In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications.

Several locally acting colon-targeted products to treat colonic diseases have been recently developed and marketed, taking advantage of gastrointestinal physiology to target delivery. Main mechanisms involve pH-dependent, time-controlled and/or enzymatic-triggered release. With site of action located before systemic circulation and troublesome colonic sampling, there is room for the introduction of meaningful in vitro methods for development, quality control (QC) and regulatory applications of these formulations. A one-size-fits-all method seems unrealistic, as the selection of experimental conditions should resemble the physiological features exploited to trigger the release. This article reviews the state of the art for bio-predictive dissolution testing of colon-targeted products. Compendial methods overlook physiological aspects, such as buffer molarity and fluid composition. These are critical for pH-dependent products and time-controlled systems containing ionizable drugs. Moreover, meaningful methods for enzymatic-triggered products including either bacteria or enzymes are completely ignored by pharmacopeias. Bio-predictive testing may accelerate the development of successful products, although this may require complex methodologies. However, for high-throughput routine testing (e.g., QC), simplified methods can be used where balance is struck between simplicity, robustness and transferability on one side and bio-predictivity on the other. Ultimately, bio-predictive methods can occupy a special niche in terms of supplementing plasma concentration data for regulatory approval.

Colonic delivery of metronidazole-loaded capsules for local treatment of bacterial infections: A clinical pharmacoscintigraphy study.

Drug delivery to the colon offers great promise for local treatment of colonic diseases as it allows bypassing systemic absorption in the small intestine, thereby increasing luminal drug concentrations in the colon. The primary objective of this in vivo pharmaco-scintigraphy study was to assess the colon drug targeting accuracy of a metronidazole benzoate colonic drug delivery system intended for local treatment of Clostridioides difficile infections. Additionally, it was assessed if the concept of mucoadhesion would increase colonic residence time and promote higher drug bioavailability. Two different capsule formulations were designed and tested in healthy human subjects. Capsules contained either non-mucoadhesive (NM) or mucoadhesive (M) microgranules, both loaded with 100 mg metronidazole benzoate (antibiotic prodrug) and 5 mg samarium oxide (scintigraphy tracer). Filled capsules were coated with a colonic-targeting technology consisting of two functional layers, which allow for accelerated drug release mediated by the intestinal pH in combination with colonic bacteria. Coated capsules were neutron-activated to yield the radioisotope 153Sm prior to administration to 18 healthy subjects. Gamma-scintigraphy imaging was combined with the measurement of drug plasma levels. Formulation NM showed high colon-targeting accuracy. Initial capsule disintegration within the targeted ileocolonic region was observed in 8 out of 9 subjects (89%) with colonic arrival times in the range of 3.5-12 h and reduced systemic exposure. In contrast, the mucoadhesive formulation M showed some inconsistency regarding the site of initial capsule disintegration (targeting accuracy 56%). Variability of drug release was attributed to self-adhesion and agglomeration of the mucoadhesive microparticles within the capsule. Accurate ileocolonic delivery of metronidazole-loaded microgranules was achieved following oral administration of colonic-targeted capsules. Delayed drug release from NM microparticles in the colon leads to a reduced systemic exposure compared to immediate-release data from literature and presumably elevated drug concentrations in the colonic lumen. This approach offers promising options for the local treatment of colonic diseases.

A dual pH and microbiota-triggered coating (Phloral™) for fail-safe colonic drug release.

