Colonic Drug Delivery System Research Articles

Development and in-vitro evaluation of a colon-specific controlled release drug delivery system

Abstract The major challenges in targeting drug to various parts of the gastrointestinal tract include control of drug release with respect to its environment and transit time. These two variables should be taken into consideration in designing a rational colonic drug delivery system. To this end, a swelling matrix core containing pectin, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose and 5-aminosalicylic acid was developed. This was subjected to a dual coating operation: an inner pH-sensitive enteric and an outer semi-permeable membrane coat with a pore former. In-vitro dissolution studies were carried out in USP apparatus-I using sequential pH media. The first 2 h of dissolution studies were done in HCl buffer at pH 1.5, the next 2 h in pH 5.5 and, finally, in phosphate buffer at pH 6.8 with and without pectinolytic enzyme present. Less than 2% drug was released in the first 6 h and about 90% released in the following 12 h in a controlled manner. The stability studies of the coated systems were performed for 90 days under various conditions and it was found that drug release was not adversely affected. Results indicate that this delivery system has potential for site-specific delivery of drugs to the colon irrespective of transit time and rapid changes in the proximal pH of the gastrointestinal tract.

Hydrogels for Potential Colon Drug Release by Thiol‐ene Conjugate Addition of a New Inulin Derivative

Inulin was chosen as a starting polymer for biocompatible, pH-sensitive and biodegradable hydrogels. Three INUDVSA-TT hydrogels were obtained by crosslinking inulin derivatives with trimethylolpropane tris(3-mercaptopropionate) under varying conditions. The resulting hydrogels were cell compatible, as demonstrated by MTS and trypan blue exclusion assays acting on Caco-2 cells, and were biodegraded by inulinase and esterase, thus suggesting their use as colonic drug delivery systems. 2-Methoxyestradiol, an anti-cancer drug, was soaked in INUDVSA-TT hydrogels and its in vitro release and apoptotic effect on Caco-2 cells were evaluated.

Design of a Potential Colonic Drug Delivery System of Mesalamine

The aim of the present investigation was to develop a site-specific colonic drug delivery system, built on the principles of the combination of pH and time sensitivity. Press-coated mesalamine tablets with a coat of HPMC E-15 were over-coated with Eudragit® S100. The in vitro drug release study was conducted using sequential dissolution technique at pH 1.2, 6.0, 7.2 and 6.4 mimicking different regions of gastrointestinal tract. The optimized batch (F2) showed less than 6% of drug release before reaching colonic pH 6.4 and complete drug release was obtained thereafter within 2 hr. A short-term dissolution stability study demonstrated statistical insignificant difference in drug release.

Studies on development of oral colon targeted drug delivery system of locust bean and xanthan gum.

Colon drug delivery system of Aceclofenac was attempted using locust bean and xanthan gum. The influence of buffer pH and drug/polymer ratio on the drug release was studied. Dissolution studies were performed in HCl buffer pH1.2, Phosphate buffer pH 7.4 and Phosphate buffer pH 6.8. The results were then compared by pretreatment of all formulations with HCl buffer pH1.2 for 2 hours followed by next 3 hours in Phosphate buffer pH 7.4 and then in 100 ml Phosphate buffer pH 6.8 that contained 4% w/v rat caecal contents for further 19 hours. The rapid release of drug was seen from formulation having 100% locust bean gum. Whereas, it was relatively slow for matrices containing optimum concentration of xanthan gum and locust bean gum. Thus it can be concluded that locust bean and xanthan gums have good potential to act as carrier for developing Colon drug delivery system. Key words: Colon specific drug delivery, Locust bean gum, Xanthan gum, aceclofenac.

