Micromachined devices: the impact of controlled geometry from cell-targeting to bioavailability.

Advances in microelectomechanical systems (MEMS) have allowed the microfabrication of polymeric substrates and the development of a novel class of controlled delivery devices. These vehicles have specifically tailored three-dimensional physical and chemical features which, together, provide the capacity to target cells, promote unidirectional controlled release, and enhance permeation across the intestinal epithelial barrier. Examining the biological response at the microdevice biointerface may provide insight into the benefits of customized surface chemistry and structure in terms of complex drug delivery vehicle design. Therefore, the aim of this work was to determine the interfacial effects of selective surface chemistry and architecture of tomato lectin (TL)-modified poly(methyl methacrylate) (PMMA) drug delivery microdevices on the Caco-2 cell line, a model of the gastrointestinal tract.     

Bioadhesive microdevices with multiple reservoirs: a new platform for oral drug delivery.

A variety of delivery systems have been devised, in recent years, to improve the oral bioavailability of drugs including enterically coated tablets, capsules, particles, and liposomes. Microfabrication technology may offer some potential advantages over conventional drug delivery technologies. This technology, combined with appropriate surface chemistry, may permit the highly localized and unidirectional release of drugs, permeation enhancers, and/or promoters. In this study, we demonstrate the fabrication of prototype reservoir-containing microdevices and a surface chemistry protocol that can be used to bind lectin via avidin-biotin interactions to these micromachined drug delivery vehicles. The use of microfabrication allows one to tailor the size, shape, reservoir volume, and surface characteristics of the drug delivery vehicle. In vitro studies show enhanced bioadhesion of these lectin conjugated silicon microdevices. This approach may be used to improve the absorption of pharmacologically active biopolymers such as peptides, proteins and oligonucleotides into circulation at targeted sites in the GI system via the creation of a robust hybrid organic/inorganic delivery system. This paper describes one of the first applications of microfabrication to oral drug delivery.     

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.     

Surface modifications and molecular imprinting of polymers in medical and pharmaceutical applications.

Recent developments in the field of biomaterials are based on molecular design of polymers with improved surface and bulk properties. Novel techniques of surface modification by addition of tethered chains can lead to materials with the ability to recognize biological and pharmaceutical compounds. Methods based on molecular imprinting can increase the recognition capabilities of such systems. Chain tethering can also can improve the mucoadhesive behavior of a delivery device and the effectiveness of a drug by allowing targeting and localization of a drug at a specific site. Acrylic-based hydrogels are well-suited for mucoadhesion due to their flexibility and nonabrasive characteristics which reduce damage-causing attrition to the tissues in contact. However, the adhesive and drug delivery capabilities of these devices can continue to be improved as presently known bioadhesive materials are modified and more bioadhesive materials are discovered. Tethering of long PEG chains on PAA hydrogels and their copolymers can be achieved by grafting reactions involving thionyl chloride, followed by PEG grafting. The ensuing materials exhibit mucoadhesive properties due to enhanced anchoring of the chains with the mucosa. Theoretical calculations can lead to optimization of the tethered structure.     

应用生物可降解材料玉米醇溶蛋白制备胃肠道生物黏附控释片

背景:胃肠道生物黏附控释制剂能延长药物制剂在胃肠道的停留时间,提高药物的生物利用度。目的:制备5-氟尿嘧啶胃肠道生物黏附控释片。方法:利用生物可降解性玉米醇溶蛋白为骨架材料和黏附材料,氟尿嘧啶为模型药,制备氟尿嘧啶胃肠道黏附控释片。对片芯工艺进行正交设计,优化包衣液的选择,观察生物黏附缓释片的体外黏附力及体内外相关性。结果与结论:5-氟尿嘧啶玉米醇溶蛋白生物黏附片体外释放10h内均符合零级释放特征,片剂具有较好的体外黏附力,且在2～8h内体内血药浓度较为平稳,没有明显峰谷现象,体内外释放吸收具有良好的相关性。     

