Comparison of poly(acryl starch) and poly(lactide-co-glycolide) microspheres as drug delivery system for a rotavirus vaccine.

Drug delivery systems allowing controlled release of antigen are of particular interest in the development of vaccines. We have compared poly(acrylic starch) microspheres (PAS) and poly(lactide-co-glycolide) microspheres (PLG) as drug delivery systems for a rotavirus vaccine. The polymers are both biodegradable but have different degradation mechanisms and antigen release profiles. PAS are enzymatically degraded and have a continuous fast antigen release rate compared to the hydrolytically degraded PLG which release the incorporated antigen in a pulsatile manner. In this study mice were immunised intramuscularly and orally on three occasions with formalin-inactivated rotavirus (FRRV) incorporated in PAS and PLG and with FFRV alone. Serum and faeces samples were collected and analysed by ELISA for rotavirus specific IgG and IgA antibodies. A neutralising assay was also conducted on both serum and faeces antibodies. The two different polymer drug delivery systems induced different immune responses depending on administration route. PAS elicited significant antibody levels and neutralising effect after oral administration while PLG showed high antibody levels after intramuscular administration. The immune response appears to be dependent on the differences in antigen release and degradation mechanism for the two polymer systems.     

On the importance and mechanisms of burst release in matrix-controlled drug delivery systems.

Although the significance of burst release in controlled delivery systems has not been entirely ignored, no successful theories have been put forth to fully describe the phenomenon. Despite the fact that the fast release of drug in a burst stage is utilized in certain drug administration strategies, the negative effects brought about by burst can be pharmacologically dangerous and economically inefficient. Therefore a thorough understanding of the burst effect in controlled release systems is undoubtedly necessary. In this article, we review experimental observations of burst release in monolithic polymer controlled drug delivery systems, theories of the physical mechanisms causing burst, some of the unique ideas used to prevent burst, and the treatment of burst release in controlled release models.     

Development of controlled drug release systems based on thiolated polymers.

The purpose of the present study was to generate mucoadhesive matrix-tablets based on thiolated polymers. Mediated by a carbodiimide, L-cysteine was thereby covalently linked to polycarbophil (PCP) and sodium carboxymethylcellulose (CMC). The resulting thiolated polymers displayed 100+/-8 and 1280+/-84 micromol thiol groups per gram, respectively (means+/-S.D.; n=6-8). In aqueous solutions these modified polymers were capable of forming inter- and/or intramolecular disulfide bonds. The velocity of this process augmented with increase of the polymer- and decrease of the proton-concentration. The oxidation proceeded more rapidly within thiolated PCP than within thiolated CMC. Due to the formation of disulfide bonds within thiol-containing polymers, the stability of matrix-tablets based on such polymers could be strongly improved. Whereas tablets based on the corresponding unmodified polymer disintegrated within 2 h, the swollen carrier matrix of thiolated CMC and PCP remained stable for 6.2 h (mean, n=4) and more than 48 h, respectively. Release studies of the model drug rifampicin demonstrated that a controlled release can be provided by thiolated polymer tablets. The combination of high stability, controlled drug release and mucoadhesive properties renders matrix-tablets based on thiolated polymers useful as novel drug delivery systems.     

Mathematical model of a hybrid dispersed network-membrane-based controlled release system.

A mathematical model with an exact solution is presented for the controlled release of a drug from a hybrid dispersed network-membrane based system. Both hollow fiber and flat membrane device geometries are considered. The reservoir is loaded with a drug dispersed in a liquid phase. This reservoir is bounded by a microporous membrane, the pores of which are filled with liquid immiscible with the reservoir phase liquid. The drug dissolves from the solid network into the reservoir liquid and migrates through the reservoir toward the microporous membrane. At the interface between the reservoir and the pore, the solute partitions between the reservoir and the pore liquid phases, before diffusing outward through the membrane pore. Experimental results are in close agreement with the release profiles predicted by the mathematical model. Parametric studies reveal the interaction between system parameters and the controlled release behavior. The presence of a dispersed drug phase in the reservoir results in the release of drug for an extended time. The release rate of the drug may be controlled by its rate of diffusion through the membrane pores or by its rate of dissolution into the reservoir liquid.     