Preparation and In Vitro Evaluation of pH, Time-Based and Enzyme-Degradable Pellets for Colonic Drug Delivery

The preparation of pH-dependent, time-based and enzyme degradable pellets was investigated for use as an oral colonic drug delivery system. It was expected that drug would be released immediately once the pellets reached the colon. The pellets were prepared using extrusion-spheronizing equipment and subsequently coated with three layers of three functional polymers by an air-suspension technique. The core consisted of 5-aminosalicylic acid (5-ASA) as a model drug, CaP as an enzyme-degradable material and microcrystalline cellulose (MCC) as an additive. As far as the three coated layers were concerned, the outer layer was coated with Eudragit L30D-55 for protection against gastrointestinal juices, the intermediate layer was coated with ethylcellulose (EC) to inhibit drug release during passage through the small intestine, and the inner film was coated with pectin for swelling and enzyme-degradation, which required a 30, 10, and 12% weight gain, respectively. Several micromeritic properties of the core pellets, including particle size distribution, particle size, degree of circularity, and friability, were evaluated to investigate the effects of the formulations of the cores and preparation conditions. Also, dissolution testing of the cores showed that the presence of calcium pectinate (CaP) markedly increased the drug release rate from the cores, as determined by scanning electron microscopy (SEM). In-vitro release studies indicated that the coated pellets completely protected the drug release in 0.1 mol/L HCl, while the drug release was delayed for 3–4 hr in pH 6.8 PBS. A synergistic effect of enzyme dependence for the coated pellets was seen following removal of the coated layer and during contact with colonic enzymes. Consequently, it was possible to achieve colon-specific drug delivery using this triple-dependence system.

Characterization of diffusion of macromolecules in konjac glucomannan solutions and gels by fluorescence recovery after photobleaching technique

Konjac glucomannan (KGM) is a neutral polysaccharide with interesting properties as gelling agent and thickener. Its peculiar biodegradability, being not degradable in the small intestine but degradable by the anaerobic human intestinal bacteria, turn it into a promising candidate for colonic drug delivery systems. In this study aqueous systems (0.5%, w/v,) of KGM from three different origins and their mixtures with xanthan gum (XG) (1:1) were evaluated as regards their rheological properties and the diffusion coefficients and mobile fraction of macromolecules (dextrans of different molecular weight). Rheological data illustrate the synergism between KGM and XG at a stoichiometric relationship 1:1. Moreover, fluorescence recovery after photobleaching (FRAP) data indicate that diffusion of probes through the polysaccharide systems cannot be completely explained by the macroscopic properties of the medium but it is related to their molecular size and as a consequence to a sieving mechanism. The strong differences between KGM from different suppliers suggest the convenience of establishing specifications for this material in order to use it as pharmaceutical excipient.

Colon drug delivery

Oral drug delivery to the colon has attracted significant attention during the past 20 years. Colon targeting is recognised to have several therapeutic advantages, such as the oral delivery of drugs that are destroyed by the stomach acid and/or metabolised by pancreatic enzymes. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Local treatment of colonic pathologies, such as ulcerative colitis, colorectal cancer and Crohn’s disease, is more effective with the delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents requires smaller doses. This article aims to provide an insight into the design and manufacturing considerations, and an evaluation of colonic drug delivery systems in order to understand why there are still few delivery technologies that have reached the market, despite intensive research in this field. For this purpose, various approaches to colon-specific drug delivery are discussed.

Polymer Colon Drug Delivery Systems and their Application to Peptides, Proteins, and Nucleic Acids

Most therapeutic peptides and proteins are administered via the parenteral route, which presents numerous drawbacks and limitations. To overcome these drawbacks, alternative administration routes, such as oral or mucosal routes, have been investigated. The oral route presents a series of attractive advantages for the administration of therapeutic compounds, such as the avoidance of the pain and discomfort associated with injections, good patient compliance, and being less expensive to produce. However, oral administration of peptides, proteins, or nucleic acids also presents several difficulties because of their instability in the upper gastrointestinal (GI) tract and their poor transport across biologic membranes. Among the various approaches developed to improve the oral delivery of peptides, proteins, or nucleic acids, specific delivery to the colon has attracted a lot of interest because of its potential for the local treatment of colonic diseases, systemic delivery of poorly absorbed drugs, and vaccine delivery. Numerous pharmaceutical approaches described in this review have been exploited for the development of colon-targeted drug delivery systems using various concepts, such as pH-dependent, time-dependent, pressure-controlled, or bacterially triggered delivery systems. The action of the pH-dependent delivery systems is based on pH differences between the stomach and the ileum. Time-dependent delivery systems are based on the transit time of pharmaceutical dosage forms in the GI tract, drug release being delayed until they reach the colon. A combination of pH- and time-dependent delivery systems has also been described to avoid the drawbacks of both strategies. The pressure-controlled delivery concept exploits the physiologic luminal pressure of the colon as the driving force for site-specific delivery of drugs. Finally, bacterially triggered delivery systems exploit the enormous diversity of enzymatic activity associated with the colonic microflora. Bacterially triggered delivery systems are generally composed of polymers, which are specifically degraded by colonic enzymes of microbial origin. These polymers have been used to form prodrugs with the drug moiety, as coating materials for the drug core, or as embedding media to entrap the drug into matrix or hydrogel systems. Each of these concepts has advantages and limitations. They present varied colonic specificity and, among them, bacterially triggered delivery systems in particular show the greatest potential for colonic delivery of peptides, proteins, and nucleic acids.

