Pulsatile drug delivery systems using hydrogels

Department of Chemical Engineering, Waseda University, Tokyo, Japan; Institute of Biomedical Engineering, Tokyo Women's Medical College, Tokyo, Japan
Advanced Drug Delivery Reviews 01/1993; DOI: 10.1016/0169-409X(93)90028-3

ABSTRACT In recent years, temporal control of drug delivery has been of interest to achieve improved drug therapies. Intelligent drug delivery systems (DDS) are one expected result, demonstrating an ability to sense external environmental changes, judge the degree of external signal, and release appropriate amounts of drug. Intelligent DDS may be achieved using stimuli-responsive polymeric hydrogels which alter their structure and physical properties in response to external stimuli. Pulsatile drug release has the advantages of avoiding drug tolerance or matching the body's release of specific peptides or hormones. In this review, recent studies for pulsatile drug delivery in response to stimuli such as chemical agents, pH, electric fields, and temperature are discussed. Achievement of pulsatile drug release from stimuli-responsive polymeric hydrogels as on-off switches and its mechanism are reviewed in terms of control for stimuli-responsive swelling.

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    ABSTRACT: We report a new thermal targeting method in which a thermally responsive drug carrier selectively accumulates in a solid tumor that is maintained above physiological temperature by externally applied, focused hyperthermia. We synthesized two thermally responsive polymers that were designed to exhibit a lower critical solution temperature (LCST) transition slightly above physiological temperature: (1) a genetically engineered elastin-like polypeptide (ELP) and (2) a copolymer of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm). The delivery of systemically injected polymer-rhodamine conjugates to solid tumors was investigated by in vivo fluorescence video microscopy of ovarian tumors implanted in dorsal skin fold window chambers in nude mice, with and without local hyperthermia. When tumors were heated to 42 degrees C, the accumulation of a thermally responsive ELP with a LCST of 40 degrees C was approximately twofold greater than the concentration of the same polymer in tumors that were not heated. Similar results were also obtained for a thermally responsive poly(NIPAAM-co-AAm), though the enhanced accumulation of this carrier in heated tumors was lower than that observed for the thermally responsive ELP. These results suggest that enhanced delivery of drugs to solid tumors can be achieved by conjugation to thermally responsive polymers combined with local heating of tumors.
    Journal of Controlled Release 08/2001; 74(1-3):213-24. · 7.63 Impact Factor
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    ABSTRACT: The research on soft materials is interdisciplinary. In the present work we focus on "smart hydrogels" as most promising representatives studied by complementary Scanning Force Microscopy (SFM) and high resolution Scanning Electron Microscopy (SEM). The extremely large range of water uptake of these hydrogels (up to 10 3 times of their mass) on one hand and their distinct softness (Young´s modulus < some tens of kPa) on the other hand constitute real challenges for the characterization of their local structure, the caging of nano-scaled particles, and some micromechanical properties. SFM images were compared with those obtained by SEM in the dry, swollen and deswollen state of the "smart gel" PNIPAAm [poly-(N-isopropylacrylamide)]. PNIPAAm reacts on tiny variations of the temperature around 33°C by significantly changing its volume. While both imaging techniques revealed very similar results concerning the surface structure in the dry state, highly resolved structural features remained unapproachable for SFM in the wet state. In a contrary, SEM at high resolution revealed after state-of-the-art cryo-preparation, freeze-drying and subsequent ultrathin Pt/C-coating a sponge-like structure with cavity sizes of around 40 nm in the swollen state and 20 nm in the deswollen state. SFM proved to be an appropriate instrument revealing the local elastic surface properties. For example, at the swollen state at 10 °C, the Young's modulus was found to be more than 100 times lower than for the deswollen state at 35 °C. In addition, SEM also proved to be very suitable for the structural research of microgels and filled hydrogels. The application of both SFM and SEM contribute complimentarily to a characterization of different hydrogel systems at different states. RESUMEN La investigación en materiales blandos es interdisciplinaria. En este trabajo nos concentraremos en "hidrogeles smart" como representantes más prometedores estudiados complementariamente por Microscopía de Fuerza Atómica (MFA) y Microscopía Electrónica de Barrido (MEB) de alta resolución. Los hidrogeles muestran una alta capacidad de absorción de agua (hasta 10 3 veces su masa) y un amplio rango de propiedades mecánicas (Módulo de Young < algunas decenas de KPa). El estudio sistemático de estas propiedades y su estrecha relación con la microestructura constituyen un verdadero desafío para la caracterización de su estructura local, la incorporación y distribución de nanopartículas en su estructura interna y algunas propiedades micromecánicas. En esta revisión se hace un análisis comparativo de imágenes obtenidas desde SFM y SEM del "smart gel" PNIPAAm [poli-(N-isopropil-acrilamida)] en estado xerogel, hinchado y deshinchado. El PNIPAAm modifica significativamente su volumen ante pequeñas variaciones de temperatura alrededor de 33 ºC. Mientras ambas técnicas revelaron resultados muy similares relativos a la estructura superficial en el estado seco, las características estructurales de mayor resolución han permanecido inalcanzables para el SFM en estado húmedo. Al contrario, el SEM a alta resolución después de una crio-preparación, congelación-secado y subsiguienre deposición de una capa ultrafina de Pt/C, revela una estructura esponjosa con cavidades de dimensiones cercanas a los 40 nm en su estado hinchado y 20 nm en el estado deshinchado. SFM ha demostrado ser un instrumento apropiado para revelar las propiedades locales elásticas superficiales. Por ejemplo, en el estado hinchado a 10 ºC, el módulo de Young era más de 100 veces el del estado deshinchado a 35 ºC. Adicionalmente, SEM ha demostrado ser muy adecuado para la investigación estructural de microgeles e hidrogeles nanoestructurados. La aplicación de SFM y SEM contribuyen complementariamente a la caracterización de diversos sistemas de hidrogeles en diferentes estados.
    Acta Microscopica. 01/2008; 17:45-61.
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    ABSTRACT: Pulsatile drug delivery aims to release drugs on a programmed pattern i.e.: at appropriate time and/or at appropriate site of action. Currently, it is gaining increasing attention as it offers a more sophisticated approach to the traditional sustained drug delivery i.e: a constant amount of drug released per unit time or constant blood levels. Technically, pulsatile drug delivery systems administered via the oral route could be divided into two distinct types, the time controlled delivery systems and the site-specific delivery systems. The simplest pulsatile formulation is a two layer press coated tablet consisted of polymers with different dissolution rates. Homogenicity of the coated barrier is mandatory in order to assure the predictability of the lag time. The disadvantage of such formulation is that the rupture time cannot be always adequately manipulated as it is strongly correlated with the physicochemical properties of the polymer. Gastric retentive systems, systems where the drug is released following a programmed lag phase, chronopharmaceutical drug delivery systems matching human circadian rhythms, multiunit or multilayer systems with various combinations of immediate and sustained-release preparation, are all classified under pulsatile drug delivery systems. On the other hand, site-controlled release is usually controlled by factors such as the pH of the target site, the enzymes present in the intestinal tract and the transit time/pressure of various parts of the intestine. In this review, recent patents on pulsatile drug delivery of oral dosage forms are summarized and discussed.
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