Development of a poly(ortho ester) prototype with a latent acid in the polymer backbone for 5-fluorouracil delivery.

A study has been carried out to determine whether the latest family of poly(ortho esters) can be converted into a practical delivery system. This polymer differs from the previously described polymers in that it incorporates a short segment of a latent acid in the polymer backbone. The following issues were specifically addressed: (a) can the erosion and drug release be reproducibly controlled to yield the desired drug release kinetics and erosion rates? (b) Is the polymer stable during radiation sterilization, on storage and on fabrication? (c) Can the polymer be prepared reproducibly at the desired molecular weights and molecular weight distribution? (d) Is the polymer safe for its intended application and does the in vivo erosion proceed to completion? (e) Can the polymer be easily fabricated into desired configurations? Studies have shown that if the synthesis is carefully controlled, the desired molecular weights can be reproducibly prepared, that the polymer is reasonably stable after irradiation at 24 kGy and during storage at room temperature under anhydrous conditions, and that it can be safely thermally fabricated at temperatures in the neighborhood of 120 degrees C. When polymer devices were implanted intraperitoneally in rats the polymer eroded to completion without any overt toxicity as determined by the measured parameters.     

Delivering DNA from photocrosslinked, surface eroding polyanhydrides.

Sustained delivery of DNA has the potential to enhance long-term gene therapy; however, precise control of a wide range of DNA release profiles may be needed. In this work, multifunctional anhydride monomers were photocrosslinked to produce hydrophobic, highly crosslinked polymer networks that degrade by surface erosion. Surface-eroding polymers can deliver molecules of a wide range of sizes at sustained, steady rates, which is advantageous for DNA delivery, where the high molecular weight may complicate control of the release profiles. When plasmid DNA was released from photocrosslinked polyanhydride matrices, DNA recovery was low (approximately 25%). Electrophoresis indicated that the plasmid DNA was released primarily in the relaxed and supercoiled forms, yet the relative fraction of released DNA in the supercoiled form decreased over time. To improve DNA recovery and reduce the damaging effects of polymer degradation, DNA was pre-encapsulated in alginate microparticles, which served as a temporary coating that quickly dissolved upon microparticle release from the polyanhydride matrix. As photocrosslinked polyanhydrides have highly predictable drug release profiles that depend on the polymer erosion rate and implant geometry and not on the entrapped molecule size, they can serve dual purposes in many biomaterial applications where structural support and drug release would be beneficial.     

Feasibility study on the retention of superporous hydrogel composite polymer in the intestinal tract of man using scintigraphy.

In recent years, many complex oral drug delivery systems have been developed using various polymers in order to achieve better drug targeting and drug absorption in the intestinal tract. Superporous hydrogel (SPH) and SPH composite (SPHC)-based drug delivery systems were also developed for the targeted delivery of peptide drugs into the intestinal tract. In the present study, the retention time of SPHC polymer is studied in man using the scintigraphy technique. To that purpose, SPHC polymers were radiolabelled with Tc-99m and administered orally in an enteric-coated gelatin capsule. The location of the radiolabelled polymer was monitored in five healthy volunteers while the subjects were sitting in front of a large field of view gamma camera. The results showed that enteric-coated gelatin capsules remained in the stomach for 75 to 150 min after oral administration to fasted volunteers and that the SPHC polymers thereafter attached to the upper part of the small intestine for at least 45 to 60 min due to their mechanical fixation properties. No discomfort was observed in any of the volunteers after oral administration of these polymers, which indicates that they are safe to be applied for oral drug delivery systems in man.     

Blends of enteric and GIT-insoluble polymers used for film coating: physicochemical characterization and drug release patterns.

