Fabrication and characterizations of a novel drug delivery device liposomes-in-microsphere (LIM)

In the present work, we developed a novel drug delivery system, liposomes-in-microsphere (LIM) of biodegradable polymers, which is conceived from a combination of the polymer- and the lipid-based delivery systems and can thus integrate the advantages and avoid the drawbacks of the two systems. Liposomes were encapsulated into microspheres of biodegradable polymers by the solvent extraction/evaporation process to form LIMs. The integrity of the liposomes was preserved by modifying the microencapsulation process and coating the liposomes with chitosan. We demonstrated by scanning electron microscopy, laser light scattering and fluorescence spectroscopy that the particle size and surface morphology of the polymeric microspheres did not change significantly with the liposomes encapsulated, the liposomes remained intact within the polymeric matrix of the microspheres, and the encapsulated liposomes could be released from the microspheres in a controlled manner at a nearly constant release rate after an initial off-release period. Decreasing the particle size of liposomes and increasing the pore size of the polymeric matrix shortened the initial off-release period and increased the liposome release rate. In conclusion, a novel drug delivery system, liposomes-in-microsphere, was successfully developed and characterized. The liposome release kinetics could be controlled by the composition and fabrication parameters of the liposomes and polymeric microspheres. Such a novel controlled release system may have potential to be applied for drug delivery and gene therapy.     

Soluble sustained release gene delivery system

Delivery of genetic substance to target cells remains an obstacle for efficient utilization of gene therapy approaches. In this study, we describe a formulation of methacrylate acid copolymer carrier of DNA, in which the release rate of the gene can be controlled by pH. Plasmid release was coupled with the polymer's dissolution, which was accelerated in alkali conditions. The released plasmid was intact and bioactive, although alteration from closed circular supercoil to relaxed conformation was observed. Confocal laser scanning microscopy detected the plasmid DNA along the central layers of the polymeric film. Gene delivery systems controlled by the dissolution of the polymeric films offer flexibility in quantity and size of the incorporated DNA, and therefore could have a potential for in vivo use.     

Subcutaneous polymeric matrix system p(HEMA-BGA) for controlled release of an anticancer drug (5-fluorouracil). II: Release kinetics

A subcutaneous polymeric drug delivery system, which consists of a polymeric matrix of poly(hydroxyethyl methacrylate-bisglycol acrylate), was developed. 5-fluorouracil was used as the model anticancer drug. Polymer-drug beads with a diameter of 3 mm were prepared by low-temperature radiation polymerization. In order to modify the release rate, polymeric beads with different composition, drug loading and crosslinking density were obtained. The kinetics of drug release were described by the expression Mt/M infinity = ktn. The diffusional release exponent 'n', which was calculated from the release curves, indicated that the mechanism of drug release from the polymeric matrix is due to the anomalous (non-Fickian) type of diffusion.     

Design of a Self-Regulated Drug Delivery Device

Most conventional drug delivery systems are based on polymers or lipid vesicles. These chemically synthesized materials can be designed to be biocompatible and have good functionality, but they often lack well-defined properties, due to an inherent size and structure distribution resulting from chemical synthesis. On the other hand, micro-fabrication technology developed for microelectronic applications is capable of mechanically creating devices with more precisely defined features, in a size range similar to polymeric and lipid materials. In this paper, we describe the design of a self-regulated drug delivery device based on the integration of both mechanical and chemical methods. In this device, a constant release rate can be achieved by carefully designing the shape of the drug reservoir, while a pH-sensitive hydrogel switch is used to regulate the drug release.     

Injectable in situ forming controlled release implant composed of a poly-ether-ester-carbonate and applications in the field of chemotherapy

Polymeric controlled delivery systems hold great promise in the field of modern medicine. Such technology has already been converted into commercially viable products in a myriad of fields. Chemotherapy is an example of such an area where constant efficacious levels of drug can greatly enhance clinical outcomes. The key to designing such therapies is the preparation of the proper delivery system. To this end, a series of bioresorbable polyether-ester-carbonate copolymers have been developed, which when combined with a diluent, are capable injection into the body and consistently forming a drug delivery depot. The study delineated here aimed at producing a more effective treatment of a common drug, paclitaxel, using the polymeric carrier. The polymer carrier system exhibited controlled release of paclitaxel both in vitro and in vivo. Drug concentrations were analyzed by high performance liquid chromatography and apoptotic activity was confirmed through flow cytometry. Relevant success was exhibited by the regression of tumor size following a multiple injection treatment regimen in a murine xenograft model. This multiple injection treatment shows promising results when compared to the traditional paclitaxel paradigm of a single injection for a period of 3 weeks.     