Enteric-coated dosage forms are widely used for targeting the ileo-colonic region of the gastrointestinal (GI) tract. However, accurate targeting is challenging due to intra- and inter-individual variability in intestinal paramaters such as fluid pH and transit times, which occasionally lead to enteric coating failure. As such, a unique coating technology (Phloral™), which combines two independent release mechanisms - a pH trigger (Eudragit® S; dissolving at pH 7) and a microbiota-trigger (resistant starch), has been developed, offering a fail-safe approach to colonic targeting. Here, we demonstrate that the inclusion of resistant starch in the coating does not affect the pH mediated drug release mechanism or the robustness of the coating in the upper GI tract. In order to make the resistant starch more digestible by bacterial enzymes, heat treatment of the starch in the presence of butanol was required to allow disruption of the crystalline structure of the starch granules. Under challenging conditions of limited exposure to high pH in the distal small intestine fluid and rapid transit through the colon, often observed in patients with inflammatory bowel disease, particularly in ulcerative colitis, this dual-trigger pH-enzymatic coating offers a revolutionary approach for site specific drug delivery to the large intestine.

OPTICORE™, an innovative and accurate colonic targeting technology.

Inflammatory bowel disease (IBD) is a debilitating condition, estimated to affect 7 million people worldwide. Current IBD treatment strategies are substandard, relying on colonic targeting using the pH gradient along the gastrointestinal tract. Here, we describe an innovative colonic targeting concept, OPTICORE™ coating technology. OPTICORE™ combines two release triggers (pH and enzyme: Phloral™) in the outer layer, with an inner layer promoting a release acceleration mechanism (Duocoat™). The technology comprises an inner layer of partially neutralized enteric polymer with a buffer agent and an outer layer of a mixture of Eudragit® S and resistant starch. 5-aminosalicylic acid (5-ASA) tablets were coated with different inner layers, where the type of polymer, buffer salt concentration and pH of neutralization, were investigated for drug release acceleration. Buffer capacity of polymethacrylate neutralized polymer significantly contributes to the buffer capacity of the inner layer formulation, while buffer salt concentration is a major contributor to dispersion buffer capacity in the case of hypromellose enteric polymer formulations. An interplay between buffer capacity, pH and ionic strength contributes to an accelerated drug release. Resistant starch does not impact the enteric properties but allows for drug release mediated by colonic bacterial enzymes, ensuring complete drug release. Therefore, OPTICORE™ technology is designed to offer significant advantages over standard enteric coatings, particularly allowing for more accurate colonic drug delivery in ulcerative colitis patients.

A slippery slope: On the origin, role and physiology of mucus.

The mucosa of the gastrointestinal tract, eyes, nose, lungs, cervix and vagina is lined by epithelium interspersed with mucus-secreting goblet cells, all of which contribute to their unique functions. This mucus provides an integral defence to the epithelium against noxious agents and pathogens. However, it can equally act as a barrier to drugs and delivery systems targeting epithelial passive and active transport mechanisms. This review highlights the various mucins expressed at different mucosal surfaces on the human body, and their role in creating a mucoid architecture to protect epithelia with specialized functions. Various factors compromising the barrier properties of mucus have been discussed, with an emphasis on how disease states and microbiota can alter the physical properties of mucus. For instance, Akkermansia muciniphila, a bacterium found in higher levels in the gut of lean individuals induces the production of a thickened gut mucus layer. The aims of this article are to elucidate the different physiological, biochemical and physical properties of bodily mucus, a keen appreciation of which will help circumvent the slippery slope of challenges faced in achieving effective mucosal drug and gene delivery.

Mucoadhesive microparticles for local treatment of gastrointestinal diseases.

