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Bacteria aided biopolymers as carriers for colon specific drug delivery system: A Review
Abstract
Biopolymers are promising materials in the delivery of drugs due to their compatibility, degradation behaviour, and nontoxic nature on administration. On suitable chemical modification, these polymers can provide better materials for drug delivery systems. Biopolymers like natural polysaccharides obtained from various sources are being extensively used for the development of solid dosage forms for delivery of drug to the colon. The rationale for the development of a biomaterial based drug 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. β-D-glucosidase, β-D-galactosidase, amylase, pectinase, xylanase, β-D-xylosidase, dextranase, etc.. A large number of polysaccharides have already been studied for their potential as colon-specific drug carrier systems, such as the polysaccharides, from algal origin (e.g. alginates), plant origin (e.g. pectin, guar gum, locust bean gum, khaya gum, konjac glucomannan) microbial origin (e.g. dextran, xanthan gum) and animal origin (Chitosan, chondroitin, hyaluronic acid). The ability of these natural polysaccharides to act as substrates for the bacterial inhabitants of the colon together with their properties, such as swelling and film forming has appeal to area of colon specific drug delivery as it is comprised of polymer with large number of derivatizable groups, with wide range of molecular weight, varying chemical composition, biocompatibility, low toxicity and biodegradability and a high stability .Various major approaches utilizing biopolymers in modified or unmodified form, for colon-specific delivery like fermentable coating of the drug core, embedding of the drug in biodegradable matrix and multiparticulate formulation of drug-saccharide conjugate (prodrugs) are discussed.
... However, oral administration has drawbacks, for instance, low bioavailability resulted from first-pass effect for some drugs like aspirin (a kind of antipyretic analgesics) ( 2003). And low effective utilization of protein and peptide drugs, for they will be destroyed under some relatively hostile in vivo environments such as stomach and small intestine (Patel-Parul, Satwara-Rohan, & Pandya, 2012). In order to improve bioavailability and obtain effective utilization of these drugs, three main approaches are adopted. ...
... For these excipients degraded by colonic bacterial enzymes specifically, some natural polysaccharides are included, such as chitosan, guar gum, amylase, inulin, konjac glucomannan, locust bean gum are usually used to prepare and study OCDDS (Sinha & Kumria, 2001;Vandemme, Lenourry, Charrueau, & Chaumeil, 2002). They are biodegradable in colon and have good gel-forming ability (Patel-Parul et al., 2012). It was known that KGM gel systems were able to maintain integrity and control the release of theophylline and diltiazem for 8 h (Avachat, Dash, & Shrotriya, 2011). ...
... Being studied early in late 19th century (Smith & Srivastava, 1959), KGM, a natural neutral polysaccharide produced from tubers of Amorphophallus konjac (Fang & Wu, 2004), has been found a promising excipient for colon targeting drugs in recent decades for it can specifically degraded by colon -mannanase (Li, Qi, Li, Ding, & Zong, 2004), a kind of enzyme generated by human colon bacteria (Patel-Parul et al., 2012). Ma, Wang, Du and Guo (2009) studied extraction, purification, physical and chemical properties of KGM, content and toxicity tests indicated that KGM was a stable and safety material for medicinal purpose. ...
Oral colon targeting drug delivery system (OCDDS) is a highly effective formulation for drugs absorbed by colon, or to treat colonic diseases specifically. To obtain colon targeting, many pharmaceutical approaches have been studied, among which, taking advantage of specific degradation of excipients by colon enzymes is one of the most promising strategies. With properties of specific colon β-mannanase degradation, biocompatibility, gel-forming, low toxicity and high stability, konjac glucomannan (KGM) becomes a promising natural excipient for oral OCDDS. This paper summaries structure and properties of KGM, reviews achievements and prospects on KGM and modified konjac glucomannan about their application as pharmaceutic excipient for the OCDDS recently.