应用生物可降解材料玉米醇溶蛋白制备胃肠道生物黏附控释片

背景：胃肠道生物黏附控释制剂能延长药物制剂在胃肠道的停留时间,提高药物的生物利用度。目的：制备5-氟尿嘧啶胃肠道生物黏附控释片。方法：利用生物可降解性玉米醇溶蛋白为骨架材料和黏附材料,氟尿嘧啶为模型药,制备氟尿嘧啶胃肠道黏附控释片。对片芯工艺进行正交设计,优化包衣液的选择,观察生物黏附缓释片的体外黏附力及体内外相关性。结果与结论：5-氟尿嘧啶玉米醇溶蛋白生物黏附片体外释放10h内均符合零级释放特征,片剂具有较好的体外黏附力,且在2～8h内体内血药浓度较为平稳,没有明显峰谷现象,体内外释放吸收具有良好的相关性。     

Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach.

Peptides and proteins remain poorly bioavailable upon oral administration. One of the most promising strategies to improve their oral delivery relies on their association with colloidal carriers, e.g. polymeric nanoparticles, stable in gastrointestinal tract, protective for encapsulated substances and able to modulate physicochemical characteristics, drug release and biological behavior. The mechanisms of transport of these nanoparticles across intestinal mucosa are reviewed. In particular, the influence of size and surface properties on their non-specific uptake or their targeted uptake by enterocytes and/or M cells is discussed. Enhancement of their uptake by appropriate cells, i.e. M cells by (i) modeling surface properties to optimize access to and transport by M cells (ii) identifying surface markers specific to human M cell allowing targeting to M cells and nanoparticles transcytosis is illustrated. Encouraging results upon in vivo testing are reported but low bioavailability and lack of control on absorbed dose slow down products development. Vaccines are certainly the most promising applications for orally delivered nanoparticles.     

PERCUTANEOUS DELIVERY OF PROTEINS AND PEPTIDES USING IONTOPHORETIC TECHNIQUES

There has been much interest recently in the delivery of proteins and peptides following the research and development of biotechnology: derived drugs and other bioactive substances. This article summarizes the use of iontophoresis to deliver proteins and peptides across the skin. This technique offers considerable promise for delivering drugs in therapeutic amounts by bypassing the gastrointestinal tract (GIT) and liver metabolism. This article discusses the theory underlying iontophoretic drug delivery and the devices available. The future development of these systems would require the use of specialized approaches to enhance delivery of larger molecules but overall there is considerable optimism.     

An in vitro mucosal model predictive of bioadhesive agents in the oral cavity.

The formulation of a drug/carrier complex that can be distributed and retained for extended periods within the oral cavity would be advantageous in the treatment of local conditions. In this study, an in vitro system was developed to investigate the binding of bioadhesive macromolecules to buccal epithelial cells, without having to alter their physicochemical properties by the addition of 'marker' entities. In this innovative approach a lectin binding inhibition technique, involving an avidin-biotin complex and a colourmetric detection system, was used to evaluate polymer binding. 0.5% w/v polymer solutions in saline (pH 7.6) were left in contact with a standardized number of freshly collected human buccal cells for 15 min. The cells were then exposed to 10 mg L(-1) biotinylated lectin from Canavalia ensiformis followed by 5 mg L(-1) streptavidin peroxidase. The inhibition of lectin binding (i.e. by 'masking' of the binding site on the cell surface by the attached bioadhesive polymer) was measured and expressed as a percentage reduction in the rate of o-phenylenediamine oxidation over 1 min. From the wide range of polymer solutions screened, chitosan gave the greatest inhibition of lectin binding to the surface of buccal cells, while methylcellulose, gelatin, Carbopol 934P and polycarbophil also produced a substantial reduction. Lectin binding inhibition was also observed for a selected number of polymer solutions when screened at pH 6.2. The presence of bound chitosan, polycarbophil and Carbopol 934P on the buccal cell surface was confirmed using direct staining techniques. It was concluded that this assay can be used to detect polymer binding to the cells present on the buccal mucosa, and the information gained used in the development of retentive drug/polymer formulations.     