Avaliação das propriedades de intumescimento e permeabilidade de filmes isolados de polimetacrilato contendo polissacarídeo da raiz de Lótus (Nelumbo nucifera)

Polissacarídeo extraído da raiz de Lótus (Nelumbo nucifera) adicionado a polimetacrilato foi utilizado para a obtenção de filmes isolados, constituindo material candidato ao revestimento de formas farmacêuticas sólidas orais, sendo estas voltadas à liberação modificada de fármacos, potencialmente suscetíveis à degradação pela microflora presente exclusivamente na região distal do trato gastrintestinal. A adição do polissacarídeo ao polímero de base, dispersão aquosa Eudragit®RS 30D, ocorreu em diferentes proporções: 100:0, 90:10, 80:20, 70:30. Os filmes isolados foram caracterizados pela determinação do índice de intumescimento e pela transmissão de vapor de água. Os resultados registraram, para as diferentes associações testadas, características de transparência (opacidade) e de flexibilidade alteradas e dependentes do aumento da concentração do polissacarídeo: 100:0>90:10>80:20>7030, o mesmo ocorrendo no tocante à permeabilidade ao vapor d'água. Todavia estas diferenças não foram significativas entre si, demonstrando manutenção das propriedades físico-químicas do polímero sintético contendo polissacarídeo, o que permite sugerir o material obtido como candidato potencial ao desenvolvimento de sistema para liberação colônica.

Preparation and Characterization of Theophylline-Chitosan Beads as an Aapproach to Colon Delivery

Chitosan with excellent biodegradable and biocompatible characteristics has received attention as an oral drug delivery vehicle for controlled-release formulations. In this study an enteric-coated capsule containing theophylline-chitosan beads based on 2 3 factorial designs was prepared as a colon drug delivery system. The theophylline-chitosan gel beads were formulated by adding the drug-containing solution of chitosan into tripolyphosphate solutions, dropwise. The obtained beads were washed with water and freeze-dried before filling into the capsules. Eudragit ® S100 was then used to enteric-coat the prepared capsules. Drug entrapment efficiency and the effects of different variables including: bead morphology, swelling behavior of the beads and the release behavior of the system on these parameters were investigated. Results showed that the highest and lowest swelling ratio is obtained at pH 4.5 and 7.2, respectively. These studies have shown that chitosan concentration and drug polymer weight ratio significantly affect the drug entrapment. Decreasing the drug solubility in external phase caused a significant increase in drug loading. External phase saturation with theophylline and tripolyphosphate, as well as decreasing temperature, have increased drug loading. Furthermore, the lowering of temperature had a significant effect on bead's hardness. The release of theophylline from freeze-dried beads filled in enteric-coate d capsules was also investigated. Release of theophylline was prolonged with saturation of both drug and tripolyphosphate in the external phase. Results showed that the release of theophylline from chitosan beads is possibly due to more than one mechanism, possibly dissolution, diffusion and relaxation of the polymer chains.