THE OBJECTIVES OF THIS STUDY WERE: (i). to use blends of gastrointestinal tract (GIT)-insoluble and enteric polymers (ethyl cellulose and Eudragit L) as coating materials for multiparticulate controlled release dosage forms; (ii). to investigate the effects of the polymer blend ratio and coating level on the resulting drug release patterns; and (iii). to explain the observed phenomena based on the physicochemical properties of the systems. Propranolol HCl-loaded pellets were coated in a fluidized bed coater with organic polymer solutions; thin, drug-containing and drug-free, polymeric films were prepared using a casting knife. In vitro drug release, water uptake and dry weight loss studies were performed in 0.1 M HCl and phosphate buffer pH 7.4, respectively. The apparent drug diffusion coefficients within the polymeric systems were determined using different experimental and theoretical techniques (side-by-side diffusion cells, in vitro drug release from thin films; exact and approximate solutions of Fick's second law of diffusion). A broad range of drug release patterns from coated pellets could be achieved by varying the GIT-insoluble:enteric polymer blend ratio. With increasing relative amounts of Eudragit L, the release rates in both media significantly increased. The increase at low pH could be attributed to an increase in water uptake, as observed with thin films. Interestingly, only partial Eudragit L leaching occurred in phosphate buffer pH 7.4 even at high enteric polymer contents, indicating that the GIT-insoluble polymer effectively hindered the dissolution of the entrapped Eudragit L. At high pH, both polymer leaching and polymer swelling contributed to the control of drug release. The determined apparent drug diffusion coefficients take the two effects adequately into account.     

Optimising the incorporation and release of a neurotrophic factor using conducting polypyrrole.

In this study, a neurotrophin delivery system based on an inherently conducting polymer (ICP) has been developed. Direct incorporation of neurotrophin-3 (NT-3) was investigated and controlled release was tested under various electrochemical conditions. The loading capacity and amount of NT-3 released from the polymer was determined using (125)I-labelled NT-3. Electrochemical stimulation of polypyrrole by pulsed voltage, pulsed current or cyclic voltammetry promoted the release of NT-3 at a greater rate than natural diffusion of NT-3. NT-3 was released from polypyrrole as an initial burst in the first 24 h followed by prolonged release over a subsequent 6 days of sampling. The amount of NT-3 incorporated into the polymer could be controlled by varying the polymerisation time, with longer growth periods incorporating more NT-3. The NT-3 release results indicated that the polymers grown for longer released a lower percentage of the incorporated NT-3 compared to the polymers grown for shorter times. Polymer-based neurotrophin delivery systems have the potential to be incorporated into future treatments for nerve injuries to prevent nerve degradation and promote nerve protection.     

Hydrophilic poly(DL-lactide-co-glycolide) microspheres for the delivery of DNA to human-derived macrophages and dendritic cells.

Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres have a proven track record for drug delivery and are suggested to be ideal carrier systems to target therapeutics into phagocytic cells such as macrophages (MPhis) and dendritic cells (DCs). Microspheres prepared by spray-drying from different PLGA-type polymers were evaluated regarding their effect on phagocytosis, intracellular degradation and viability of human-derived macrophages MPhis and DCs. Even the microspheres prepared from the most hydrophilic polymer RG502H, were efficiently phagocytosed by primary human MPhis and DCs. Interestingly, uptake of PLGA microspheres by DCs as potent immune modulator cells was almost as efficient as uptake by the highly phagocytic MPhis. Phagocytosed microspheres remained inside the cells until decay with none of the microsphere preparations induced significant apoptosis or necrotic cell death. Acidic pH and the phagosomal environment inside the cells enhanced microsphere decay and release of encapsulated material. Degradation of microspheres consisting of the most hydrophilic PLGA polymer RG502H occurred in a reasonable time frame of less than 2 weeks ensuring the release of encapsulated drug during the life span of the cells. To explore important technical and biological aspects of DNA microencapsulation, we have studied DNA loading and in vitro DNA release of microspheres from different PLGA type polymers. Hydrophobicity and molecular weight of the PLGA polymers had profound influence on both the encapsulation efficiency of DNA and its release kinetics in vitro: the hydrophilic polymers showed higher encapsulation efficiency and faster release of intact DNA compared to the hydrophobic ones. These results suggest that microspheres from the PLGA polymer RG502H have improved characteristics for DNA delivery to human MPhis and DCs.     