... Polysaccharides can also be used in colon delivery systems as a system sensitive to microbial degradation. Bacterial activity in the colon, which leads to the production of azoreductase, nitroreductase, glucosidase, glucuronidase, and esterase enzymes, can be the breakdown and destruction of the polysaccharide in the dosage form and causes a specific release of drug in the colon area (Patel Parul et al. 2012). Therefore, all these items should be considered in the formulation design. ...
Synthetic drugs and monoclonal antibodies are the typical treatments to combat inflammatory bowel disease (IBD). However, side effects are present when these treatments are used, and their continued application could be restricted by the high relapse rate of the disease. One potential alternative to these treatments is the use of plant-derived products. The use curcumin is one such treatment option that has seen an increase in usage in treating IBD. Curcumin is derived from a rhizome of turmeric (Curcuma longa), and the results of studies on the use of curcumin to treat IBD are promising. These studies suggest that curcumin interacts with cellular targets such as NF-κB, JAKs/STATs, MAPKs, TNF-α, IL-6, PPAR, and TRPV1 and may reduce the progression of IBD. Potentially, curcumin can be used as a therapeutic agent for patients with IBD when it reduces the incidence of clinical relapse. This review discusses the strategies utilized in designing and developing an oral colonic delivery dosage form of curcumin.
... The recent interest in the colonic delivery focused on the use of colonic microflora as a mechanism for drug release. Indeed, it represents a noncontinuous event, independent of GI transit time [6]. The use of non-starch polysaccharide for the development of colon targeting delivery systems is based on the fact that they could be degraded by the variety of enzymes of colonic bacteria. ...
Arabinoxylans (AX) microspheres with different insulin/AX mass ratio were prepared by formation of phenoxy radical issued from the ferulic acid by enzymatic oxidation (entrapped in situ of insulin). Phenolic acid content and FT-IR spectrum of unloaded and insulin-loaded AX microspheres revealed that the phenoxy radical issued from the ferulic acid by enzymatic oxidation did not interact covalently with insulin. The microspheres showed a spherical shape, smooth surface and an average diameter of particles of 320 μm. In vitro control release found that AX microspheres minimized the insulin loss in the upper GI tract, retaining high percentage (~75%) of insulin in its matrix. The stability of the secondary structure of insulin was studied by dichroism circular (CD). The CD spectra of insulin released from AX microspheres did not change according to the insulin/AX mass ratio of the microsphere. Significant hypoglycemic effects with improved insulin-relative bioavailability tested on an in vivo murine model revealed the efficacy of these enzymatically cross-linked arabinoxylans microspheres as a new oral insulin carrier.
... 26 Además, estos biopolímeros no son degradados por las enzimas del estómago ni del intestino delgado y sí por la microflora presente en el colon proporcionándose una liberación vectorizada o dirigida. 27,28 Dentro de los polímeros sintéticos más representativos se encuentran el poli (ácido acrílico), el poli (ácido metacrílico) y los polímeros con grupos amino cuaternarios en su estructura. 29,30 Su ventaja radica en la obtención de materiales con propiedades controlables y reproducibles; por lo que son modulados con facilidad para alcanzar las propiedades deseadas de acuerdo a cada aplicación. ...
Annual increase in the number of patients diagnosed with inflammatory bowel diseases has drawn the attention of scientists and physicians, due to the severe side effects of these conditions and the many times patients need to attend medical consultation, both of which considerably lower their quality of life. The present review deals with the potential of pH-sensitive hydrogels as one of the best therapeutic strategies capable of releasing the bioactive substance in the colon, improving the chances of achieving better results. An analysis is conducted of their hydrophilicity, their capacity to respond to pH variations and the versatility of their preparation methods, reaching micro- and nanoscale sizes. The purpose of the analysis is to show the advantages, limitations, recent advances and future perspectives of their oral administration.