Development of Enteric-coated Pectin-based Matrix Tablets for Colonic Delivery of Theophylline

The present work was aimed at developing a new colonic drug delivery system which takes advantage of the combined approaches of a specifically colon-biodegradable pectin matrix with a pH-sensitive Eudragit® S100 polymeric coating. The developed system was able to suitably retard the onset of drug release and to provide a colon-specific delivery, thus overcoming the problems of pectin solubility in the upper gastrointestinal tract and low site-specificity of simple pH-dependent systems. Due to the poor compactability properties of pectin, it was used in mixture with Emdex®, a hydrophilic directly-compressible material, in order to make it possible to prepare tablets by direct compression. Theophylline (TP) was used as model drug due to its suitable pharmacokinetic properties for colonic delivery and good absorption in the large intestine. The effects of varying the type of pectin (low and high methoxylated, or amidated), the pectin:Emdex® ratio and the level of the pH-dependent polymeric coating on drug release behavior were investigated. Release tests were performed using sequential liquids simulating the physiological variation of pH and the effect of the presence or not of pectinolytic enzymes into the simulated colonic medium was evaluated. Thirty percent (w/w) was the the minimum content of Emdex® for obtaining directly compressible tablets with sufficient hardness to withstand the coating process and 27% (w/w) was the minimum coating amount for obtaining an adequate lag time before the onset of drug release. After lag time, linear nearly zero-order profiles were obtained whose slope (i.e. the drug release rate) depended on both the Emdex® content and the pectin type. Comparison of the results obtained in the presence or not of pectynolitic enzymes allowed selection of the high methoxylated pectin as the most interesting candidate for specific colonic delivery since it was the least water-soluble and the most susceptible to enzymatic degradation, thus assuring a greater site-specificity of drug release. Finally, the importance of using appropriate dissolution test conditions to adequately characterize the drug release profiles from delivery systems endowed with a microflora-activated drug release triggering mechanism has been demonstrated.

Colonic drug delivery: an updated review.

Specific targeting of drug to the colon is recognized to have several therapeutic advantages. Drugs that are destroyed by the acidic environment of the stomach or metabolized by pancreatic enzymes are only slightly affected in the colon. Sustained colonic delivery of drugs can be useful in the treatment of nocturnal asthma, angina, and arthritis. Treatment of colonic diseases such as ulcerative colitis, Crohn's disease, and colorectal cancer is more effective with direct delivery of drugs to the colon. This article is aimed at providing insight into the design considerations and evaluation of colonic drug delivery systems. The anatomy and physiology of the lower gastrointestinal tract is discussed; then the biopharmaceutical aspects are considered in relation to drug absorption in the colon. Various approaches to colon-specific drug delivery are discussed.

Investigation of Potential Ionic Interactions Between Anionic and Cationic Polymethacrylates of Multiple Coatings of Novel Colonic Delivery System

ABSTRACTThe objective of this work was to investigate potential interactions between anionic (Eudragit FS) and cationic (Eudragit RL) polymethacrylates of multiple coatings of a novel colonic drug delivery system. Aqueous films of pure polymers Eudragit FS (FS) and Eudragit RL (RL) and their superimposed film (FS–RL) were cast on glass slabs. The potential ionic interactions were studied by analyzing the dried films using differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and nuclear magnetic resonance (NMR). The glass transition temperatures (Tg) of pure RL and FS were 60°C and 22°C, respectively; FS–RL showed two distinct glass transitions at 59°C and 24°C in the second heating cycle. In the 13C-MAS spectra of the samples in the solid state, no shifts of the resonance could be detected in the superimposed film compared with the pure polymers. The FT-IR spectra of the superimposed film did not show any significant shift of the bands of the group of RL and the –COO− function of FS compared with the spectra of the pure polymers. No ionic interactions between anionic and cationic polymethacrylates were revealed by DSC, FT-IR, and NMR.

A novel pH- and time-based multi-unit potential colonic drug delivery system. I. Development

A novel delivery system was developed for delivering drugs to the colon by selecting polymethacrylates with appropriate pH dissolution characteristics for the distal end of the small intestine and relying upon the relatively constant transit time of the small intestine. Pellets were prepared by powder layering of 5-aminosalicylic acid (5-ASA) on nonpareils (0.5–0.6 mm) in a conventional coating pan. Drug-layered pellets were coated with an inner layer of a combination of two pH-independent polymers Eudragit ® RL and RS (2:8), and an outer layer of a pH-dependent polymer, Eudragit FS. Scanning electron micrograph (SEM) pictures of the coated pellets showed the uniformity of both the coatings. The release profile of 5-ASA was studied in three phosphate buffers after a simulated gastric pre-soak for 2 h in pH 1.2 media. There was no drug release for 12 h at pH 6.5. There was a sustained release of 5-ASA for over 12 h both at pH 7.0 and 7.5 after a lag time at pH 7.0 and no lag time at pH 7.5. The release rate was faster at pH 7.5 than at pH 7.0. The delivery system demonstrated its potential for colonic delivery by resisting drug release until pH 6.5 and the combination of Eudragit RL and RS proved successful for the sustained delivery of 5-ASA at the expected pH of the colon.