Mucoadhesive microparticles formulated in a capsule and delivered to the gastrointestinal tract might be useful for local drug delivery. However, swelling and agglomeration of hydrophilic polymers in the gastrointestinal milieu can have a negative influence on particle retention of mucoadhesive microparticles. In this work, we investigated the impact of dry-coating with nano-sized hydrophilic fumed silica on dispersibility and particle retention of mucoadhesive microparticles. As a model for local treatment of gastrointestinal diseases, antibiotic therapy of Clostridium difficile infections with metronidazole was selected. For particle preparation, we used a two-step fluidized-bed method based on drug loading of porous microcarriers and subsequent outer coating with the mucoadhesive polymer chitosan. The prepared microparticles were analysed for drug content, and further characterized by thermal analysis, X-ray diffraction, and scanning electron microscopy. The optimal molecular weight and content of chitosan were selected by measuring particle retention on porcine colonic mucosa under dynamic flow conditions. Mucoadhesive microparticles coated with 5% (weight of chitosan coating/total weight of particles) of low molecular weight chitosan showed good in vitro particle retention, and were used for the investigation of dispersibility enhancement. By increasing the amount of silica, the dissolution rate measured in the USPIV apparatus was increased, which was an indirect indication for improved dispersibility due to increased surface area. Importantly, mucoadhesion was not impaired up to a silica concentration of 5% (w/w). In summary, mucoadhesive microparticles with sustained-release characteristics over several hours were manufactured at pilot scale, and dry-coating with silica nanoparticles has shown to improve the dispersibility, which is essential for better particle distribution along the intestinal mucosa in humans. Therefore, this advanced drug delivery concept bears great potential, in particular for local treatment of gastrointestinal diseases.

Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets.

Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.

Gastrointestinal stability of therapeutic anti-TNF α IgG1 monoclonal antibodies.

Monoclonal antibodies (mAbs) are highly effective therapeutic agents, administered exclusively by the parenteral route owing to their previously-documented instability in the gastrointestinal (GI) tract when delivered orally. To investigate the extent of the validity of this assumption, the stability of the tumor necrosis factor alpha (TNF-α) neutralizing IgG1 mAbs, infliximab and adalimumab, was studied in human GI conditions. In gastric fluid, infliximab and adalimumab degraded rapidly, with complete degradation occurring within 1 min. In small intestinal fluid, the molecules were shown to be more stable, but nonetheless degraded within a short time frame of 30 min. Investigations into the mechanisms responsible for infliximab and adalimumab instability in the small intestine revealed that the proteolytic enzyme elastase, and to a lesser extent the enzymes trypsin and chymotrypsin, was responsible for their degradation. By contrast, in the human colon, 75% and 50% of the dose of infliximab and adalimumab, respectively, were intact after 60 min, with conversion of mAbs into F(ab')2 Fab and Fc fragments detected in colonic conditions. These data indicate that therapeutic IgG1 antibodies are more stable in the colon than in the upper GI tract, therefore highlighting the potential for oral delivery of anti-TNF-α mAbs targeted to the colon.

A Systematic Study on Manufacturing of Prilled Microgels into Lipids for Oral Protein Delivery.

The development of novel systems with oral protein delivery as ultimate goal represents an important field of pharmaceutics. Prilling of protein-loaded polymeric solutions into lipid-based hardening baths could provide here an attractive formulating technology. As the obtained microgel dispersion can be directly capsule-filled, no drying step is required and thermal drug degradation is avoided. This study aims to find excipient combinations for the novel prilling process and investigate systematically diverse material and process factors. Bovine serum albumin and mono-N-carboxymethyl chitosan were selected as model protein and prilling polymer, respectively. The prilling suitability of 880 formulations was screened with 60 ternary phase diagrams comprising two co-solvents, 10 different glycerides, and three so-called complementary excipients. Preliminary capsule compatibility was tested for one month on 245 formulations in hard and soft capsules with different shell materials. Ternary phase diagrams' center points were used to evaluate morphology, encapsulation efficiency, and protein stability of the prilled microgels. As result, several formulations proved suitable for prilling and compatible for capsule filling. Statistical analysis using partial least square regression revealed significant factors regarding different quality attributes of microgel dispersions. Therefore, an improved understanding was obtained for this promising drug delivery approach.

Marker-ion analysis for quantification of mucoadhesivity of microparticles in particle-retention assays.

