Branched biodegradable polyesters for parenteral drug delivery systems.

Continuous, 'infusion-like' drug release profiles from biodegradable parenteral delivery systems are difficult to achieve for proteins and other hydrophilic macromolecular drugs with commonly used linear polyesters from lactic acid (PLA) and its random copolymers with glycolic acid (PLG). Drug release rates can be modified either by increasing the hydrophilicity of polyesters or by manipulating the polymer architecture to adjust polymer degradation rates and thus drug release. Therefore, we investigated different branching concepts for biodegradable polyesters of PLA and PLG. For one four- and eight-arm poly(ethylene oxide)s (PEO) were grafted with shorter polyester chains leading to star-branched structures. Secondly we obtained comb-like polyesters using both charged and uncharged dextrans or poly(vinyl alcohol)s (PVA) as hydrophilic backbones. The star-shaped and brush-like grafted polymers were intensively characterized by methods, such as NMR, IR, SEC-SLS, DSC and viscosity measurements. Tailor-made properties make these novel biodegradable polyesters promising candidates for parenteral protein delivery systems. While the star-branched polyesters have shown some interesting properties with respect to their degradation behavior, retaining the PEO blocks longer than ABA triblock copolymers, their release properties need further optimization. Brush-like branched polyesters on the other hand seem to possess both degradation and release properties meriting further investigations for parenteral protein delivery systems.     

Drug permeability of modified silicone polymers. III. Hydrophilic pressure-sensitive adhesives for transdermal controlled drug release applications

A new class of hydrophilic silicone/organic pressure-sensitive adhesives (PSAs) was formulated from polydimethylsiloxane-poly(ethylene oxide) graft copolymers and silicone resins. The following effects of the structure of the graft copolymers and silicone resins on the adhesion and the drug permeability were investigated: (a) the size and the degree of the grafting, (b) the degree of polymerization of the polysiloxane and (c) the loading level and molecular weight of the silicone resin. It was demonstrated that a number of therapeutic agents could be incorporated into the PSAs without compromising their functional adhesive tape properties. The PSAs not only had excellent drug permeabilities but also retained their adhesion upon aging, thus permitting their use in transdermal controlled drug release applications. This family of PSAs has a distinct advantage over other PSAs because it also enhanced the release rates of hydrophilic drugs.     

Model prodrugs for the intestinal oligopeptide transporter: model drug release in aqueous solution and in various biological media.

The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a target for increasing intestinal transport of low permeability compounds by creating prodrugs designed for the transporter. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for benzyl alcohol have been shown to have affinity for hPepT1. Furthermore, in aqueous solution at pH 5.5 to 10, the release of the model drug seems to be controlled by a specific base-catalyzed hydrolysis, indicating that the compounds may remain relatively stable in the upper small intestinal lumen with a pH of approximately 6.0, but still release the model drug at the intercellular and blood pH of approximately 7.4. Even though benzyl alcohol is not a low molecular weight drug molecule, these results indicate that the dipeptide prodrug principle is a promising drug delivery concept. However, the physico-chemical properties such as electronegativity, solubility, and log P of the drug molecule may also have an influence on the potential of these kinds of prodrugs. The purpose of the present study is to investigate whether the model drug electronegativity, estimated as Taft substitution parameter (sigma*) may influence the acid, water or base catalyzed model drug release rates, when released from series of D-Glu-Ala and D-Asp-Ala pro-moieties. Release rates were investigated in both aqueous solutions with varying pH, ionic strength, and buffer concentrations as well as in in vitro biological media. The release rates of all the investigated model drug molecules followed first-order kinetics and were dependent on buffer concentration, pH, ionic strength, and model drug electronegativity. The electronegativity of the model drug influenced acid, water and base catalyzed release from D-Asp-Ala and D-Glu-Ala pro-moieties. The model drug was generally released faster from D-Asp-Ala- than from the D-Glu-Ala pro-moieties. In biological media the release rate was also dependent on the electronegativity of the model drug. These results demonstrate that the model drug electronegativity, estimated as Taft (sigma*) values, has a significant influence on the release rate of the model drug.     

Micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine A.

The commercial formulation of Cyclosporine A (CsA) for intravenous administration contains Cremophor EL, a low molecular weight surfactant known to be toxic. In this study, micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) were investigated as alternative vehicles for the solubilization and delivery of CsA. PEO-b-PCL block copolymers having identical PEO chain lengths and PCL molecular weights of 5000, 13,000, or 24,000 g mol(-)(1) were synthesized and assembled into polymeric micelles using a co-solvent evaporation method. PEO-b-PCL micelles were then compared to Cremophor EL micelles for their functional properties in drug delivery including micellar size, thermodynamic stability, core viscosity, CsA encapsulation, and in vitro CsA release. Among different PCL block lengths, optimum solubilization was achieved by utilizing polymeric micelles having a PCL block of 13,000 g mol(-)(1). CsA reached an aqueous solubility of 1.3 mg/mL in the presence of PEO-b-PCL micelles. This concentration is comparable to injectable CsA levels in its Cremophor EL formulation (0.5-2.5 mg/mL). In contrast to the Cremophor EL formulation, the in vitro rate of CsA release was significantly sustained by the polymeric micellar carrier. Within 12 h, only 5.8% of CsA was released from polymeric micelles while Cremophor EL micelles released 77% of their drug content. Accordingly, viscosity of the PEO-b-PCL micellar core was found to be significantly higher than Cremophor EL micelles. The results points to a potential for PEO-b-PCL micelles as nanoscopic drug carriers for efficient solubilization and controlled delivery of CsA.     

Brush-like branched biodegradable polyesters, part III. Protein release from microspheres of poly(vinyl alcohol)-graft-poly(D,L-lactic-co-glycolic acid).

Brush-like branched polyesters, obtained by grafting poly(lactic-co-glycolic acid), PLGA, onto water-soluble poly(vinyl alcohol) (PVAL) backbones, were investigated regarding their utility for the microencapsulation of proteins. Poly(vinyl alcohol)-graft-poly(lactic-co-glycolic acid), PVAL-g-PLGA, offers additional degrees of freedom to manipulate properties such as e.g. molecular weight, glass transition temperature and hydrophilicity. PLGA chain length was varied at a constant molecular weight (M(w)) of the PVAL backbone and secondly M(w) of the PVAL backbone was varied keeping the PLGA chain lengths constant. The most striking feature of these polymers is their high M(w). Microencapsulation of hydrophilic macromolecules, such as bovine serum albumin, ovalbumin, cytochrome c and FITC-dextran using a w/o/w double emulsion technique was investigated. Surface morphology, particle size, encapsulation efficiencies and protein release profiles were characterized as well. Microencapsulation of model compounds was feasible at temperatures of 0-4 degrees C with yields typically in the range of 60-85% and encapsulation efficiencies of 70-90%. Both, encapsulation efficiency and initial protein release (drug burst) were strongly affected by the glass transition temperature, T(g), of the polymer in contact with water, whereas the in vitro protein release profile depended on the PVAL-g-PLGA structure and composition. In contrast to PLGA, protein release patterns were mostly continuous with lower initial drug bursts. Shorter PLGA chains increased drug release in the erosion phase, whereas initial pore diffusion was affected by the M(w) of PVAL backbone. Release profiles from 2 to 12 weeks could be attained by modification of composition and molecular weight of PVAL-g-PLGA and merit further investigations under in vivo conditions. The in vitro cytotoxicity of PVAL-g-PLGA is comparable to PLGA and therefore, this new class of biodegradable polyesters has considerable potential for parenteral drug delivery systems.     

Design of a novel hydrogel-based intelligent system for controlled drug release.