A novel pH- and time-based multi-unit potential colonic drug delivery system. II. Optimization of multiple response variables

The objective of this work was to optimize a novel potential colonic drug delivery system by using a statistical procedure. Pellets were prepared by powder layering of 5-aminosalicylic acid (5-ASA) on nonpareils (0.5–0.6 mm) in a coating pan. Drug-layered pellets were coated with an inner layer of a combination of Eudragit ® RL and RS and an outer layer of Eudragit FS in a fluidized-bed apparatus. Central composite design was used to study the effect of three independent variables. The proportion of the more hydrophilic polymer Eudragit RL had the most significant effect on drug release – higher proportion gave faster release; the amount of inner and outer coat did not have a significant effect on the rate of drug release at either 6 or 12 h in the range studied. A second order polynomial equation was fitted to the data, and the resulting equation was used to predict the responses in the optimal region. An optimized formulation was prepared and evaluated for individual responses. The experimental values of the response variables highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of coated pellets having predictable drug release for colonic delivery of 5-ASA.

In vitro evaluation of colonic drug delivery system based on a disulphide-linked polymer: [formula omitted], MA Khan, PJ Watts, CD Melia, SS Davis. Department of Pharmaceutical Sciences, University of Nottingham NG7 2RD, UK

In vitro evaluation of colonic drug delivery system based on a disulphide-linked polymer: [formula omitted], MA Khan, PJ Watts, CD Melia, SS Davis. Department of Pharmaceutical Sciences, University of Nottingham NG7 2RD, UK

Polysaccharide gels for colon targeting

AbstractPolysaccharides appear to have a potential as drug carriers for site‐specific drug delivery to the colon due to the well‐known fermentation of polysaccharides by the anaerobic microflora in the colon. This paper gives a short presentation of the rationale of colon‐specific drug delivery and briefly describes various in vitro and in vivo methods for testing of polysaccharide gels for colonic drug delivery. The application of dextran hydrogels is used as an illustrative example of a polysaccharide based colonic drug delivery system.

In vitro evaluation of pectin-based colonic drug delivery systems

Pectin-based dosage forms with the potential for site-specific delivery to the colon have been evaluated using isolated enzymes and cultures of Bacteroides ovatus. The system used was designed and validated to allow systematic testing of colonic dosage forms which depend on the action of colonic bacteria for drug release. Preliminary experiments show the similarity in release patterns for the dosage form tested with isolated enzymes and bacterial cultures. This should enable further experiments to be performed to ascertain valid in vitro testing conditions.

Amylose as a coating for drug delivery to the colon: Preparation and in vitro evaluation using glucose pellets

The potential of amylose a constituent of starch, as a novel colonic drug delivery system has been investigated. In this study glucose was used as a model drug and incorporated into pellets (diameter 1.40–1.70 mm) that were prepared by extrusion and spheronisation. The behaviour of different glucose containing pellets coated with an amylose-Ethocel® mixture (ratio 1:4 w/ w) has been investigated in vitro. Dissolution release profiles of the formulation demonstrated in vitro gastric and small intestine resistance. High volatile fatty acid and carbon dioxide concentrations during in vitro fermentation studies showed that the formulation was susceptible to bacterial enzymatic attack.

An evaluation of pectin as a carrier for drug targeting to the colon

A novel colonic drug delivery system based on the polysaccharide pectin has been investigated. In vitro experiments demonstrated that high methoxy pectin (pectin USP), when applied as a compression coat, proved capable of protecting a core tablet during conditions mimicking mouth-to-colon transit and was susceptible to enzymatic attack. In vivo gamma scintigraphic studies confirmed the in vitro findings. In all the volunteers, the pectin-coated tablets disintegrated in the colon indicating that site-specificity had been achieved and illustrating the potential of a colonic drug delivery system utilising pectin.