Lectin-mediated drug delivery: the second generation of bioadhesives.

This paper reviews some recent developments in the area of bioadhesive drug delivery systems. The area of bioadhesion in drug delivery had started some 20 years ago by using so-called mucoadhesive polymers. Many of these polymers were already used as excipients in pharmaceutical formulations. This has facilitated the development of the first bioadhesive drug products, which are now commercially available. A major disadvantage of the hitherto known mucoadhesives, however, is their non-specificity with respect to the substrate. In particular for gastro-intestinal applications, this may cause some premature inactivation and moreover limits the duration of mucoadhesive bonds to the relatively fast mucus turnover. Nevertheless, for some mucoadhesive polymers other interesting functionalities were discovered, such as their ability to modulate epithelial permeability and to inhibit proteolytic enzymes. In contrast to the mucoadhesive polymers, lectins and some other adhesion molecules specifically recognize receptor-like structures of the cell membrane and therefore bind directly to the epithelial cells themselves ("cytoadhesion") rather than to the mucus gel layer. Furthermore, when bioadhesion is receptor-mediated, it is not only restricted to mere binding, but may subsequently trigger the active transport of large molecules or nanoscalic drug carrier systems by vesicular transport processes (endo-/transcytosis). Rather than only acting as a platform for controlled release systems, the concept of lectin-mediated bioadhesion therefore bears the potential for the controlled delivery of macromolecular biopharmaceuticals at relevant biological barriers, such as the epithelia of the intestinal or respiratory tract.     

Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms

Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the “magic bullets” concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know‐how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products.     

Multimodal delivery of irinotecan from microparticles with two distinct compartments

In the last several decades, research in the field of drug delivery has been challenged with the fabrication of carrier systems engineered to deliver therapeutics to the target site with sustained and controlled release kinetics. Herein, we report the fabrication of microparticles composed of two distinct compartments: i) one compartment containing a pH responsive polymer, acetal-modified dextran, and PLGA (polylactide-co-glycolide), and ii) one compartment composed entirely of PLGA. We demonstrate the complete release of dextran from the microparticles during a 10-hour period in an acidic pH environment and the complete degradation of one compartment in less than 24 h. This is in congruence with the stability of the same microparticles in neutral pH over the 24-hour period. Such microparticles can be used as pH responsive carrier systems for drug delivery applications where their cargo will only be released when the optimum pH window is reached. The feasibility of the microparticle system for such an application was confirmed by encapsulating a cancer therapeutic, irinotecan, in the compartment containing the acetal-modified dextran polymer and the pH dependent release over a 5-day period was studied. It was found that upon pH change to an acidic environment, over 50% of the drug was first released at a rapid rate for 10 h, similar to that observed for the dextran release, before continuing at a more controlled rate for 4 days. As such, these microparticles can play an important role in the fabrication of novel drug delivery systems due to the selective, controlled, and pH responsive release of their encapsulated therapeutics.     

Development of a biodegradable nanoparticle platform for sildenafil: formulation optimization by factorial design analysis combined with application of charge-modified branched polyesters

Biodegradable nanoparticles have gained tremendous attraction as carriers for controlled drug delivery to the lung. Despite numerous advances in the field, e.g. development of suitable methods for pulmonary administration of polymeric nanoparticles, a sufficient association of the therapeutic agent with the carrier system as well as drug release in a controlled fashion remain considerable challenges. Hence, this study examines the optimization of biodegradable sildenafil-loaded nanoparticle formulations intended for aerosol treatment of pulmonary hypertension. A factorial design analysis was employed to identify the important experimental factors involved in the preparation of nanoparticles by the solvent evaporation technique. The effect of tailored charge-modified branched polyesters on drug loading and in vitro drug release from nanoparticles was also evaluated. Moreover, colloidal stability of obtained nanoparticles was assessed, and stabilization of nanoparticles by lyophilization was accomplished without additional excipients. Essential experimental factors were identified and optimized to allow the preparation of nanoparticles composed of linear polyesters with a sildenafil content of ~5 wt.%. The in vitro drug release profile from these nanoparticles demonstrated a sustained release of sildenafil over ~90 min. Application of charge-modified branched polyesters enhanced the drug content in nanoparticles and drug release profile, according to the charge-density present in the employed polymer. Accordingly an increase in drug loading by a factor of ~1.4, a prolonged drug release profile from nanoparticles over ~240 min was achieved. Sildenafil release from nanoparticles made of linear and charge-modified branched polyesters was governed by a diffusion process. The obtained drug diffusion coefficients were decreased as the charge-density present in the applied polymer was increased, which promotes the strategy to improve drug loading and release rates by electrostatic interactions between polymer and drug. In addition, nanoparticles showed high colloidal stability in different media of importance for pulmonary application and were successfully stabilized by lyophilization. In conclusion, optimization of the nanoparticle preparation process together with the application of tailored polymeric materials facilitated the synthesis of promising drug carriers for sildenafil that permit a novel treatment modality for severe pulmonary hypertension.     

