Cutting-edge technologies in colon-targeted drug delivery systems

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.     

基于炎症环境的口服结肠靶向给药系统研究进展

口服结肠靶向给药系统由于能改善结肠局部疾病的治疗效果和降低副作用而成为该领域的研究热点。口服给药系统设计方法的不断发展显著提高了药物在结肠部位的生物利用度,然而,要使药物在发病期能够发挥治疗效果,还须关注到结肠炎症时胃肠道出现生理条件变化的影响。纳米技术已经作为提高药物在结肠炎症病灶区摄取的新策略而应用于口服剂型设计中,本文主要介绍该纳米给药系统的设计方法和研究进展。     

Getting into the colon: approaches to target colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the world and the second most common cause of cancer related deaths. Conventional treatment of CRC is comprised of drug (chemotherapeutic agents) administration by parenteral route, which delivers the drug to both normal as well as cancerous tissues, thus leading to numerous undesirable effects. Enormous research is going on worldwide for designing an alternative route of administration, among which oral colon-targeted drug delivery systems have gained immense attention amongst scientific community. Direct delivery of drugs at the site of action leads to an increase in the availability of drugs at the targeted region. This causes a reduction in the amount of drug required to exert same therapeutic effect, thus reducing the incidents of adverse effects. Various maneuvers (pH-dependent, time-dependent and microflora-activated systems) have been attempted by researchers for targeting drugs successfully to the colonic region by circumventing the upper part of gastrointestinal tract. This Editorial article aims to put forth an overview of the formulation technologies that have been developed for attaining colon specific drug delivery for the treatment of CRC.     

Polymers for colon targeted drug delivery

The colon targeted drug delivery has a number of important implications in the field of pharmacotherapy. Oral colon targeted drug delivery systems have recently gained importance for delivering a variety of therapeutic agents for both local and systemic administration. Targeting of drugs to the colon via oral administration protect the drug from degradation or release in the stomach and small intestine. It also ensures abrupt or controlled release of the drug in the proximal colon. Various drug delivery systems have been designed that deliver the drug quantitatively to the colon and then trigger the release of drug. This review will cover different types of polymers which can be used in formulation of colon targeted drug delivery systems.     

Chitosan: a potential polymer for colon-specific drug delivery system

Introduction: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.

Areas covered: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.

Expert opinion: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).     

Target-specific drug release to the colon

Background: The ability to deliver drugs to the human colon in a specific manner has become feasible over the years. Targeting pharmaceutical drugs to the colon makes it possible to achieve local or systemic drug delivery to this site. Objective: To deliver the compounds in a non-degraded form to the lower part of the gastrointestinal tract, they must first pass through the stomach and the upper part of the intestine before releasing the contents in the colon. Methods: This review provides an overview of the various approaches to targeted drug delivery to the colon using different drug delivery systems, their limitations and the future developments in this field. Results/conclusions: A microbially controlled system, which is a well-accepted approach, based on natural polymers, has the greatest potential for colonic delivery, particularly in terms of site specificity and safety. However, close attention should be paid to the performance of these products in the heterogeneous environment of the human gastrointestinal tract.     

Colon targeted drug delivery systems--an overview

In the last two decades colon targeted drug delivery has gained increased importance not just for the deliver drugs for the treatment of various colonic diseases but also for its potential for delivery of proteins and therapeutic peptides. In the past various traditional approaches used for colon targeted delivery like prodrugs, pH, time dependent, and microflora activated systems, have achieved limited success. For successful colon targeted drug delivery, the drug needs to be protected from absorption and/or the environment of the upper gastrointestinal tract and then be abruptly released into the colon. Hence continuous efforts have been made on designing colon targeted drug delivery systems with improved site specificity and versatile drug release kinetics to fulfill different therapeutic needs. In last couple of years few new systems have been developed for colon targeted drug delivery such as pressure dependent systems, CODES technology, microsponges, pectin and galactomannan coating, microbially triggered osmotic systems, lectins and neoglyconjugated etc. which are reported to have better in-vivo site specificity and design rationale than the earlier approaches. This review article gives an overview of various approaches for colonic targeted drug delivery with emphasis on newer systems, their merits and demerits, in vitro/ in-vivo evaluation and market status of such delivery systems.     