The present work focused on the design of an assembled drug delivery system (DDS) to provide multifunctions, such as drug protection, self-regulated oscillatory release, and targeted uni-directional delivery by a bilayered self-folding gate and simple surface mucoadhesion. In this device, a pH-sensitive hydrogel together with a poly(hydroxyethyl methacrylate) (HEMA) barrier was used as a gate to control drug release. In addition, poly(HEMA) coated with poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO) surfactant was utilized to enhance mucoadhesion on the device surface. The release profiles of two model drugs, acid orange 8 (AO8) and bovine serum albumin (BSA) were studied in this assembled system, which compared with the conventional drug-entrapped carriers and enteric-coating systems. Furthermore, targeted uni-directional release was demonstrated in a side-by-side diffusion cell. In conclusion, for such an assembled device, the poly(HEMA) layer not only affects the folding direction but also serves as a barrier to protect the model drugs. The release time can be controlled by the thickness of the bilayered gate and the drug reservoir. Due to the reversible swelling behavior of poly(methyacrylic acid-g-ethylene glycol) (p(MAA-g-EG)) gels, the bilayered gate can sense the environmental pH change and achieve an oscillatory release pattern. Moreover, the local targeting and uni-directional release have been successfully demonstrated in vitro.     

磁性聚乳酸-羟基乙酸氧化酚砷纳米微粒的制备及其特性

背景:基于纳米技术发展起来的纳米载体介导的磁性载药系统,在外加磁场作用下,能实现位点特异性靶向给药的目的,有利于提高病灶部位的局部药物浓度,从而进一步提高治疗效果,减少全身毒副作用.目的:研究磁性聚乳酸-羟基乙酸氧化酚砷纳米微粒的制备工艺,评价纳米粒子特性.设计:首先选择几个可能影响纳米微粒特性的因素进行了单因素实验,然后再根据实验结果,结合统计学中的正交设计,获得了最佳优化处方.单位:解放军第二军医大学长海医院特诊科.材料:实验于2005-01/2006-03在解放军第二军医大学药学院药剂教研室完成.实验用氧化酚砷购自美国Sigma公司,聚乳酸-羟基乙酸由山东医疗器械研究所提供,纳米级四氧化三铁购自美国Sigma公司,聚乙烯醇购自北京有机化工厂,二氯甲烷等其他试剂均为分析纯,购于上海国药集团化学试剂有限公司.方法:运用超声乳化-溶剂挥发法制备磁性聚乳酸-羟基乙酸氧化酚砷纳米微粒,通过透射电镜观察微粒形态,振动样品磁强计确证纳米微粒磁性的存在,激光粒径仪测定纳米粒的粒径大小和分布,高效液相法测定氧化酚砷的载药量及包封率,并计算氧化酚砷体外释放百分率.主要观察指标:磁性聚乳酸-羟基乙酸氧化酚砷纳米微粒的形态、粒径、载药量、包封率、磁性及体外释放情况.结果:①微粒包封率和载药量:实验制备的纳米粒平均包封率为34.2%;5批纳米粒载药量分别为3.06%,3.15%,3.18%,3.21%,3.41%,平均载药量为3.20%,批间差异较小,说明工艺稳定性、重现性好.②微粒形态:纳米微粒呈圆形,表面光滑,分布均匀,不粘连,磁性微球中可见非均匀分散的黑色不透光区,为四氧化三铁微粒.③微粒粒径:分布范围窄(140～500 nm),平均290 nm.④微粒磁性:在不断改变外加磁场的大小与方向的情况下,微粒具有不同的磁化强度,说明氧化酚砷聚乳酸纳米微粒具有一定的磁响应性.⑤体外释放实验:氧化酚砷经过最初的快速释放后,进入缓慢控释阶段,于第8天时达到最终基本稳定的平台期.结论:实验获得了较满意的磁性聚乳酸-羟基乙酸氧化酚砷纳米微粒制备工艺;该纳米微粒在外加磁场的情况下有较好磁靶向性的作用,同时具备良好药物缓释作用.     

Doxorubicin-loaded poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance.

