment biochemical parameters (i.e., partition and mass transfer coefficients). A log likelihood optimization scheme was used to determine the best model structure and parameter sets for each tissue. Most tissues required a 3-subcompartment structure to adequately describe the observed data. The global model was then reconstructed with an arterial blood and rest of body compartments that provided predicted OX concentrations in agreement with the data. The model development strategy provides a systematic approach to physiological pharmacokinetic model development.Partial financial support was obtained from DuPont Merck Pharmaceutical Company.     

环境响应的智能化递药系统在肿瘤靶向治疗研究的应用(英文)

环境响应的智能化递药系统可对肿瘤组织特殊生理环境及体外环境变化而发生相应变化,特异地靶向分布于肿瘤组织或在肿瘤组织的特殊生理环境下释放药物,从而可有效改善并提高抗癌药物对肿瘤靶向治疗效果,降低药物毒副作用,已成为近年来肿瘤靶向治疗研究领域的热点之一。本文综述了环境响应的智能化递药系统的靶向机理及其在肿瘤靶向治疗中的应用,以期为新型肿瘤靶向递药系统的开发及其对肿瘤的治疗提供参考。