Selection of drug candidates for gastroretentive dosage forms: Pharmacokinetics following continuous intragastric mode of administration in a rat model

The purpose of the study was to evaluate the pharmacokinetic effects obtained by gastroretentive dosage form (GRDF) for drugs absorbed by passive paracellular diffusion (atenolol, acyclovir) or active transport (valacyclovir). Model drugs were delivered as gastric infusion (GInf) through an implanted catheter (resembling GRDF), intravenous, oral (PO), and colonic administration to rats. For atenolol (highly soluble drug), GInf resulted in a prolonged T_max and reduced C_max in comparison to PO, whereas bioavailability was similar. Bioavailability after colonic bolus was significantly lower. Results were also simulated by a pharmacokinetic model. For acyclovir, GInf and PO demonstrated almost the same pharmacokinetic profile with low bioavailability, most probably due to the solubility-limited absorption. Valacyclovir demonstrated the significant change in the shape of pharmacokinetic profile as a function of the rate of gastric delivery, without variation in bioavailability. Valacyclovir was not absorbed from colon. Experimental and theoretical methodologies to assess the pharmacokinetic influences of GRDF mode of administration were developed, avoiding the need to compound the drug in a dosage form. GRDF provides a mean for controlled release of compounds that are absorbed by active transport in the upper intestine. It also enables controlled delivery for paracellularly absorbed drugs without a decrease in bioavailability.     

Novel gastroretentive dosage forms: evaluation of gastroretentivity and its effect on riboflavin absorption in dogs

Purpose. The purpose of this study was to design novel gastroretentive dosage forms (GRDFs) based on unfolding multilayer polymeric films, to investigate the mechanism of their gastroretentivity in dogs, and to assess the effect of compounding a narrow absorption window drug in a GRDF on the drug's absorption properties. Methods. Dosage forms (DFs) with different dimensions and mechanical properties were administered to beagle dogs with acidic buffer (pH=1.5), whose gastric retention time (GRT) was then determined by X-ray pictures. Concurrent administration of radiopaque markers was used to assess the effect of the GRDF and/or acidic buffer on GRT. The absorption of riboflavin from a prototype GRDF was compared with a nongastroretentive controlled-release DF and to an oral solution of the drug. Results. Large DFs (2.5 × 2.5 cm) containing rigid frame had prolonged GRT (>4 h). Administration of 400 mL of acidic buffer (or water) prolonged GRT whereas the GRDF did not cause additional prolongation. The extended absorption phase (>48 h) of riboflavin administered in a GRDF led to 4-fold increased bioavailability. Conclusion. The combination of large dimensions with rigidity produce gastroretentivity that can be used to improve absorption properties of a model of narrow absorption window drugs in the gastrointestinal tract.     

Furosemide pharmacokinetics and pharmacodynamics following gastroretentive dosage form administration to healthy volunteers

The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of furosemide following gastroretentive dosage from (GRDF) administration. A furosemide (60 mg) GRDF, releasing the drug during 6 hours in vitro, or an immediate-release tablet was administered to healthy male volunteers (N = 14) in a crossover design. Food and liquid intake were standardized; urine was collected, weighed, and assayed for furosemide and sodium concentrations. Pharmacokinetics of furosemide following the GRDF administration, as compared to the tablet, showed lower Cmax and indicated a prolonged absorption phase leading to longer mean residence time in the stomach. The sustained input of the drug significantly improved diuretic and natriuretic efficiencies during the first 5 hours and thereby increased the total effects measured over 24 hours. The unfolding controlled-release GRDF of furosemide improved the pharmacodynamic actions due to the sustained absorption in the stomach and jejunum, which delayed the body's counteractivity to the drug effect.     