A polymeric device for controlled transscleral multi-drug delivery to the posterior segment of the eye

The design of drug delivery systems that can deliver multiple drugs to the posterior segment of the eye is a challenging task in retinal disease treatments. We report a polymeric device for multi-drug transscleral delivery at independently controlled release rates. The device comprises a microfabricated reservoir, controlled-release cover and three different fluorescent formulations, which were made of photopolymeized tri(ethyleneglycol)dimethacrylate (TEGDM) and poly(ethyleneglycol)dimethacrylate (PEGDM). The release rate of each fluorescent is controlled by varying the PEGDM/TEGDM ratio in its formulation and the cover. The release kinetics appeared to be related to the swelling ratio of the PEGDM/TEGDM polymers. When the devices were implanted onto rat sclerae, fluorescence was observable in the ocular tissues during 4 weeks’ implantation and distributed locally around the implantation site. Our polymeric system, which can administer multiple compounds with distinct kinetics, provides prolonged action and less invasive transscleral administration, and is expected to provide new tools for the treatment of posterior eye diseases with new therapeutic modalities.     

生长因子缓释制剂在神经系统退变性疾病中的应用

利用缓释系统包载生长因子,既能保护生长因子的生物活性,又可以使其缓慢释放。从载体材料与生长因子的简单混合到生长因子缓释微球系统,生长因子缓释技术不断更新并得到广泛应用。就生物可降解生长因子缓释制剂在神经系统退变性疾病中的应用做一综述。     

Crystallization of beta-estradiol in an acrylic transdermal drug delivery system.

Transdermal drug delivery systems are pharmaceutical products that can deliver controlled doses of drugs from polymeric patches applied on the human skin. The long-term stability of these patches is a critical issue relative to their performance in delivering drugs at a constant rate. Where a drug has been dissolved in the polymeric adhesive patch, crystallization has been reported in several systems. This study uses a variety of characterization tools to determine the physical and chemical nature of the precipitates formed in situ in estradiol patches. Optical microscopy revealed that crystals were formed in a single layer inside the adhesive matrix and that there were two distinctly different morphologies: needle-like crystals and aggregates around the needles. From IR measurements it was evident that estradiol probably was present in more than one crystal form in these patches. Raman microscopy showed that the needle-like crystals contain the adhesive component and the aggregates some modified crystal form of estradiol, indicating that in addition to the drug, the polymeric adhesive also crystallizes during storage.     

Review paper: critical issues in tissue engineering: biomaterials, cell sources, angiogenesis, and drug delivery systems

Tissue engineering is a newly emerging biomedical technology, which aids and increases the repair and regeneration of deficient and injured tissues. It employs the principles from the fields of materials science, cell biology, transplantation, and engineering in an effort to treat or replace damaged tissues. Tissue engineering and development of complex tissues or organs, such as heart, muscle, kidney, liver, and lung, are still a distant milestone in twenty-first century. Generally, there are four main challenges in tissue engineering which need optimization. These include biomaterials, cell sources, vascularization of engineered tissues, and design of drug delivery systems. Biomaterials and cell sources should be specific for the engineering of each tissue or organ. On the other hand, angiogenesis is required not only for the treatment of a variety of ischemic conditions, but it is also a critical component of virtually all tissue-engineering strategies. Therefore, controlling the dose, location, and duration of releasing angiogenic factors via polymeric delivery systems, in order to ultimately better mimic the stem cell niche through scaffolds, will dictate the utility of a variety of biomaterials in tissue regeneration. This review focuses on the use of polymeric vehicles that are made of synthetic and/or natural biomaterials as scaffolds for three-dimensional cell cultures and for locally delivering the inductive growth factors in various formats to provide a method of controlled, localized delivery for the desired time frame and for vascularized tissue-engineering therapies.     