Oral drug delivery with nanoparticles into the gastrointestinal mucosa

The oral route of protein and peptide drugs has been a popular method of drug delivery in recent years, although it is often a challenge to achieve effective drug release and minimize the barrier functions of the gastrointestinal tract. Gastrointestinal mucosa can capture and remove harmful substances; similarly, it can limit the absorption of drugs. Many drugs are effectively captured by the mucus and rapidly removed, making it difficult to control the release of drugs in the gastrointestinal tract. The use of drug carrier systems can overcome the mucosal barrier and significantly improve bioavailability. Nanoparticle drug carriers can protect the drug from degradation, transporting it to a predetermined location in the gastrointestinal tract to achieve more efficient and sustained drug delivery. It is becoming clearer that the characteristics of nanoparticles, such as particle size, charge, and hydrophobicity, are related to permeability of the mucosal barrier. This review focuses on the latest research progress of nanoparticles to penetrate the mucosal barrier, including the delivery methods of nanoparticles on the surface of gastrointestinal mucosa, and aims to summarize how successful oral nanoparticle delivery systems can overcome this biological barrier in the human body. In addition, the in vitro model based on gastrointestinal mucus is an important tool for drug research and development. Here, we discuss different types of drug delivery systems and their advantages and disadvantages in design and potential applications. Similarly, we reviewed and summarized various methods for evaluating oral nanoparticles in in vitro and in vivo models.     

Biodegradable microspheres for protein delivery

In a very short time, since their emergence, the field of controlled delivery of proteins has grown immensely. Because of their relatively large size, they have low transdermal bioavailabilities. Oral bioavailability is generally poor since they are poorly absorbed and easily degraded by proteolytic enzymes in the gastrointestinal tract. Ocular and nasal delivery is also unfavorable due to degradation by enzymes present in eye tissues and nasal mucosa. Thus parenteral delivery is currently most demanding and suitable for delivery of such molecules. In systemic delivery of proteins, biodegradable microspheres as parenteral depot formulation occupy an important place because of several aspects like protection of sensitive proteins from degradation, prolonged or modified release, pulsatile release patterns. The main objective in developing controlled release protein injectables is avoidance of regular invasive doses which in turn provide patient compliance, comfort as well as control over blood levels. This review presents the outstanding contributions in field of biodegradable microspheres as protein delivery systems, their methods of preparation, drug release, stability, interaction with immune system and regulatory considerations.     

A novel bioadhesive intranasal delivery system for inactivated influenza vaccines

The aim of the current studies was to evaluate a bioadhesive delivery system for intranasal administration of a flu vaccine, in combination with a mucosal adjuvant (LTK63). A commercially available influenza vaccine, containing hemagglutinin (HA) from influenza/A Johannesberg H1N1 1996, and LTK63 or LTR72 adjuvants, which are genetically detoxified derivatives of heat labile enterotoxin from Escherichia coli, were administered IN in a bioadhesive delivery system, which comprised esterified hyaluronic acid (HYAFF) microspheres, to mice, rabbits and micro-pigs at days 0 and 28. For comparison, additional groups of animals were immunized intranasally with the HA vaccine alone, with soluble HA+LTK63, or IM with HA. In all three species, the groups of animals receiving IN immunization with the bioadhesive microsphere formulations, including LT mutants, showed significantly enhanced serum IgG responses (P<0.05) and higher hemagglutination inhibition (HI) titers in comparison to the other groups. In addition, the bioadhesive formulation also showed a significantly enhanced nasal wash IgA response (P<0.05). Most encouragingly, in pigs, the bioadhesive microsphere vaccine delivery system induced serum immune responses following IN immunization, which were significantly more potent than those induced by traditional IM immunization at the same vaccine dose (P<0.05).     

Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery

Cell-derived membrane vesicles (CMVs) are endogenous carriers transporting proteins and nucleic acids between cells. They appear to play an important role in many disease processes, most notably inflammation and cancer, where their efficient functional delivery of biological cargo seems to contribute to the disease progress. CMVs encompass a variety of submicron vesicular structures that include exosomes and shedding vesicles. The lipids, proteins, mRNA and microRNA (miRNA) delivered by these vesicles change the phenotype of the receiving cells. CMVs have created excitement in the drug delivery field, because they appear to have multiple advantages over current artificial drug delivery systems. Two approaches to exploit CMVs for delivery of exogenous therapeutic cargoes in vivo are currently considered. One approach is based on engineering of natural CMVs in order to target certain cell types using CMVs loaded with therapeutic compounds. In the second approach, essential characteristics of CMVs are being used to design nano-scaled drug delivery systems. Although a number of limiting factors in the clinical translation of the exciting research findings so far exist, both approaches are promising for the development of a potentially novel generation of drug carriers based on CMVs.     