Colonic Drug Delivery: Prodrug Approach

The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. One of the approaches used for colon specific drug delivery is the formation of a prodrug which optimizes drug delivery and improves drug efficacy. Many prodrugs have been evaluated for colon drug delivery. These prodrugs are designed to pass intact and unabsorbed from the upper GIT and undergo biotransformation in the colon releasing the active drug molecule. This biotransformation is carried out by a variety of enzymes, mainly of bacterial origin present in the colon (e.g. azoreductase, glucuronidase, glycosidase, dextranase, esterase, nitroreductase, cyclodextranase, etc.). The present review includes varius prodrug approaches investigated for colon drug delivery and their site specificity.     

Enhanced therapeutic effect of LK-423 in treating experimentally induced colitis in rats when administered in colon delivery microcapsules

LK-423 is a phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity. In the present study the therapeutic efficacy of a colon-specific drug delivery system–LK-423 microcapsules–was examined in the 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced ulcerative colitis model in rats. The colon-specific delivery of the drug using microcapsules relies on the combination of pH (outer gastroresistant coating), time (inner retard coating of Eudragit® RS and RL) and enzyme (pectin core) controlled drug release mechanisms. The optimal in vitro dissolution profile for LK-423 delivery to the colon of rats was obtained after coating newly developed LK-423 loaded pectin cores with 20% w/w of retard coating with a Eudragit® RS/RL ratio of 8.5/1.5 and 30% w/w of enteric coating. Orally administered LK-423 microcapsules were therapeutically more beneficial in treating TNBS-induced ulcerative colitis in rats than orally or rectally administered LK-423 in the form of suspension. Clinical activity scores and colon weight to length ratio were insignificantly lower and the macroscopically estimated degree of healing was significantly greater. On the histological level, the administration of LK-423 microcapsules resulted in most physiological regeneration of intestinal mucosa, indicated by regular architecture of all mucosal tissue components, what is probably related to local drug delivery near the site of inflammation achieved using microcapsules. These results demonstrate that LK-23 colon delivery microcapsules enhance the therapeutic efficacy of the drug and therefore appear to be a useful approach for treating various inflammatory diseases in the large intestine.     

Polysaccharides in colon-specific drug delivery

Natural polysaccharides are now extensively used for the development of solid dosage forms for delivery of drug to the colon. The rationale for the development of a polysaccharide based delivery system for colon is the presence of large amounts of polysaccharidases in the human colon as the colon is inhabited by a large number and variety of bacteria which secrete many enzymes e.g. beta-D-glucosidase, beta-D-galactosidase, amylase, pectinase, xylanase, beta-D-xylosidase, dextranase, etc. Various major approaches utilizing polysaccharides for colon-specific delivery are fermentable coating of the drug core, embedding of the drug in biodegradable matrix, formulation of drug-saccharide conjugate (prodrugs). A large number of polysaccharides have already been studied for their potential as colon-specific drug carrier systems, such as chitosan, pectin, chondroitin sulphate, cyclodextrin, dextrans, guar gum, inulin, amylose and locust bean gum. Recent efforts and approaches exploiting these polysaccharides in colon-specific drug delivery are discussed.     