The objective of the present work was to develop an improved method to quantify particle retention on mucosal tissue under dynamic flow conditions with simultaneous determination of drug dissolution. The principle was to dissolve the collected inert carrier material and quantify specific marker ions by reliable analytical methods. The mucoadhesive model particles consisted of drug-loaded porous calcium carbonate microcarriers coated with chitosan, and quantification of calcium ions by capillary electrophoresis enabled to determine particle-retention kinetics on colonic mucosal tissue. The method was validated by image analysis, and the particle-retention assay was successfully applied to granulate material (125-250 mm) and small particles (<90 µm) with mucoadhesive properties. Particle retention on colonic mucosa was improved by increasing the chitosan content, demonstrating the sensitivity and usefulness of marker-ion analysis for quantification of detached particles. Furthermore, we showed that drug dissolution from mucoadhesive microparticles followed comparable kinetics in the particle-retention assay and the standard USP IV method. Our findings are helpful for the development of micro-sized colonic drug delivery systems, in particular for optimization of mucoadhesive properties and sustained drug release kinetics of porous drug carriers.

On prilling of hydrophilic microgels in lipid dispersions using mono-N-carboxymethyl chitosan for oral biologicals delivery.

Oral delivery of biologicals is a thriving field in pharmaceutics and the first challenge is to achieve a stable drug product. Interesting is prilling of a drug-containing polymeric solution as microgel into an aqueous hardening bath where crosslinking occurs. However, to deliver a final dosage form, for example, soft gelatin capsules, the aqueous hardening bath must be removed, thus leading to manufacturing processes that are potentially harmful for the active. The current work introduces a prilling method with a lipid-based hardening bath, which could theoretically be filled directly into capsules. Bovine serum albumin (BSA) and mono-N-carboxymethyl chitosan (MCC) were selected as model biological and encapsulating polymer, respectively. Several nonaqueous formulations of the receiving bath were investigated; calcium chloride was added to these formulations to allow the MCC gelling. The obtained microgels had average diameters of ∼300 µm and spherical to toroidal shapes, according to the hardening bath composition. Along with a high encapsulation efficiency (>85%), the microgels protected the BSA from any denaturing effect of the hardening bath. The release study showed a rather fast BSA release within the first 10 min from most microgels. This novel approach demonstrated technical viability for encapsulation of biologicals using lipid formulations regarding oral delivery.

Influence of ageing on the gastrointestinal environment of the rat and its implications for drug delivery.

Age-mediated changes in gut physiology are considerations central to the elucidation of drug performance from oral formulations. Using rats of different age groups we measured the pH, buffer capacity, fluid volume, osmolality, and surface tension of gastrointestinal (GI) fluids, and therein explored the impact of these variables on prednisolone and mesalazine solubility in luminal fluids. We also studied the distribution of gut associated lymphoid tissue (GALT) and mucus layer thickness across the GI tract in rats of different age groups. At a mucosal level, there was an increase in GALT from young to adult rat. Gastrointestinal pH and buffer capacity remained mostly unchanged with age, except some pH differences in stomach and distal small intestine and a higher buffer capacity in the large intestinal fluids of young rats. Osmolality and surface tension also remained unaffected with the exception of a lower osmolality in elderly stomach and a lower surface tension in the small intestine of young rats. The difference in luminal environment on ageing influenced the solubility of studied drugs, for instance prednisolone solubility was shown to be higher in adult rats (mid small intestine and caecum) and solubility of mesalazine was significantly higher in the elderly distal small intestine.

Accelerating the dissolution of enteric coatings in the upper small intestine: evolution of a novel pH 5.6 bicarbonate buffer system to assess drug release.