Molecular release from a polymeric microreservoir device: Influence of chemistry, polymer swelling, and loading on device performance

A polymeric microreservoir device for controlled-release drug delivery relies on the degradation of thin poly(lactic-co-glycolic acid) membranes that seal each reservoir to achieve pulsatile drug delivery. In vitro release studies in which the swelling of the reservoir membranes was measured indicate a correlation between the release times of various radiolabeled molecules from the devices and the time at which the maximum membrane swelling was observed. Varying the chemistry (lipophilicity/hydrophilicity) or molecular weight of the molecules loaded into the devices did not appear to affect the degree of membrane swelling that was observed, or the time at which the molecules were released from the devices. The amount of drug that was loaded into the reservoirs also did not appear to affect the observed release time of the drug from the device, a significant departure from the behavior of many matrix-type polymeric drug delivery systems.     

聚乳酸类定向缓释疫苗微粒投递系统的应用进展

本文综述了以聚乳酸、聚乙醇酸及其共聚物为生物降解材料 ,制备疫苗微粒投递系统的常用方法 ,讨论了影响微粒特性的主要因素 ,并着重介绍了近年来聚乳酸及其共聚物在疫苗微粒投递系统的研究进展。     

Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery

Noninvasive ultrasound has been shown to increase the release rate on demand from drug delivery systems; however, such systems generally suffer from background drug leaching. To address this issue, a drug-containing polymeric monolith coated with a novel ultrasound-responsive coating was developed. A self-assembled molecular structure coating based on relatively impermeable, ordered methylene chains forms an ultrasound-activated on-off switch in controlling drug release on demand, while keeping the drug inside the polymer carrier in the absence of ultrasound. The orderly structure and molecular orientation of these C12 n-alkyl methylene chains on polymeric surfaces resemble self-assembled monolayers on gold. Their preparation and characterization have been published recently (Kwok et al. [Biomacromolecules 2000;1(1):139-148]). Ultrasound release studies showed that a copolymer of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate (MW 400) coated with such an ultrasound-responsive membrane maintained sufficient insulin for multiple insulin delivery, compared with a substantial burst release during the first 2 h from uncoated samples. With appropriate surface coating coverage, the background leach rate can be precisely controlled. The biological activity of the insulin releasate was tested by assessing its ability to regulate [C14]-deoxyglucose uptake in 3T3-L1 adipocyte cells in a controlled cell culture environment. Uptake triggered by released insulin was comparable to that of the positive insulin control. The data demonstrate that the released insulin remains active even after the insulin had been exposed to matrix synthesis and the methylene chain coating process.     

Polymer hollow fiber three-dimensional matrices with controllable cavity and shell thickness

Hollow fibers find useful applications in different disciplines like fluid transport and purification, optical guidance, and composite reinforcement. In tissue engineering, they can be used to direct tissue in-growth or to serve as drug delivery depots. The fabrication techniques currently available, however, do not allow to simultaneously organize them into three-dimensional (3D) matrices, thus adding further functionality to approach more complicated or hierarchical structures. We report here the development of a novel technology to fabricate hollow fibers with controllable hollow cavity diameter and shell thickness. By exploiting viscous encapsulation, a rheological phenomenon often undesired in molten polymeric blends flowing through narrow ducts, fibers with a shell-core configuration can be extruded. Hollow fibers are then obtained by selective dissolution of the inner core polymer. The hollow cavity diameter and the shell thickness can be controlled by varying the polymers in the blend, the blend composition, and the extrusion nozzle diameter. Simultaneous with extrusion, the extrudates are organized into 3D matrices with different architectures and custom-made shapes by 3D fiber deposition, a rapid prototyping tool which has recently been applied for the production of scaffolds for tissue engineering purposes. Applications in tissue engineering and controlled drug delivery of these constructs are presented and discussed.     

Redox and pH responsive polymeric vesicles constructed from a water-soluble pillar[5]arene and a paraquat-containing block copolymer for rate-tunable controlled release

Herein, for rate-tunable controlled release, pH and redox dual responsive polymeric vesicles were constructed based on host–guest interaction between a water soluble pillar[5]arene (WP5) and a paraquat-containing block copolymer (BCP) in water. The yielding polymeric vesicles can be further applied in the controlled release of a hydrophilic model drug, doxorubicin hydrochloride (DOX). The drug release rate is regulated depending on the type of single stimulus or the combination of two stimuli. Meanwhile, DOX-loaded polymeric vesicles present anticancer activity in vitro comparable to free DOX under the studied conditions, which may be important for applications in the therapy of cancers as a controlled-release drug carrier.     