Colon targeting: an emerging frontier for oral insulin delivery

Subcutaneous administration of insulin is associated with several limitations such as discomfort, local pain, irritation, infections, immune reactions and lipoatrophy as well as lipohypertrophy manifestations at the injection site. To overcome these drawbacks, enormous research is currently going on worldwide for designing of an alternative noninvasive route of administration. Pulmonary and oral route seem to be the most promising ones, with respect to the market value. However, after the letdown by pulmonary delivery of insulin, oral colon targeted delivery of insulin has gained tremendous interest among researchers. Although bioavailability remains a challenge for oral colon specific delivery of insulin, the employment of protease inhibitors, permeation enhancers and polymeric delivery systems have proved to be advantageous to overcome the said problem. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the strategies employed for attaining non-erratic bioavailability of insulin, and to highlight some of the formulation technologies that have been developed for attaining oral colon-specific delivery of insulin.     

Polysaccharides: a targeting strategy for colonic drug delivery

Introduction: Colon targeting has gained increasing importance for the topical treatment of diseases of the colon, such as Crohn's disease, ulcerative colitis, colorectal cancer and amebiasis. Various strategies used for targeting drugs to the colon include formation of a prodrug, coating with time or pH-dependent polymers, use of colon-specific biodegradable polymers, osmotic systems and pressure-controlled drug delivery systems. Among the different approaches used, polysaccharides that are precisely activated by the physiological conditions of the colon hold great promise, as they provide improved site specificity and meet the desired therapeutic needs.

Areas covered: This review aims to summarize the natural and modified properties of polysaccharides that are responsible for their colon targeting abilities. Emphasis is placed on describing formulation approaches that use polysaccharides as a strategy for targeting drugs to the colon.

Expert opinion: Polysaccharide-based colon-targeted drug delivery systems are effective when they are precisely activated by the physiological conditions of the colon. Absence of enzymes during colonic disorders might hinder the activation of the delivery system. To guarantee delivery of the drug to the colon, it is preferable to combine polysaccharides with enteric or cellulose polymers.     

Recent trends in microbially and/or enzymatically driven colon-specific drug delivery systems

Colon-specific drug delivery systems have recently gained enormous importance for the delivery of a variety of therapeutic compounds. To deliver a drug molecule intact to the colon, the delivery system must pass through the upper part of the gastrointestinal tract without being degraded. Researchers have attempted various approaches in the formulation of colon-specific drug delivery systems. Among them, the most promising are the microbially and/or enzymatically driven drug delivery systems, consisting of biodegradable polymers (polysaccharides) and prodrugs. The major advantage of the microbially and/or enzymatically driven colon-specific drug delivery systems is that they can sense the arrival of the formulation in the colon and release the drug upon activation. This review familiarizes readers with the recent advancements in microbially and/or enzymatically driven colon-specific drug delivery systems, along with their in vitro and in vivo evaluation.     

pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.     

Eudragit®: a technology evaluation

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

Areas covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed.

Expert opinion: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150^oC. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH ≥ 5, can prevent drug release in saliva and finds application in taste masking.     

In vitro evaluation of chondroitin sulphate-chitosan microspheres as carrier for the delivery of proteins

A novel formulation based on chondroitin sulphate/chitosan microspheres (CS/CH) has been investigated for oral delivery of macromolecules using ovalbumin as the model protein (OVA). The microspheres were prepared by a new emulsion-complex coacervation method. Physico-chemical properties of the polymers constituting microparticulate matrix were investigated by IR, DSC, TGA and X-ray diffraction analyses. In vitro tests were performed to evaluate the drug delivery system degradation and the protein release under conditions simulating the intestinal fluids. The ability of colonic enzymes to degrade the microparticulate systems was simulated employing the chondroitinase ABC enzyme. Results showed that the different CS/CH compositions influenced both microparticles stability and the protein release rate. Only the microspheres composed by 1:1 chondroitin sulphate–chitosan ratio achieved an OVA release profile suitable to a possible colon targeting. These microspheres released ～30% of ovalbumin encapsulated in 24 h in the different aqueous media tested, while they released 100% of protein in the presence of chondroitinase. The preliminary results demonstrated that chondroitin sulphate-chitosan microspheres can be a suitable delivery system for protein drug envisaged to oral administration.     