Despite rapid dissolution in compendial phosphate buffers, gastro resistant (enteric coated) products can take up to 2 h to disintegrate in the human small intestine, which clearly highlights the inadequacy of the in vitro test method to predict in vivo behaviour of these formulations. The aim of this study was to establish the utility of a novel pH 5.6 bicarbonate buffer, stabilized by an Auto pH™ System, as a better surrogate of the conditions of the proximal small intestine to investigate the dissolution behaviour of standard and accelerated release enteric double coating formulations. Prednisolone tablets were coated with 3 or 5 mg/cm(2) of partially neutralized EUDRAGIT(®) L 30 D-55, HP-55 or HPMC adjusted to pH 6 or 8. An outer layer of EUDRAGIT(®) L 30 D-55 was applied at 5mg/cm(2). For comparison purposes, a standard single layer of EUDRAGIT(®) L 30 D-55 was applied to the tablets. Dissolution was carried out using USP II apparatus in 0.1 M HCl for 2 h, followed by pH 5.6 bicarbonate buffer. EUDRAGIT(®) L 30 D-55 single-coated tablets showed a slow drug release with a lag time of 75 min in buffer, whereas release from the EUDRAGIT(®) L 30 D-55 double-coated tablets was accelerated. These in vitro lag times closely match the in vivo disintegration times for these coated tablets reported previously. Drug release was further accelerated from modified double coatings, particularly in the case of coatings with a thinner inner layer of HP-55 or HPMC (pH 8 and KH2PO4). This study confirms that the pH 5.6 bicarbonate buffer system offers significant advantages during the development of dosage forms designed to release the drug in the upper small intestine.

Drug loading into porous calcium carbonate microparticles by solvent evaporation.

Drug loading into porous carriers may improve drug release of poorly water-soluble drugs. However, the widely used impregnation method based on adsorption lacks reproducibility and efficiency for certain compounds. The aim of this study was to evaluate a drug-loading method based on solvent evaporation and crystallization, and to investigate the underlying drug-loading mechanisms. Functionalized calcium carbonate (FCC) microparticles and four drugs with different solubility and permeability properties were selected as model substances to investigate drug loading. Ibuprofen, nifedipine, losartan potassium, and metronidazole benzoate were dissolved in acetone or methanol. After dispersion of FCC, the solvent was removed under reduced pressure. For each model drug, a series of drug loads were produced ranging from 25% to 50% (w/w) in steps of 5% (w/w). Loading efficiency was qualitatively analyzed by scanning electron microscopy (SEM) using the presence of agglomerates and drug crystals as indicators of poor loading efficiency. The particles were further characterized by mercury porosimetry, specific surface area measurements, differential scanning calorimetry, and USP2 dissolution. Drug concentration was determined by HPLC. FCC-drug mixtures containing equivalent drug fractions but without specific loading strategy served as reference samples. SEM analysis revealed high efficiency of pore filling up to a drug load of 40% (w/w). Above this, agglomerates and separate crystals were significantly increased, indicating that the maximum capacity of drug loading was reached. Intraparticle porosity and specific surface area were decreased after drug loading because of pore filling and crystallization on the pore surface. HPLC quantification of drugs taken up by FCC showed only minor drug loss. Dissolution rate of FCC loaded with metronidazole benzoate and nifedipine was faster than the corresponding FCC-drug mixtures, mainly due to surface enlargement, because only small fractions of amorphous drug (12.5%, w/w, and 8.9%, w/w, respectively) were found by thermal analysis. Combination of qualitative SEM analysis and HPLC quantification was sufficient to proof the feasibility of the solvent-evaporation method for the loading of various drugs into FCC. Mechanistic investigation revealed that a high specific surface area of the carrier is required to facilitate heterogeneous nucleation, and large pore sizes (up to 1 µm) are beneficial to reduce crystallization pressures and allow drug deposition within the pores. The solvent-evaporation method allows precise drug loading and appears to be suitable for scale-up.

Mucus thickness in the gastrointestinal tract of laboratory animals.