Critical factors in the release of drugs from sustained release hydrophilic matrices

Hydrophilic matrix systems are one of the most interesting drug delivery systems, and they are currently some of the most widely used to control the release rate of drugs. There are too much factors involved in drug release from hydrophilic matrix systems. The most important factors to be taken into account when developing a formulation based on hydrophilic matrices are the percentage, solubility and drug particle size; the type of polymer, the percentage incorporated, its degree of viscosity and the polymer particle size. Also important are the drug/polymer ratio and the amount of water entering the matrix. Other factors have been shown to be involved in the release of drugs, such as the percentage and mixtures of polymers and the dimensions of the matrix. The compression force is important among the formulation factors to the extent that it determines the amount of air trapped in the matrix. Knowledge of these factors involved in the release of the drugs is crucial for the optimal development of formulations based on hydrophilic systems.     

Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres.

A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to release from polydisperse microspheres. Each of the model drugs exhibited different release mechanisms. Drug distribution within the polymer was investigated by laser scanning confocal microscopy and scanning electron microscopy. Rhodamine, the most hydrophilic compound investigated, was localized strongly toward the microsphere surface, while the much more hydrophobic compound, piroxicam, distributed more evenly. Furthermore, all three compounds were most uniformly distributed in the smallest microspheres, most likely due to the competing effects of drug diffusion out of the nascent polymer droplets and the precipitation of polymer upon solvent extraction, which effectively "traps" the drug in the polymer matrix. The differing drug distributions were manifested in the drug release profiles. Rhodamine was released very quickly independent of microsphere size. Thus, extended release profiles may not be obtainable if the drug strongly redistributes in the microspheres. The release of p-nitroaniline was more prolonged, but still showed little dependence on microsphere size. Hence, when water-soluble drugs are encapsulated with hydrophobic polymers, it may be difficult to tailor release profiles by controlling microsphere size. The piroxicam-loaded microspheres exhibit the most interesting release profiles, showing that release duration can be increased by decreasing microsphere size, resulting in a more uniform drug distribution.     

Uptake and release of budesonide from mucoadhesive, pH-sensitive copolymers and their application to nasal delivery.

Microparticles of novel, bioadhesive graft copolymers of polymethacrylic acid and polyethylene glycol (P(MAA-g-EG)) were prepared. The aims of this study were to investigate the uptake and release kinetics of budesonide from P(MAA-g-EG) in vitro as well as the pharmacokinetics following nasal administration of the polymer contained budesonide. The loading of budesonide into the pH-sensitive polymers was examined using various ethanol solutions. Ethanol was required for drug solubilization but hindered hydrogel swelling at pH 7.2. Maximum loading of the drug in the polymer was obtained using 25% ethanol solutions. The release of budesonide from the polymer swollen in 25% ethanol solutions obeyed classical Fickian release behavior after an initial rapid drug burst. For nasal administration of budesonide-containing P(MAA-g-EG) the plasma concentration of budesonide was kept constant following a peak concentration of the drug approximately 45 min after administration.     

Micelle-like nanoparticles of star-branched PEO-PLA copolymers as chemotherapeutic carrier.