Factors affecting mechanism and kinetics of drug release from matrix-based oral controlled drug delivery systems

Matrix technologies have often proven popular among the oral controlled drug delivery technologies because of their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form, and ease of scale-up and process validation. Technological advancements in the area of matrix formulation have made controlled-release product development much easier than before, and improved upon the feasibility of delivering a wide variety of drugs with different physicochemical and biopharmaceutical properties. This is reflected by the large number of patents filed each year and by the commercial success of a number of novel drug delivery systems based on matrix technologies. Matrix-based delivery technologies have steadily matured from delivering drugs by first-order or square-root-of-time release kinetics to much more complex and customized release patterns. In order to achieve linear or zero-order release, various strategies that seek to manipulate tablet geometry, polymer variables, and formulation aspects have been applied. Various drug, polymer, and formulation-related factors, which influence the in situ formation of a polymeric gel layer/drug depletion zone and its characteristics as a function of time, determine the drug release from matrix systems. Various mathematical models, ranging from simple empirical or semi-empirical (Higuchi equation, Power law) to more complex mechanistic theories that consider diffusion, swelling, and dissolution processes simultaneously, have been developed to describe the mass transport processes involved in matrix-based drug release. Careful selection of an appropriate model for drug release provides insight to the underlying mass transport mechanisms and helps in predicting the effect of the device design parameters on the resulting drug-release rate. Thus, a basic understanding of release kinetics and appropriate mechanisms of drug release from matrix system and their inter-relationships may minimize the number of trials in final optimization, thereby improving formulation development processes.     

Recent developments in buccal and sublingual delivery systems

Introduction: There have been several advances in the delivery of drugs through the buccal mucosa over the last 5 years, which have resulted in a number of new buccal delivery products appearing on the market.

Areas covered: This review discusses the most recent developments in the area of buccal and sublingual drug delivery, with a focus on marketed drugs. Likely future directions are also considered and reported.

Expert opinion: The future potential of buccal and sublingual delivery systems looks favorable. It is envisaged that in the future, buccal and sublingual delivery technologies will provide a platform for the successful delivery of vaccines and antigens. It is also foreseen that physical means of enhancing drug uptake (e.g., sonophoresis, iontophoresis and electroporation) will be commercialized for buccal delivery, thereby expanding the current drug candidate list for this area. The formulation of delivery systems for photosensitizers in photodynamic therapy is a potential emerging area, while buccal and sublingual delivery, in general, is attractive for the development of intellectual property.     

口服结肠定位给药系统

综述了近年来口服结肠定位给药系统的发展状况 ,并评价了各类结肠定位给药系统的优、缺点和发展前景     

Oral colon-specific drug delivery of protein and peptide drugs

With the advent of new technologies and radical growth in the field of biotechnology, dozens of protein and peptide drugs have been marketed. However, there are several challenges for successful delivery of such molecules. A number of routes have been used for the delivery of these fragile molecules by exploring various novel delivery technologies, including microspheres, liposomes, gel spheres, nano-spheres, niosomes, microemulsions, use of permeation enhancers, use of protease inhibitors, etc. But the route that has attracted the attention of worldwide drug delivery scientists is the oral route due to its various advantages. Even though the proteolytic activity is higher in a few segments of the gastrointestinal tract (GIT), this route has certain segments that have lower proteolytic activity, for example, the colon. The colon has captured attention as a site for the delivery of these molecules because of its greater responsiveness to absorption enhancers, protease inhibitors, and novel bioadhesive and biodegradable polymers. Although the success rate of these approaches, when used alone is pretty low, when used in combinations, these agents have demonstrated wonders in increasing the drug bioavailability. This review focuses on the challenges, pharmaceutical concepts, and approaches involved in the delivery of these fragile molecules, specifically to the colon. This review also includes studies conducted on colonic targeting of such drugs. Further studies may lead to improvements in therapy using protein/peptide drugs and refinements in the technology of colon-specific drug delivery.