OBJECTIVES: The objective of this study was to systematically assess the mucus thickness in the gastrointestinal tract of laboratory animals commonly used in preclinical studies. METHODS: Mucus thickness was studied post-mortem in the rat, rabbit and pig, using cryosections stained by the modified periodic acid Schiff/Alcian blue method. KEY FINDINGS: The mucus thickness in the fundus region of the stomach was higher in the pig (190.7 ± 80.7 µm) than in the rabbit (155.1 ± 85.8 µm) and the rat (31.3 ± 11.4 µm). However, along the small intestine (ileum), mucus was thicker in the rabbit (147.8 ± 115.6 µm), followed by the pig (53.8 ± 22.1 µm) and the rat (34.1 ± 14.9 µm). This rank order was also observed in the ascending colon. CONCLUSIONS: Inter-species variability in mucus thickness along the gut was demonstrated and suggests that the pig resembles more closely the mucus pattern of humans. This may be highly relevant when preclinical animal models are used in drug absorption studies or in the development of oral mucoadhesive drug delivery systems.

Mucoadhesive platforms for targeted delivery to the colon.

A novel platform system, comprising a mucoadhesive core and a rapid release carrier, was designed for targeted drug delivery to the colon. Prednisolone pellets containing different carbomers, including Carbopol 971P, Carbopol 974P and Polycarbophil AA-1, with or without organic acids, were produced by extrusion-spheronization. Mucoadhesive pellets were coated with a new enteric double-coating system, which dissolves at pH 7. This system comprises an inner layer of partially neutralized Eudragit S and buffer salt and an outer coating of standard Eudragit S. A single layer of standard Eudragit S was also applied for comparison purposes. Dissolution of the coated pellets was assessed in USP II apparatus in 0.1N HCl followed by Krebs bicarbonate buffer pH 7.4. Visualization of the coating dissolution process was performed by confocal laser scanning microscopy using fluorescent markers in both layers. The mucoadhesive properties of uncoated, single-coated and-double coated pellets were evaluated ex vivo on porcine colonic mucosa. Mucoadhesive pellets coated with a single layer of Eudragit S release its cargo after a lag time of 120 min in Krebs buffer. In contrast, drug release from the double-coated mucoadhesive pellets was significantly accelerated, starting at 75 min. In addition, the mucoadhesive properties of the core of the double coated pellets were higher than those from single-coated pellets after the core had been exposed to the buffer medium. This novel platform technology has the potential to target the colon and overcome the variability in transit and harmonize drug release and bioavailability.

Oral modified-release formulations in motion: the relationship between gastrointestinal transit and drug absorption.

Oral modified-release dosage forms can be designed with the aim of achieving specific pharmacokinetic profiles, delivering to specific gut localities or reducing the number of drug administrations. Multiple-unit systems, such as pellets, beads or granules, often claim superiority to single-unit modified-release formulations in terms of predictability and reproducibility of behaviour in the gastrointestinal tract. This is an oversimplification and in this review we discuss the effect of the highly variable gastrointestinal transit on the bioperformance of multiple-unit dosage forms, relative to their single-unit counterparts. We examine the sometimes contradictory literature in this area and highlight specific case studies which demonstrate the effect of intestinal transit on dosage form performance and drug absorption.

An investigation into the role of mucus thickness on mucoadhesion in the gastrointestinal tract of pig.

Mucoadhesion in the gastrointestinal tract is a complex phenomenon and both formulation and physiological features need to be well understood and considered. Mucus thickness has been inferred to play a role in this process; however no definitive influence has been established. This study aimed to investigate the influence of mucus thickness on the mucoadhesion process, using a large animal (pig) as a model to closely resemble the human physiological features. The mucus thickness of different regions of the gastrointestinal tract of pig was fully measured by means of a histochemical method (hematoxilin/eosin) employing cryostat sections. Mucoadhesion was evaluated ex vivo on porcine mucosa by tensiometry using a polyacrylic acid polymer (Carbopol 974P NF) as a mucoadhesive model material, both in a dry and swollen state. Mucus was thickest in the stomach (body 67.9+/-54.7 microm) and mucus thickness increased from proximal to distal segments in both the small intestine (duodenum 25.9+/-11.8 microm, ileum 31.0+/-15.7 microm) and large intestine (caecum 19.4+/-8.7 microm, ascending colon 31.9+/-17.2 microm, descending colon 35.1+/-16.0 microm and rectum 40.8+/-12.5 microm). Swollen polymer exhibited lower mucoadhesion than the dry form in all sections analysed. Mucus thickness plays a role on the mucoadhesion, as thicker mucus provides deeper polymer chain diffusion and entanglements; however, other factors are also involved in this complex process.