Doxorubicin (DOX) was physically loaded into micelles prepared from poly(ethylene glycol)-poly(beta-benzyl-L-aspartate) block copolymer (PEG-PBLA) by an o/w emulsion method with a substantial drug loading level (15 to 20 w/w%). DOX-loaded micelles were narrowly distributed in size with diameters of approximately 50-70 nm. Dimer derivatives of DOX as well as DOX itself were revealed to be entrapped in the micelle, the former seems to improve micelle stability due to its low water solubility and possible interaction with benzyl residues of PBLA segments through pi-pi stacking. Release of DOX compounds from the micelles proceeded in two stages: an initial rapid release was followed by a stage of slow and long-lasting release of DOX. Acceleration of DOX release can be obtained by lowering the surrounding pH from 7.4 to 5.0, suggesting a pH-sensitive release of DOX from the micelles. A remarkable improvement in blood circulation of DOX was achieved by use of PEG-PBLA micelle as a carrier presumably due to the reduced reticuloendothelial system uptake of the micelles through a steric stabilization mechanism. Finally, DOX loaded in the micelle showed a considerably higher antitumor activity compared to free DOX against mouse C26 tumor by i.v. injection, indicating a promising feature for PEG-PBLA micelle as a long-circulating carrier system useful in modulated drug delivery.     

The use of FT-IR imaging as an analytical tool for the characterization of drug delivery systems.

FT-IR imaging spectroscopy is well suited for studying dynamic processes occurring in multi-component systems. Each component is resolved spatially based on the spectral response at each detector element. Additionally, the sequential collection of images tracks the movement of each component over time. In this study, the delivery characteristics of the drug, testosterone, suspended in a poly(ethylene oxide) (PEO) matrix was observed using this technique. Drug release occurred as the hydrophilic, erodible polymer underwent controlled dissolution, exposing the drug to the aqueous environment. The subsequent conversion of the drug into the therapeutic aqueous form completed the delivery process. Qualitative evaluation of the false color composite infrared images led to the elucidation of two distinct delivery mechanisms, dependent on the degree of drug loading. The spatially embedded spectral features led to the quantification of the drug release rates as well as the rates of polymer dissolution. The rates for both polymer dissolution and drug release were evaluated using well-established models. Additionally, the homogeneity of the drug dispersion for different loadings was characterized. The roles of chemical interactions across the solvent interface of species were also investigated. Changes in each component from the bulk to the solvated region were investigated, revealing changes in concentration and polymer orientation as well as inter-species interactions.     

Understanding drug release from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels.

Experimental and mathematical studies were performed to understand the release mechanism of small molecular weight compounds from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) polymer gels (trademarked Pluronic by BASF Corp.) of various concentrations. Studies of the diffusion coefficient of solutes in the polymer gels were performed using a novel technique to predict movement of drugs within the gel as release occurs. Studies were also performed to determine the diffusion coefficient of water in the polymer gel, as it is this parameter that controls the dissolution rate of the polymer, and in turn, the drug release rate. A model was formulated and solved numerically to determine the controlling release mechanism. By parameter modification, this algorithm for determining the overall mass of drug released from a drug loaded gel can be used for a number of drugs and for a wide range of initial polymer concentrations. Drug release data were obtained with a novel experimental setup and were used to verify the accuracy of the overall solution of the model. The results of the model indicate that although the rate of polymer dissolution ultimately controls the drug release, about 5% of the release is due to diffusion at the gel/liquid interface, giving rise to a slightly non-linear release. It was also found that agitation speed greatly affects the dissolution rates of these polymer gels.     

Novel design of microreservoir-dispersed matrices for drug delivery formulations: Regulative drug release from poly(ethylene oxide)- and poly(tetramethylene oxide)-based segmented polyurethanes

Drug release from the monolithic devices of segmented polyether-poly(urethane-urea) (PEUU)s based on both poly (tetramethylene oxide) (PTMO) and poly (ethylene oxide) (PEO) as their soft segments were thoroughly investigated in terms of the relationship between their microdomain structure and the drug release profiles. These PEUUs exhibited diverse microdomain structure depending upon the differences in the solubility parameter of constituting segments and their weight fractions in the polymers. The drug release profiles of these PEUUs were closely connected with the mode of microdomain structure composed of the PTMO, PEO, and hard segments. That is, the formation of distinct microdomains of the PTMO and hard segments dispersed in the PEO matrices allowed the definite regulation of both release rate and transport mode of drug release in the monolithic devices of highly water-swollen PEUUs. These results indicate that the design consisting of microdomains has distinct function as a drug reservoir and transport channel and is a promising way for regulating the release profile of drugs with a variation of solubility parameters from highly water swollen polymeric formulations.     