A monolithic polymeric microdevice for pH-responsive drug delivery

A drug-delivery microdevice integrating pH-responsive nano-hydrogel particles functioning as intelligent nano valves is described. The polymeric microdevices are monolithic without requiring peripheral control hardware or additional components for controlling drug-release rates. pH-responsive nanoparticles were synthesized and embedded into a composite membrane. The resulting pH-responsive composite membranes were integrated with PDMS micro reservoirs via a room-temperature transfer bonding technique to form the proof-of-concept microdevices. In vitro release characterization of the microdevices was conducted in which the release rate of Vitamin B₁₂ (VB₁₂) as a model drug increased dramatically when the local pH value was decreased from 7.4 to 4. This device concept can serve as a platform technology for intelligent drug delivery in response to various in vivo environmental signals.     

Systemic and Mucosal Delivery of Drugs within Polymeric Microparticles Produced by Spray Drying

Encapsulation of therapeutic and diagnostic materials into polymeric particles is a means to protect and control or target the release of active substances such as drugs, vaccines, and genetic material. In terms of mucosal delivery, polymeric encapsulation can be used to promote absorption of the active substance, while particles can improve the half-life of drugs administered systemically. Spray drying is an attractive technology used to produce such microparticles, because it combines both the encapsulation and drying steps in a rapid, single-step operation. Even so, spray drying is not classically associated with processes used for drug and therapeutic material encapsulation, since elevated temperatures could potentially denature the active substance. However, a comprehensive review of the literature revealed a number of studies demonstrating that spray drying can be used to produce microparticulate formulations with labile therapeutics. Polymers commonly employed include synthetics such as methacrylic copolymers and polyesters, and natural materials including chitosan and alginate. Drugs and active substances are diverse and included antibiotics, anti-inflammatory agents, and chemotherapeutics. Regarding the delivery of spray-dried particles, the pulmonary, oral, colonic, and nasal mucosal routes are often investigated because they offer a convenient means of administration, which promotes physician and patient compliance. In addition, spray drying has been widely used to produce polymeric microparticles for systemic delivery in order to control the delivery of drugs, vaccines, or genetic material that may exhibit poor pharmacokinetic profiles or pose toxicity concerns. This review presents a brief introduction to the technology of spray drying and outlines the delivery routes and the applications of spray-dried polymeric microparticles.     

Polymeric micelles for GSH-triggered delivery of arsenic species to cancer cells

Arsenic trioxide (ATO), dissolved in water as arsenous acid or inorganic arsenite (As^III), is an effective chemotherapeutic agent against acute promyelocytic leukemia (APL). It has been under investigation as a potential treatment for a variety of solid tumors although with much poorer efficacy than for APL. The toxicity of As^III and its derivatives is a common concern that has limited its use. The objective of the current study was to develop a polymeric micelle drug delivery system for efficient and controlled delivery of trivalent arsenicals to solid tumor cells. A polymeric micelle-based drug delivery system can potentially extend the duration of drug circulation in blood, restrict access of encapsulated drug to normal tissues, achieve tumor targeted drug delivery, enhance drug accumulation in the tumor area, and trigger drug release at tumor sites if designed properly. These, in turn, can lead to an improved therapeutic index for the polymeric micellar formulation of arsenic species compared to their free form. Towards this goal, a biodegradable block copolymer with pendent thiol groups on the hydrophobic block, i.e., methoxy poly(ethylene oxide)-block-poly[α-(6-mecaptohexyl amino)carboxylate-ε-caprolactone] [PEO-b-P(CCLC₆-SH)], was synthesized and used for conjugation of a trivalent arsenical, phenylarsine oxide (PAO), to free thiol groups on the polymer backbone. PAO-loaded micelles had refined size distribution with an average diameter of 150 nm as evidenced by dynamic light scattering (DLS) in water. Prepared polymeric micelles were characterized for the level of PAO conjugation using inductively coupled plasma mass spectrometry (ICP-MS). The results showed 65% of total free thiols were conjugated to PAO providing an arsenic/polymer loading content of ∼2.5 wt%. In vitro release study suggests prolonged release of PAO from its polymeric micellar carrier, which was accelerated in the presence of glutathione (GSH). Cytotoxicity studies against MDA-MB-435 cells show that the IC₅₀ of PEO-b-P(CCLC₆-S-PAO) is not significantly different from that of free PAO. The results indicate that PEO-b-P(CCLC₆-SH) is a promising carrier for successful arsenic delivery for cancer therapy.     