... 26 Además, estos biopolímeros no son degradados por las enzimas del estómago ni del intestino delgado y sí por la microflora presente en el colon proporcionándose una liberación vectorizada o dirigida. 27,28 Dentro de los polímeros sintéticos más representativos se encuentran el poli (ácido acrílico), el poli (ácido metacrílico) y los polímeros con grupos amino cuaternarios en su estructura. 29,30 Su ventaja radica en la obtención de materiales con propiedades controlables y reproducibles; por lo que son modulados con facilidad para alcanzar las propiedades deseadas de acuerdo a cada aplicación. ...
Annual increase in the number of patients diagnosed with inflammatory bowel diseases has drawn the attention of scientists and physicians, due to the severe side effects of these conditions and the many times patients need to attend medical consultation, both of which considerably lower their quality of life. The present reviewdeals with the potential of pH-sensitive hydrogels as one of the best therapeutic strategies capable of releasing the bioactive substance in the colon, improving the chances of achieving better results. An analysis is conducted of their hydrophilicity, their capacity to respond to pH variations and the versatility of their preparation methods, reaching micro- and nanoscale sizes. The purpose of the analysis is to show the advantages, limitations, recent advances and future perspectives of their oral administration.
... The natural polysaccharides such as chitosan, guar gum, inulin, konjac glucomannan (KGM) and locust bean gum are usually used to prepare and study controlled drug delivery system. They are biodegradable in the colon and have good gel-forming abilities (Patel-Parul et al., 2012;Yu and Xiao, 2008). KGM are involved in many other types of applications, such as encapsulation, controlled release, etc. ...
... Normal in patients with ulcerative colitis. [20,21] The best Candidates for CDDS are drugs which show poor absorption from the stomach or intestine including peptides. The drugs used in the treatment of IBD, ulcerative colitis, diarrhea, and colon cancer are ideal candidates for local colon delivery. ...
Oral delivery has become a widely accepted route of administration of therapeutic drugs. The gastrointestinal tract presents several formidable barriers to drug delivery. The delivery of drugs to the colon has a number of therapeutic implications in the field of drug delivery. The objective of the present study is to develop colon targeted drug delivery system by using polysaccharide as a carrier. The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. The various approaches that can be exploited to target the release of drug to colon include prodrug formation, coating with pH sensitive polymers, coating with biodegradable polymers, embedding in biodegradable matrices, hydrogel, timed release systems, osmotic and bioadhesive systems. In this review article we have made an attempt to give an overview on polysaccharide-based colon specific drug delivery system.
... The natural polysaccharides such as chitosan, guar gum, inulin, konjac glucomannan (KGM) and locust bean gum are usually used to prepare and study controlled drug delivery system. They are biodegradable in the colon and have good gel-forming abilities (Patel-Parul et al., 2012;Yu and Xiao, 2008). KGM are involved in many other types of applications, such as encapsulation, controlled release, etc. ...
This chapter focuses on nutritional and anti-nutritional factors, traditional processes for the removal of anti-nutrients, processing for flour, starch and discusses resistant starch from Elephant Foot Yams (EFY). Also, industrial utilization of Amorphophallus konjac into konjac flour and gum, glucomannan (KGM) and its applications as a food and pharmaceutical supplements are reviewed. The procedure for starch extraction from EFY is described by Amani et al. The EFY has many medicinal properties. In India, it is used in Ayurvedic drugs in the treatment of inflammatory conditions, hemorrhoids, rheumatism and gastrointestinal disorders. This flour produces a high viscosity and forms a gel by alkaline coagulant such as calcium hydroxide or by combining with secondary gum or co-gelated gum such as K-carrageenan and xanthan gum. In recent decades, methods for the extraction and purification of konjac glucomannan (KGM) have been studied and developed.
... [2][3][4][5] Polysaccharides belong to such class of biodegradable materials which are normally metabolized in the colon by bacterial enzymes. This approach is exploited to deliver various drugs using polysaccharides such as pectin, alginate, guar gum, amylase, inulin, dextran, chitosan, chondroitin sulphate etc. 6,7 The Multiparticulate system were developed in comparison to single unit systems because of their potential benefits like increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation. Most commonly investigated multiparticulate formulations for colon specific drug delivery include pellets, granular matrices, beads, microspheres and nanoparticles. ...