Development of sustained release gastroretentive drug delivery system for ofloxacin: in vitro and in vivo evaluation

Sustained release (SR)-gastroretentive dosage forms (GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new strategy is proposed for the development of gastroretentive dosage forms for ofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation, with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems. Different polymers, such as psyllium husk, HPMC K100M, crospovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk concentration. It was also found that in vitro drug release rate increased with increasing amount of crospovidone due to the increased water uptake, and hence increased driving force for drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. In vivo studies were carried out for the optimized formulation in 24 healthy human volunteers and the pharmacokinetic parameters of developed formulations were compared with the marketed once daily (Zanocin) formulation. Based on the in vivo performance in a parallel study design in healthy subjects, the developed formulation shows promise to be bioequivalent to the marketed product (Zanocin). The percent relative bioavailability of developed formulation was found to be 97.55%.     

Floating microspheres as drug delivery system: newer approaches

A controlled drug delivery system with prolonged residence time in the stomach can be of great practical importance for drugs with an absorption window in the upper small intestine. The main limitations are attributed to the inter- and intra-subject variability of gastro-intestinal (GI) transit time and the non-uniformity of drug absorption throughout the alimentary canal. Floating drug delivery systems (FDDSs) are expected to remain buoyant in a lasting way upon the gastric contents and consequently to enhance the bioavailability of drugs. The various buoyant preparations include hollow microspheres, granules, powders, tablets, capsules, pills and laminated films. Floating microspheres are specially gaining attention due to their wide applicability in the targeting of drugs to stomach. These floating microspheres have the advantage that they remain buoyant and distributed uniformly over the gastric fluid to avoid the vagaries of gastric emptying and release the drug for prolonged period of time. A major drawback of low-density floating drug delivery systems is that their performance is strongly dependent upon the gastric emptying process of stomach. Multiparticulate low-density particles can successfully prolong the gastric retention time of drugs. This article is a review of two important approaches utilized to prepare and improve the performance of floating microspheres.     

Pulsatile drug-delivery systems.

Delivery systems with a pulsatile-release pattern are receiving increasing interest for the development of drugs for which conventional controlled drug-release systems with a continuous release are not ideal. These drugs often have a high first-pass effect or special chronopharmacological needs. A pulsatile-release profile is characterized by a time period of no release (lag time) followed by a rapid and complete drug release. Pulsatile drug-delivery systems can be classified into site-specific systems in which the drug is released at the desired site within the intestinal tract (e.g., the colon), or time-controlled devices in which the drug is released after a well-defined time period. Site-controlled release is usually controlled by environmental factors, like the pH or enzymes present in the intestinal tract, whereas the drug release from time-controlled systems is controlled primarily by the delivery system and, ideally, not by the environment. This review covers various single- and multiple-unit oral pulsatile drug-delivery systems with an emphasis on time-controlled drug-release systems.     

Floating drug delivery systems for prolonging gastric residence time: a review

Oral delivery of the drug is the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in the formulations. Recent technological advancements have been made in controlled oral drug delivery systems by overcoming physiological difficulties, such as short gastric residence time and highly variable gastric emptying time. Gastroretentive dosage forms have been designed over the past three decades to overcome these difficulties. Several technical approaches are currently utilized in the prolongation of gastric residence time, including highdensity, swelling and expanding, polymeric mucoadhesive, ion-exchange, raft forming, magnetic and floating drug delivery systems (FDDS), as well as other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed.     

经鼻纳米递药系统在中枢神经系统疾病治疗中的研究进展

中枢神经系统疾病治疗药物的脑内递送通常受限于血脑屏障。经鼻给药作为脑靶向递药的一种无创给药方式，可绕开血脑屏障，实现药物至脑部的直接、高效靶向输送，在中枢神经系统疾病治疗中具有极大应用潜力。然而，鼻腔黏液纤毛清除力等屏障限制了经鼻给药递送效果。依托纳米递药技术的发展，经鼻纳米递药系统为中枢神经系统疾病的治疗带来了新的希望。本文综述了经鼻入脑递药通路、常见经鼻纳米递药系统及其特性和治疗应用进展，为基于中枢神经系统疾病治疗的经鼻纳米递药系统设计提供思路和方法。     