Dissolution behaviour of hydrophilic matrix tablets containing two different polyethylene oxides (PEOs) for the controlled release of a water-soluble drug. Dimensionality study.

Hydrophilic matrix tablets containing polyethylene oxides as the retarding polymer have been successfully employed in the controlled release of drugs. To evaluate the relative influence of drug diffusion and polymer erosion mechanisms in the drug delivery process, we studied the hydration behaviour of matrix tablets containing a water-soluble drug and PEOs of two different molecular weights: Polyox WSRN 1105 (Mw = 0.9 x 10(6)) and Polyox WSRN 301 (Mw = 4 x 10(6)). The hydration rate, the extent of swelling, and the erosion rate of matrices containing the polymer, the drug and tableting excipients were evaluated in comparison to tablets made of pure polymer. The results of these studies on function of the release behaviour were then discussed. The results show that the higher molecular weight PEO swells to a greater extent and tends to form, upon hydration, a stronger gel, which is therefore less liable to erosion, if compared to the lower molecular weight PEO. This difference in the erosion behaviour can explain the different efficiencies of the two polymeric products in modulating the delivery rate of the water-soluble drug. Moreover, the presence of other soluble components (drug and excipients) in the dosage form enhances the erosion trend of the tablets with a consequent reduction of the efficiency of the polymer in drug release control.     

Prevention of calcification of glutaraldehyde pretreated bovine pericardium through controlled release polymeric implants: studies of Fe, Al, protamine sulphate and levamisole

Calcification is the principal cause of the clinical failure of bioprosthetic heart valves fabricated from glutaraldehyde pretreated porcine aortic valves or bovine pericardium. The present study investigated controlled-release implants for prevention of the calcification of glutaraldehyde pretreated bovine pericardium in a rat subdermal model. Either Al³⁺ and Fe³⁺ (inhibitors of the growth and dissolution rate of hydroxyapatite crystals), levamisole (alkaline phosphatase inhibitor) or protamine sulphate (charge modifier) were individually incorporated into various polymeric carriers (either silicone rubber. Polyurethane or silicone rubber-polyurethane copolymer). Polymeric implants were evaluated for in vitro release kinetics, which revealed that sustained drug release was obtained from 21 d to more than 90 d from various drug matrices. In vivo efficacy was studied by co-implanting the polymeric delivery systems with glutaraldehyde pretreated bovine pericardium for 21 d using a subdermal rat model; glutaraldehyde pretreated bovine pericardium calcium levels were quantitated by atomic absorption spectroscopy in the explanted tissues. Fe³⁺ and Al³⁺ polymeric implants were the most effective for inhibiting deposition of calcium mineral. Al³⁺ demonstrated 82% inhibition of calcification compared to controls and Fe³⁺ resulted in 80% inhibition of calcification. Specific histologie staining methods showed that Fe³⁺ and Al³⁺ were localized within the devitalized cells of the explanted glutaraldehyde pretreated bovine pericardium. No adverse effects on somatic growth or recipient bone morphology were noted following controlled-release drug administration. Controlled release of protamine sulphate or levamisole did not significantly inhibit glutaraldehyde pretreated bovine pericardium calcification. It is concluded that regional controlled release of Fe³⁺ or AI³⁺ inhibits glutaraldehyde pretreated bovine pericardium calcification in the rat subdermal model without adverse effects.     

Functionalized chitosan/NIPAM (HEMA) hybrid polymer networks as inserts for ocular drug delivery: synthesis, in vitro assessment, and in vivo evaluation

A series of hybrid polymeric hydrogels, prepared by the reaction of acrylic acid-functionalized chitosan with either N-isopropylacrylamide or 2-hydroxyethyl methacrylate monomers, were synthesized, pressed into minitablets, and investigated for their ability to act as controlled release vehicles for ophthalmic drug delivery. For comparison, interpolymeric complex analogues synthesized using the same monomers and pure, unfunctionalized chitosan were examined by means of an identical characterization protocol. The effects of network structure and composition upon the swelling properties, adhesion behavior, and drug release characteristics were investigated. Comparative in vitro studies employing chloramphenicol, atropine, norfloxacin, or pilocarpine informed the selection of drug-specific carrier compositions for the controlled delivery of these compounds. In addition, in vivo (rabbit model) experiments involving the delivery of pilocarpine indicated that chitosan-based hybrid polymer networks containing 2-hydroxyethyl methacrylate are useful carriers for the delivery of this therapeutic agent.