Estudos de mucoadesão no trato gastrointestinal para o aumento da biodisponibilidade oral de fármacos: [revisão] / Mucoadhesion studies in the gastrointestinal tract to increase oral drug bioavailability: [revision]

A biodisponibilidade oral de muitos fármacos é limitada pelo tempo de residência das formas farmacêuticas ao longo do trato gastrointestinal. A mucoadesão tem sido proposta como forma de prolongar o tempo de residência em determinada zona, contribuindo para o aumento do efeito terapêutico dos fármacos. O estômago e o intestino delgado têm sido preferencialmente os alvos de estudo da mucoadesão, tendo sido observados resultados promissores em ensaios in vitro. Contudo, alguns ensaios em humanos, usando a técnica de γ-cintigrafia, têm revelado o insucesso da mucoadesão como forma de aumentar o tempo de contacto de formulações no trato gastrointestinal superior. A falta de correlação in vitro/in vivo pode ser atribuída à complexidade do trato gastrointestinal humano. Muitos dos modelos in vitro reproduzem apenas em parte as condições observadas in vivo. Outros fatores, tais como a motilidade, o pH, a espessura e a taxa de renovação de muco, presença de enzimas e alimentos, não têm sido simulados em ensaios in vitro. A taxa de renovação do muco, a sensibilidade aos estímulos secretores e a motilidade são mais baixas no cólon que no estômago e intestino delgado. Portanto, a mucoadesão no cólon poderá constituir um conceito mais bem sucedido. Contudo, são necessários mais estudos quer em modelos animais quer em humanos para avaliar o seu verdadeiro potencial. Além disso, são necessários estudos de farmacocinética para determinar a libertação e posterior absorção do fármaco a partir do sistema mucoadesivo.

The oral bioavailability of many drugs can be limited by the residence time of pharmaceutical dosage forms in the gastrointestinal tract. Mucoadhesion has been proposed as a method to increase residence time at a specific area, hence increasing the therapeutic effect of drugs. Most research efforts on mucoadhesion have focused on the stomach and small intestine, with promising results observed from in in vitro studies. However, γ-scintigraphy data obtained in human studies have revealed the lack of success of mucoadhesion approaches in order to increase the contact time of formulations in the upper gut. The lack of in vitro/in vivo correlation can be attributed to the complex nature of the human gastrointestinal tract, with most in vitro models providing little resemblance to the in vivo situation, such as motility, pH, mucus thickness and mucus turnover, presence of enzymes and food. In the colon, the mucus turnover, the sensibility to mucus secretory stimulus and motility are lower than in the stomach and small intestine. Therefore, colonic mucoadhesion may be a more successful approach. Nevertheless, more studies in animals and humans are needed to evaluate its potential, as well as, pharmacokinetic studies to investigate drug release and absorption from mucoadhesive systems.

Mucoadhesion and the gastrointestinal tract.

The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption or improve topical therapy. A variety of approaches have been investigated for mucoadhesion in the gastrointestinal tract, particularly for the stomach and small intestine. Despite interesting results in these sites, mucoadhesive approaches have not yet shown success in humans. The potential of the lower gut for these applications has been largely neglected, although the large intestine in particular may benefit, and the colon has several factors that suggest mucoadhesion could be successful there, including lower motility and the possibility of a lower mucus turnover and thicker mucus layer. In vitro studies on colonic mucoadhesion show promise, and rectal administration has shown some positive results in vivo. This review considers the background to mucoadhesion with respect to the physiological conditions of the gastrointestinal tract as well as the principles that underlie this concept. Mucoadhesive approaches to gastrointestinal drug delivery will be examined, with particular attention given to the lower gut.