Drug delivery to the retina: challenges and opportunities

Retinal drug delivery is a challenging area in the field of ophthalmic drug delivery. An ideal drug delivery system for the retina and vitreous humor has not yet been found, despite extensive research. Drug delivery to retinal tissue and vitreous via systemic administration is constrained due to the presence of a blood-retinal barrier (BRB) which regulates permeation of substances from blood to the retina. Although intravitreal administration overcomes this barrier, it is associated with several other problems. In recent years, transporter targeted drug delivery has become a clinically significant drug delivery approach for enhancing the bioavailabilities of drug molecules with poor membrane permeability characteristics. Various nutrient transporters, which include peptide, amino acid, folate, monocarboxylic acid transporters and so on, have been reported to be expressed on the retina and BRB. Prodrug derivatisation of drug molecules which target these transporters could result in enhanced ocular bioavailability. Highlighted in this review are various strategies currently employed for drug delivery to the posterior chamber, and novel opportunities that can be exploited to enhance ocular bioavailability of drugs.     

Mucoadhesive drug carriers based on complexes of poly(acrylic acid) and PEGylated drugs having hydrolysable PEG-anhydride-drug linkages.

We have designed a new mucoadhesive drug delivery formulation based on H-bonded complexes of poly(acrylic acid) (PAA) or poly(methacrylic acid) (PMAA) with the poly(ethylene glycol) (PEG), of a (PEG)-drug conjugate. The PEGylated prodrugs are synthesized with degradable PEG-anhydride-drug bonds for eventual delivery of free drug from the formulation. In this work we have used indomethacin as the model drug which is PEGylated via anhydride bonds to the PEG. The complexes are designed first to dissociate as the formulation swells in contact with mucosal surfaces at pH 7.4, releasing PEG-indomethacin, which then hydrolyses to release free drug and free PEG. We found that as MW of PAA increases, the dissociation rate of the complex decreases, which results in decreased rate of release of the drug. On the other hand, the drug release from PEG-indomethacin alone and from solid mixture of PEG-indomethacin+PAA was much faster than that from the H-bonded complexes. Due to the differences in the thermal stability, PMAA complex exhibited slightly faster drug release than that of the PAA complex of comparable MW. These H-bonded complexes of degradable PEGylated drugs with bioadhesive polymers should be useful for mucosal drug delivery.     

Influence of the surface characteristics of PVM/MA nanoparticles on their bioadhesive properties.

The aim of this work was to investigate the influence of the cross-linkage of poly(methylvinylether-co-maleic anhydride) (PVM/MA) nanoparticles with increasing amounts of 1,3-diaminopropane (DP) and, eventually, bovine serum albumin (BSA) on their gastrointestinal transit and bioadhesive properties. The fluorescently-labelled formulations were orally administered to rats and, at different times, the amount of nanoparticles in both the lumen content and adhered to the gut mucosa were quantified. The gut transit was evaluated by calculating the gastric (k(ge)) and intestinal (k(ie)) emptying rates. The adhered fraction of nanoparticles in the whole gut was plotted versus time and, from these curves, the intensity, capacity and extent of the adhesive interactions were estimated. The bioadhesive potential of PVM/MA was much higher when formulated as nanoparticles (NP) than in the solubilised form in water. However, k(ge) and k(ie) increased by increasing the extent of cross-linkage of nanoparticles with DP, while the capacity to develop adhesive interactions and the intensity of the adhesive phenomenon were significantly higher for non-hardened than for DP-cross-linked carriers. In contrast, the BSA-coating of cross-linked nanoparticles significantly decreased k(ge) and k(gi), whereas the intensity of the bioadhesive phenomenon was significantly higher than for NP. In summary, the adhesivity of the nanoparticles appears to modulate their gastrointestinal transit profile.     