Novel Gastroretentive Dosage Forms: Evaluation of Gastroretentivity and Its Effect on Levodopa Absorption in Humans

Purpose. To design novel expandable gastroretentive dosage forms (GRDFs) and evaluate their gastroretentive properties. Then, to assess the pharmacokinetics of levodopa compounded in such a GRDF in healthy volunteers. Methods. Thin (<0.07 cm), large-dimensioned ( 5 × 2.1 cm), multilayer dosage forms (DFs) with different rigid polymeric matrices and mechanical properties were folded into gelatin capsules and were administered to healthy volunteers with a light breakfast. GRDF unfolding and physical integrity were evaluated in vitro and in vivo (by gastroscopy and radiology). The pharmacokinetics of levodopa-GRDF were compared to Sinemet CR^® in a crossover design. Results. The combination of rigidity and large dimension of the GRDFs was a decisive parameter to ensure prolonged gastroretentivity ( 5 h). Large-dimension DFs lacking rigidity had similar gastroretentivity as a nondisintegrating tablet (10 mm). The GRDFs rapidly unfolded and maintained their mechanical integrity. The absorption phase of levodopa was significantly prolonged following GRDF administration in comparison to Sinemet CR^®. Conclusions. The combination of size and rigidity of the novel GRDF enables a significant extension of the absorption phase of a narrow absorption window drug such as levodopa. This approach is an important step toward the implementation of such GRDFs in the clinical setting.     

Keynote Lectures (L)

There is very often a great gap between the performance of oral drug delivery systems in vitro and in vivo. During the last decade modern high resolution and/or real time imaging techniques like Magnetic Marker Monitoring (MMM) [1] or Magnetic Resonance Imaging (MRI) [2, 3] have provided new insights into the in vivo performance of drug delivery systems and their interaction with the physiology of the gastrointestinal tract. The physiological conditions for drug absorption along the gastrointestinal tract are far from being constant. This applies to the expression of transport proteins and metabolizing enzymes as well as for the luminal conditions [3, 4]. Accordingly, gastrointestinal passage of a drug delivery system plays a crucial role for drug absorption. Gastrointestinal transit is also not a constant process. It is strongly controlled by feedback mechanisms that involve neuronal and hormonal signal pathways. In contrast to widespread assumption, transit times through all gastrointestinal organs, i. e. stomach, small intestine and colon, are highly variable. Gastric residence times are in general dependent on the energy content of the gastric filling. The rate of gastric emptying under fed conditions is controlled by the energy content of the meal, the energy requirement of the body and feedback mechanisms like the ileal brake mechanism. Furthermore, the rate of gastric emptying under fed conditions is also influenced by particle size. As a consequence, the emptying of drug substances from the digesting stomach is dependent on three main factors, the gastric emptying rate of the meal, the intragastric distribution of the drug and the particle size of the formulation. Examples for the in vivo behavior of different oral controlled release systems and resulting drug plasma concentration profiles will be shown and discussed.     

胃滞留给药系统的研究进展及其在中药制剂中的应用

在口服制剂中，胃滞留给药系统可以延长药物在胃内的滞留时间，进而延长其在整个胃肠道的转运时间，增加药物的吸收，从而提高临床疗效，因此它是一种理想的给药系统。本文通过查阅国内外文献进行归纳，从胃滞留给药系统的影响因素、分类、制剂研究（包括中药胃滞留制剂）及上市产品进展等方面对近年来胃滞留制剂的研究进展进行综述。     

Biomedical microelectromechanical systems (BioMEMS): Revolution in drug delivery and analytical techniques

Advancement in microelectromechanical system has facilitated the microfabrication of polymeric substrates and the development of the novel class of controlled drug delivery devices. These vehicles have specifically tailored three dimensional physical and chemical features which together, provide the capacity to target cell, stimulate unidirectional controlled release of therapeutics and augment permeation across the barriers. Apart from drug delivery devices microfabrication technology’s offer exciting prospects to generate biomimetic gastrointestinal tract models. BioMEMS are capable of analysing biochemical liquid sample like solution of metabolites, macromolecules, proteins, nucleic acid, cells and viruses. This review summarized multidisciplinary application of biomedical microelectromechanical systems in drug delivery and its potential in analytical procedures.     