Polymeric micellar pH-sensitive drug delivery system for doxorubicin.

A novel polymeric micellar pH-sensitive system for delivery of doxorubicin (DOX) is described. Polymeric micelles were prepared by self-assembly of amphiphilic diblock copolymers in aqueous solutions. The copolymers consist of a biocompatible hydrophilic poly(ethylene oxide) (PEO) block and a hydrophobic block containing covalently bound anthracycline antibiotic DOX. The starting block copolymers poly(ethylene oxide)-block-poly(allyl glycidyl ether) (PEO-PAGE) with a very narrow molecular weight distribution (Mw/Mn ca. 1.05) were prepared by anionic ring opening polymerization using sodium salt of poly(ethylene oxide) monomethyl ether as macroinitiator and allyl glycidyl ether as functional monomer. The copolymers were covalently modified via reactive double bonds by the addition of methyl sulfanylacetate. The resulting ester subsequently reacted with hydrazine hydrate yielding polymer hydrazide. The hydrazide was coupled with DOX yielding pH-sensitive hydrazone bonds between the drug and carrier. The resulting conjugate containing ca. 3 wt.% DOX forms micelles with Rh(a)=104 nm in phosphate-buffered saline. After incubation in buffers at 37 degrees C DOX was released faster at pH 5.0 (close to pH in endosomes; 43% DOX released within 24 h) than at pH 7.4 (pH of blood plasma; 16% DOX released within 24 h). Cleavage of hydrazone bonds between DOX and carrier continues even after plateau in the DOX release from micelles incubated in aqueous solutions is reached.     

Folate-conjugated methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery.

Amphiphilic block copolymers composed of methoxy poly(ethylene glycol) (MPEG) and poly(epsilon-caprolactone) (PCL) were synthesized and then conjugated with folic acid to produce a folate-receptor-targeted drug carrier for tumor-specific drug delivery. Folate-conjugated MPEG/PCL micelles containing the anticancer drug paclitaxel were prepared by micelle formation in aqueous medium. The size of the folate-conjugated MPEG/PCL micelles formed was about 50-130 nm, depending on the molecular weight of block copolymers, and was maintained at less than 150 nm even after loading with paclitaxel. The in vitro release profile of the paclitaxel from the MPEG/PCL micelles exhibited no initial burst release and showed sustained release. Paclitaxel-loaded folate-conjugated MPEG/PCL micelles (PFOL50) exhibited much higher cytotoxicity for cancer cells, such as MCF-7 and HeLa cells, than MPEG/PCL micelles without the folate group (PMEP50). Confocal image analysis revealed that fluorescent paclitaxel-loaded PFOL50 micelles were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells.     

Multimodal imaging of sustained drug release from 3-D poly(propylene fumarate) (PPF) scaffolds

The potential of poly(propylene fumarate) (PPF) scaffolds as drug carriers was investigated and the kinetics of the drug release quantified using magnetic resonance imaging (MRI) and optical imaging. Three different MR contrast agents were used for coating PPF scaffolds. Initially, iron oxide (IONP) or manganese oxide nanoparticles (MONP) carrying the anti-cancer drug doxorubicin were absorbed or mixed with the scaffold and their release into solution at physiological conditions was measured with MRI and optical imaging. A slow (hours to days) and functional release of the drug molecules into the surrounding solution was observed. In order to examine the release properties of proteins and polypeptides, protamine sulfate, a chemical exchange saturation transfer (CEST) MR contrast agent, was attached to the scaffold. Protamine sulfate showed a steady release rate for the first 24 h. Due to its biocompatibility, versatile drug-loading capability and constant release rate, the porous PPF scaffold has potential in various biomedical applications, including MR-guided implantation of drug-dispensing materials, development of drug carrying vehicles, and drug delivery for tumor treatment.     

