Felipe J.O. Varum

Food, physiology and drug delivery.

Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known variables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences of food and beverage intake as just two of these variables on oral drug delivery have been extensively documented in the wider literature, specific information on their effects remains sporadic, and is not so much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Likewise, the often detrimental effects of alcohol (ethanol) on dosage form performance have been widely observed experimentally, but knowledge of which has only moderately impacted on clinical practice. Here, we attempt to piece together the available subject matter relating to the influences of both solid and liquid foodstuffs on the gastrointestinal milieu and the implications for oral drug delivery, with particular emphasis on the behaviour of modified-release dosage forms, formulation robustness and drug absorption. Providing better insight into these influences, and exemplifying cases where formulations have been developed or modified to circumvent their associated problems, can help to appropriately direct the design of future in vitro digestive modelling systems as well as oral dosage forms resilient to these effects. Moreover, this will help to better our understanding of the impact of food and alcohol intake on normal gut behaviour and function.

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.

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.

A novel coating concept for ileo-colonic drug targeting: Proof of concept in humans using scintigraphy

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT S neutralised to pH 8.0 and a buffer salt (10% KH₂PO₄), which was overcoated with layer of standard EUDRAGIT S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1N HCl for 2h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region.

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.

Estudos de mucoadesão no trato gastrointestinal para o aumento da biodisponibilidade oral de fármacos

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.

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

Abstract 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. Graphical abstract Figure. No Caption available.

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.

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.