胃内滞留释药系统的研究新进展

介绍近年来胃内滞留释药系统的研究进展。胃内滞留释药系统可增加以胃肠道上部吸收为主的药物的吸收,延长药物作用时间,提高药物生物利用度。目前胃内滞留释药系统主要有5种类型：胃内漂浮型、胃内黏附型、胃内膨胀型、胃底沉降型和磁性胃内滞留型。     

Gastroretentive floating drug-delivery systems: a critical review

The oral delivery of drugs with a narrow absorption window in the gastrointestinal tract (GIT) is often limited by poor bioavailability with conventional dosage forms due to incomplete drug release and short residence time at the site of absorption. To overcome this drawback and to maximize the oral absorption of these drugs, gastroretentive systems such as mucoadhesive, high-density, expandable, and floating systems have been developed. These systems provide controlled delivery of drugs with prolonged gastric residence time. However, in humans, differences in various physiological and biological factors can affect the gastric residence time and drug-delivery behavior from gastroretentive systems. Some floating drug-delivery systems (FDDS) have shown the capability to accommodate these variations without affecting drug release. This review mainly focuses on various physiological considerations for development of FDDS, and highlights recent technological developments including new dosage forms and their production techniques (e.g., holt-melt extrusion, melt pelletization, and pulsed plasma-irradiation processes). Alternatives to the existing in vitro compendial methods for evaluating floating dosage forms will be discussed, and a critical analysis of the existing literature on FDDS, identifying the potential areas for future research, is provided.     

Recent advances in protein and peptide drug delivery systems

Delivery of therapeutic proteins/peptides has received a considerable amount of attention over the last 10 years, but there are number of limitations to oral delivery of proteins. The barriers to peptide bioavailability after oral administration are intestinal membrane permeability, size, intestinal and hepatic metabolism and lastly solubility. A number of approaches have been used to overcome these limitations. Poor membrane permeabilities of hydrophilic peptides might be overcome by structurally modifying the compound, thus increasing their membrane partition characteristics and their affinity for carrier proteins. Another approach is site specific delivery of the peptides to the most permeable part of the intestine. Metabolism (hepatic and intestinal) of peptides might be controlled by co-administration of competitive enzyme inhibitors, structural modifications and administration of the compound as well as absorbed prodrug that is converted into therapeutically active agent after its absorption. Various delivery systems like prolease technology, nano-particulate and microparticulate delivery system, mucoadhesive delivery of peptides and microspheres have been developed for the delivery of proteins and peptides. Non-conventional delivery systems for proteins are biodegradable and non-biodegradable systems. Besides these, some other approaches for protein and peptide delivery are vector mediated delivery of proteins using adenovirus, macroflux transdermal patches, pulmonary delivery of proteins, delivery of proteins and peptides across blood brain barrier.     

Advances in gastro retentive drug-delivery systems

INTRODUCTION: In recent years, various technological improvements have been achieved and new concepts have been developed, in the area of controlled release solid oral dosage forms, especially for products where an extended time of release is associated with an extended gastric retention time. These Gastro Retentive Systems have been quite investigated because they can improve the in-vivo performance of many drugs. AREAS COVERED: This paper summarizes current approaches in the research and development of gastro retentive dosage forms from recent literature. Apart from the numerous mechanisms of action involved, a short review of different key parameters is proposed, taking into account the stomach physiology. Most of the current technologies published, patented or marketed are presented. Promising drugs to develop in the near future are mentioned, and the importance of such systems in fixed Dose Combinations is also discussed. The importance of food effect is mentioned, and the impact of the multiple unit systems versus monolithic approach is discussed, especially regarding the dose intake. EXPERT OPINION: In conclusion, numerous mechanisms like floating, sinking, effervescence, swelling, bioadhesion, magnetic, etc. have been proposed over the years. While most of the proposed systems show promising dissolution profiles and in-vitro retention, only few of them have also shown success in-vivo. Currently, the polymeric swelling monolithic systems are the most prominent marketed forms. The possibility to combine different mechanisms in order to ensure true gastric retention even in the fasted state should be further investigated.     