Microspheres for controlled release drug delivery

Controlled release drug delivery employs drug-encapsulating devices from which therapeutic agents may be released at controlled rates for long periods of time, ranging from days to months. Such systems offer numerous advantages over traditional methods of drug delivery, including tailoring of drug release rates, protection of fragile drugs and increased patient comfort and compliance. Polymeric microspheres are ideal vehicles for many controlled delivery applications due to their ability to encapsulate a variety of drugs, biocompatibility, high bioavailability and sustained drug release characteristics. Research discussed in this review is focused on improving large-scale manufacturing, maintaining drug stability and enhancing control of drug release rates. This paper describes methods of microparticle fabrication and the major factors controlling the release rates of encapsulated drugs. Furthermore, recent advances in the use of polymer microsphere-based systems for delivery of single-shot vaccines, plasmid DNA and therapeutic proteins are discussed, as well as some future directions of microsphere research.     

Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV

The development of topical anti-human immunodeficiency virus (HIV) microbicides may provide women with strategies to protect themselves against sexual HIV transmission. Pericoital drug delivery systems intended for use immediately before sex, such as microbicide gels, must deliver high drug doses for maximal effectiveness. The goal of achieving a high antiretroviral dose is complicated by the need to simultaneously retain the dose and quickly release drug compounds into the tissue. For drugs with limited solubility in vaginal gels, increasing the gel volume to increase the dose can result in leakage. While solid dosage forms like films and tablets increase retention, they often require more than 15 min to fully dissolve, potentially increasing the risk of inducing epithelial abrasions during sex. Here, we demonstrate that water-soluble electrospun fibers, with their high surface area-to-volume ratio and ability to disperse antiretrovirals, can serve as an alternative solid dosage form for microbicides requiring both high drug loading and rapid hydration. We formulated maraviroc at up to 28 wt% into electrospun solid dispersions made from either polyvinylpyrrolidone or poly(ethylene oxide) nanofibers or microfibers and investigated the role of drug loading, distribution, and crystallinity in determining drug release rates into aqueous media. We show here that water-soluble electrospun materials can rapidly release maraviroc upon contact with moisture and that drug delivery is faster (less than 6 min under sink conditions) when maraviroc is electrospun in polyvinylpyrrolidone fibers containing an excipient wetting agent. These materials offer an alternative dosage form to current pericoital microbicides.     

Enzymatically in situ shell cross-linked micelles composed of 4-arm PPO–PEO and heparin for controlled dual drug delivery

We report a controlled dual drug delivery system using heparinized 4-arm poly(propylene oxide) (PPO)–poly(ethylene oxide) (PEO) micelles (cHTM) that are sterically stabilized by enzymatic shell cross-linking (SCL). Tyramine (TA) was chemically conjugated to 4-arm PPO–PEO (Tetronic) and heparin, resulting in Tetronic–TA (Tet–TA) and heparin–TA (Hep–TA), respectively. To prepare a series of cHTM, different amounts of Hep–TA were added to a micellar solution of Tet–TA, followed by addition of horseradish peroxidase (HRP) and hydrogen peroxide (H₂O₂) to trigger SCL between TA groups at the micellar surfaces. Increasing the feed amount of Hep–TA led to increased heparin content of cHTM, thereby resulting in increased micelle size with more negatively charged surfaces. All SCL micelles were found to be highly stable over 4 weeks, showing negligible changes in their sizes and zeta potentials. Dual drug-loaded cHTM containing indomethacin (IMC) and basic fibroblast growth factor (bFGF) were prepared via a one-pot procedure. With favorable IMC loading, the loading efficiencies of bFGF into cHTM were much higher than those in the controls due to the presence of heparin on the micellar surface. After bFGF was added to IMC loaded cHTM the surface of HTM became less negative with an increase in size, suggesting successful binding of positively charged bFGF to heparinized micelle surfaces. In vitro release data clearly showed more sustained release of IMC and bFGF as compared with non-cross-linked micelles. Based on these results, we suggest that cHTM can be used as a new drug delivery platform for controlled dual drug release.     