Developments in the area of bioadhesive drug delivery systems

This paper aims to review the current progress in bioadhesion for drug delivery applications as well as new techniques related to this field. Research started with mucoadhesive polymers that had already been in use as excipients and were rapidly used in new formulations. Their major drawback was found in their unspecific binding, as they adhere to almost any mucosal surface. As some of the polymers showed additional properties such as enzyme inhibition and permeation enhancement, however, they remain interesting as multifunctional excipients. In contrast to mucoadhesion, the concept of specific bioadhesion by use of lectins and other adhesion molecules is now gaining increasing attention as these substances bind directly to receptors on the cell surface rather than to the mucus gel layer. Since specific binding to the cell surface is often followed by uptake and intracellular transport, new chances for drug delivery evolved. Bioadhesion may, thus, enable researchers to deliver macromolecular drugs directly to specific target cells and has implications also relevant to other fields of science, such as tissue engineering, gene delivery and nanotechnology.     

Developments in the area of bioadhesive drug delivery systems

This paper aims to review the current progress in bioadhesion for drug delivery applications as well as new techniques related to this field. Research started with mucoadhesive polymers that had already been in use as excipients and were rapidly used in new formulations. Their major drawback was found in their unspecific binding, as they adhere to almost any mucosal surface. As some of the polymers showed additional properties such as enzyme inhibition and permeation enhancement, however, they remain interesting as multifunctional excipients. In contrast to mucoadhesion, the concept of specific bioadhesion by use of lectins and other adhesion molecules is now gaining increasing attention as these substances bind directly to receptors on the cell surface rather than to the mucus gel layer. Since specific binding to the cell surface is often followed by uptake and intracellular transport, new chances for drug delivery evolved. Bioadhesion may, thus, enable researchers to deliver macromolecular drugs directly to specific target cells and has implications also relevant to other fields of science, such as tissue engineering, gene delivery and nanotechnology.     

2008 Congress of the ESFH in Düsseldorf, Germany

Choosing dialyzers is more important in blood purification in critical care because therapeutic conditions (especially the amount of dialysate) are usually limited. Then, adsorption is the third major mechanism of removing toxic substances from patients in these treatments. Several commercial dialyzers designed for acute blood purification therapy were investigated by performing aqueous ultrafiltration experiments to demonstrate the importance of the membrane materials. Polymethylmethacrylate (PMMA) showed strong adsorptive characteristics to α-chymotripsinogen A (MW 25,000) but showed much less adsorptive characteristics to cytochrome C (MW 12,400). On the contrary, polyacrylonitrile (PAN) showed relatively lower affinity and polysulfone (PS) showed essentially no affinity to these proteins. Time and concentration dependent characteristics of clearance for these solutes were also demonstrated in PMMA. These facts were also verified in other dialyzers with another PMMA and polyester polymer alloy (PEPA) designed for chronic hemodialysis, which concluded that adsorption found in PMMA may be due to the occlusion of protein molecules into pores of the membrane. Choosing membrane materials is, therefore, important not only in removing inflammatory cytokines but also considering the loss of albumin in acute and chronic treatments.     

Evaluation of bioadhesive polymers as delivery systems for nose to brain delivery: in vitro characterisation studies.

There is an increasing need for nasal drug delivery systems that could improve the efficiency of the direct nose to brain pathway especially for drugs for treatment of central nervous system disorders. Novel approaches that are able to combine active targeting of a formulation to the olfactory region with controlled release bioadhesive characteristics, for maintaining the drug on the absorption site are suggested. If necessary an absorption enhancer could be incorporated. Low methylated pectins have been shown to gel and be retained in the nasal cavity after deposition. Chitosan is known to be bioadhesive and also to work as an absorption enhancer. Consequently, two types of pectins, LM-5 and LM-12, together with chitosan G210, were selected for characterisation in terms of molecular weight, gelling ability and viscosity. Furthermore, studies on the in vitro release of model drugs from candidate formulations and the transport of drugs across MDCK1 cell monolayers in the presence of pectin and chitosan were also performed. Bioadhesive formulations providing controlled release with increased or decreased epithelial transport were developed. Due to their promising characteristics 3% LM-5, 1% LM-12 pectin and 1% chitosan G210 formulations were selected for further biological evaluation in animal models.