Four-armed (star-branched) block copolymers of l-PLA and PEO were synthesized using ring opening polymerization with different LA/EO ratio. Micellar aggregates were prepared from these block copolymers and characterized. Some surface segregation of PEG was found : the extent depends on the state of the material (whether it is in film or particle form), as well as on molecular geometry. The degradation behavior of star-shaped copolymer was studied over a three week period and compared to its linear counterpart. Anti-cancer drugs 5-FU and paclitaxel were loaded into the micellar nanoparticles. The drug release profile showed that the release of paclitaxel from these polymers could be controlled over 2 weeks. The kinetics of drug release for star-branched, tri- and di-block copolymers were compared. The micelles from star-shaped branch showed more complete release of drug than the diblock copolymers; also, the lower hydrodynamic radius of star-shaped polymers may result in better clearance of the carrier polymer from the body.     

壳聚糖以及其他生物材料作为胰岛素载体的释药性能特征

目的:探讨壳聚糖作为胰岛素载体的释药特性,展望高分子材料在胰岛素载体中的应用.方法:以胰岛素,载体,壳聚糖,脂质体,聚合物为检索词,检索中国期刊全文数据库(1999-01/2009-06);以insulin,carriers, chitosan,liposomes,polymer为检索词,检索Pubmed数据库(1999-01/2009-06),文献检索语种限制为中文和英文.以药物生物利用度、药物包埋率、药物的释放率为评价指标,纳入壳聚糖及其他生物材料作为口服胰岛素载体的研究,排除注射给药及其他给药方式的研究.结果:计算机初检得到543篇文献,根据纳入排除标准,对壳聚糖及其他生物材料作为胰岛素载体的释药特性进行分析.壳聚糖及其衍生物纳米粒作为胰岛素给药系统的研究备受关注.它在黏膜给药系统中表现出独特的纳米效应,不但可以改变药物的动力学,而且可以延长在黏膜内的滞留时间,改变膜转运机制,增加药物对膜的通透性,有效地克服了酶等生物屏障,解决了胰岛素在体内易失活及半衰期短等问题.近年来,胰岛素载体的释药性研究已经取得了一些进展,但面临的困难仍然很多,主要是包封率较低,吸收有限,而且制剂质量方法不成熟,剂量较难控制,成本较高,以及对吸收部位的损坏乃至可能对人体脏器功能带来影响.随着许多新性能高分子材料的涌现以及医药制剂工业的迅猛发展,高分子载体被越来越广泛地应用于新药的研究与开发中.结论:生物相容性、生物可降解性是选择胰岛素载药体系时需要首先考虑的问题.胰岛素载体的合成,胰岛素与载体的联接方式,间隔基对释放药物性能的影响,载体结构与单克隆抗体特异性的关系对胰岛素载体的释药性有决定性的影响.     

Sequential release kinetics of two (gentamicin and BMP-2) or three (gentamicin, IGF-I and BMP-2) substances from a one-component polymeric coating on implants

The local application of antibiotics in combination with timely controlled growth factor delivery might be beneficial for the prevention of infections and to stimulate bone healing. Therefore, in this study a variable sequential drug delivery system with three distinctly different release profiles was developed: i) a burst release of gentamicin, ii) a burst release of IGF-I followed by a sustained release, and iii) a slow sustained release of BMP-2 out of an implant coating. Only one polymer [poly(D,L-lactide)], incorporating gentamicin, IGF-I or BMP-2, was used for two- or three-layer coatings of K-wires. To control the release kinetics, the polymer concentrations in the solvent were varied. The activity of early released gentamicin from a two-layer coating was confirmed microbiologically and BMP-2 stimulated the metabolic activity and alkaline phosphatase activity of C2C12 cells after 2 weeks. From the three-layer coated wires, IGF-I continuously stimulated the cell proliferation, whereas BMP-2 enhanced ALP between 1 and 3 weeks. The sequential release of growth factors revealed an additive effect on the metabolic activity and ALP of primary osteoblast-like cells compared to the single coated controls. The controlled delivery of different factors from one implant might prevent infections and subsequently stimulate the different phases of bone healing.