Formulation aspects in the development of osmotically controlled oral drug delivery systems.

Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active agent(s). Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. The release of drug(s) from osmotic systems is governed by various formulation factors such as solubility and osmotic pressure of the core component(s), size of the delivery orifice, and nature of the rate-controlling membrane. By optimizing formulation and processing factors, it is possible to develop osmotic systems to deliver drugs of diverse nature at a pre-programmed rate. In the present review, different types of oral osmotic systems, various aspects governing drug release from these systems, and critical formulation factors are discussed.     

Dipeptide model prodrugs for the intestinal oligopeptide transporter. Affinity for and transport via hPepT1 in the human intestinal Caco-2 cell line.

The human intestinal di/tri-peptide carrier, hPepT1, has been suggested as a drug delivery target via increasing the intestinal transport of low permeability compounds by designing peptidomimetic prodrugs. Model ester prodrugs using the stabilized dipeptides D-Glu-Ala and D-Asp-Ala as pro-moieties for benzyl alcohol have been shown to maintain affinity for hPepT1. The primary aim of the present study was to investigate if modifications of the benzyl alcohol model drug influence the corresponding D-Glu-Ala and D-Asp-Ala model prodrugs' affinity for hPepT1 in Caco-2 cells. A second aim was to investigate the transepithelial transport and hydrolysis parameters for D-Asp(BnO)-Ala and D-Glu(BnO)-Ala across Caco-2 cell monolayers. In the present study, all investigated D-Asp-Ala and D-Glu-Ala model prodrugs retained various degrees of affinity for hPepT1 in Caco-2 cells. These affinities are used to establish a QSAR of our benzyl alcohol modified model prodrugs, aided at elucidating the observed differences in model prodrug affinity for hPepT1; additionally, these data suggest that the hydrophobicity of the side-chain model drug is the major determinant in the compounds affinity for hPepT1. Transepithelial transport studies performed using Caco-2 cells of D-Asp(BnO)-Ala and D-Glu(BnO)-Ala showed that the K(m) for transepithelial transport was not significantly different for the two compounds. The maximal transport rate of the carrier-mediated flux component does not differ between the two model prodrugs either. The transepithelial transport of D-Asp(BnO)-Ala and D-Glu(BnO)-Ala follows simple kinetics, and the release of benzyl alcohol is pH-dependent, but unaffected by 1 mM of the esterase inhibitor Paraoxon in 80% human plasma and Caco-2 cell homogenate.     

Dual release kinetics in a single dosage from core–shell hydrogel scaffolds

The development of drug delivery systems with microencapsulated therapeutic agents is a promising approach to the sustained and controlled delivery of various drug molecules. The incorporation of dual release kinetics to such delivery devices further adds to their applicability. Herein, novel core–shell scaffolds composed of sodium deoxycholate and trishydroxymethylaminomethane (NaDC–Tris) have been developed with the aim of delivering two different drugs with variable release rates using the same delivery vehicle. Data obtained from XRD studies, sol–gel transition temperature measurement, rheology and fluorescence studies of the core–shell systems indicate a significant alteration in the core and the shell microstructural properties in a given system as compared to the pure hydrogels of identical compositions. The release of the model drugs Fluorescein (FL) and Rhodamine B (RhB) from the shell and the core, respectively, of the two core–shell designs studied exhibited distinctly different release kinetics. In the 25@250 core–shell system, 100% release of FL from the shell and 19% release of RhB from the core was observed within the first 5 hours, while 24.5 hours was required for the complete release of RhB from the core. For the 100@250 system, similar behaviour was observed with varied release rates and a sigmoidal increase in the core release rate upon disappearance from the shell. Cell viability studies suggested the minimal toxicity of the developed delivery vehicles towards NMuMG and WI-38 cells in the concentration range investigated. The reported core–shell systems composed of a single low molecular weight gelator with dual release kinetics may be designed as per the desired application for the consecutive release of therapeutic agents as required, as well as combination therapy commonly used to treat diseases such as diabetes and cancer.

A single LMW gelator based core–shell hydrogel with dual release kinetics.