Development of a gastroretentive pulsatile drug delivery platform

Objectives To develop a novel gastroretentive pulsatile drug delivery platform by combining the advantages of floating dosage forms for the stomach and pulsatile drug delivery systems. Methods A gastric fluid impermeable capsule body was used as a vessel to contain one or more drug layer(s) as well as one or more lag‐time controlling layer(s). A controlled amount of air was sealed in the innermost portion of the capsule body to reduce the overall density of the drug delivery platform, enabling gastric floatation. An optimal mass fill inside the gastric fluid impermeable capsule body enabled buoyancy in a vertical orientation to provide a constant surface area for controlled erosion of the lag‐time controlling layer. The lag‐time controlling layer consisted of a swellable polymer, which rapidly formed a gel to seal the mouth of capsule body and act as a barrier to gastric fluid ingress. Key findings By varying the composition of the lag‐time controlling layer, it was possible to selectively program the onset of the pulsatile delivery of a drug. Conclusions This new delivery platform offers a new method of delivery for a variety of suitable drugs targeted in chronopharmaceutical therapy. This strategy could ultimately improve drug efficacy and patient compliance, and reduce harmful side effects by scaling back doses of drug administered.     

Intracellular control of gene trafficking using liposomes as drug carriers.

The objective of this review is to summarize some of the critical barriers in gene delivery and recent progress in overcoming such barriers using non-viral carrier systems. Receptor-mediated endocytosis is generally considered to be a principal entering pathway. Therefore, endosomal escape is an essential step for achieving efficient transfection. The nuclear membrane is also a critical barrier in gene delivery and the application of the nuclear localization signal is discussed, based on recent strategies. It is essential to optimize the carrier system, in order to enhance the transfection ability equivalent to a viral system. The importance of developing an intracellular pharmacokinetic model of genes is emphasized in the optimization of non-viral carrier systems.     

Gastroretentive drug delivery systems

A controlled drug delivery system with prolonged residence time in the stomach is of particular interest for drugs that i) are locally active in the stomach, ii) have an absorption window in the stomach or in the upper small intestine, iii) are unstable in the intestinal or colonic environment, or iv) exhibit low solubility at high pH values. This article gives an overview of the parameters affecting gastric emptying in humans as well as on the main concepts used to design pharmaceutical dosage forms with prolonged gastric residence times. In particular, bioadhesive, size-increasing and floating drug delivery systems are presented and their major advantages and shortcomings are discussed. Both single- and multiple-unit dosage forms are reviewed and, if available, results from in vivo trials are reported.     

Controlled Release of DNA Binding Anticancer Drugs from Gold Nanoparticles with Near-Infrared Radiation

Traditional chemotherapies target rapidly developing cells in the human body resulting in harsh side effects including fatigue, immune system suppression, and nausea, among others. Delivery systems to focus the active pharmaceutical ingredients (APIs) to the diseased tissue can diminish the negative side effects while improving treatment outcomes. Gold nanoparticles (AuNP) offer many unique advantages as drug delivery vehicles, including being biologically inert, easily adaptable to various shapes and sizes, able to create a strong Au-thiol bond, and able to generate heat upon the absorption of near-infrared light. To this end, a AuNP delivery vehicle was engineered to load and release two DNA binding anti-cancer drugs, mithramycin and doxorubicin, in a controlled fashion. The drugs were loaded onto the surface of the AuNP with temperature sensitive linkages. The amount of heat generated, and subsequent release of the drugs was controlled by the irradiation time with a near-infrared laser. By modulating the linkage used to load the drugs three different release profiles were able to be achieved, indicating the feasibility of such a system for combinational therapy requiring sequential release of APIs.