Purpose:
A Multiparticulate system of Mebendazole was developed for colon targeted drug delivery by using natural polysaccharides like Chitosan and Sodium-alginate beads.
Methods:
Chitosan microspheres were formulated by using Emulsion crosslinking method using Glutaraldehyde as crosslinking agent. Sodium-alginate beads were formulated by using Calcium chloride as gelling agent. Optimization for Chitosan microspheres was carried out by using 2(3) full factorial design. 3(2) full factorial design was used for the optimization of Sodium-alginate beads. The formulated batches were evaluated for percentage yield, particle size measurement, flow properties, percent entrapment efficiency, Swelling studies. The formulations were subjected to Stability studies and In-vitro release study (with and without rat caecal content). Release kinetics data was subjected to different dissolution models.
Results:
The formulated batches showed acceptable particle size range as well as excellent flow properties. Entrapment efficiency for optimized batches of Chitosan microspheres and sodium alginate beads was found to be 74.18% and 88.48% respectively. In-vitro release of drug for the optimized batches was found to be increased in presence of rat caecal content. The best-fit models were koresmeyer-peppas for Chitosan microspheres and zero order for sodium-alginate beads.
Conclusion:
Chitosan and Sodium-alginate was used successfully for the formulation of Colon targeted Multiparticulate system.
... In the previous studies, it was reported that KGM can be specifically degraded by colon βmannanase [158], an enzyme generated by human colon bacteria [159]. On the other hand, based on the toxicity tests Ancui et al. reported KGM as a stable and safety material for medicinal purposes [160]. ...
... The various approaches that can be exploited to target the release of drug to colon include prodrug formation, coating with pH sensitive polymers, coating with biodegradable polymers, embedding in biodegradable matrices, hydrogel, timed release systems, osmotic and bioadhesive system. Among the different approaches to achieve targeted drug release to the colon, the use of polymers especially biodegradable by colonic bacteria holds great promise and to deliver proteins and peptides to the colon for their systemic absorption 12,13 . ...
Colon-specific drug delivery has gained increased importance in the delivery of drugs for the treatment of local diseases associated with the colon, such as Crohn's disease, ulcerative colitis, colorectal cancer and amoebiasis. Metronidazole, an antiprotozoal drug is clinically effective in colonic diseases, both locally and systemically. The aim of this work was to prepare and evaluate Eudragit coated chitosan microspheres of metronidazole for colon targeting. Chitosan microspheres were prepared by emulsion dehydration method using different ratios of drug and polymer. Eudragit coated chitosan microspheres were performed by solvent evaporation method and were evaluated for percentage yield, flow property, particle size analysis, surface morphology, determination of drug content, drug entrapment efficiency, degree of swelling, in vitro drug release and its kinetic profile. The percentage yield of all formulations was more than 80%. The microspheres showed a spherical structure with a smooth surface morphology. The drug entrapment efficiency was found to be in between 68.8%-81.6%. The in vitro release was found to be in following order F3>F1>F2>F4>F5>F6. In the case of F3 only 13.03% of the drug was released in 5 hrs, but it showed high and fast increase in drug release from 6th hr in pH 6.8 phosphate buffer. It shows 90.52% drug release after 12hrs.The formulations gave good fit to the Zero order and the mechanism of drug release was diffusion. The results clearly demonstrated that the Eudragit S100 coated metronidazole chitosan microspheres is a potential system for colon-specific drug delivery.
Colon-targeted delivery systems are gaining increasing attention for both local and systemic actions. This is a very promising approach for oral delivery of drugs, including peptides. Other drugs that are unstable in the microenvironments of the upper gastrointestinal (GI) tract can be given in this manner as well. Delayed absorption of the drug(s) in accordance with the principles of circadian rhythm is also facilitated by colon-specific drug release. The colon presents a unique microenvironment from the rest of the GI tract in many aspects favoring the stability and absorption of many drugs. Polysaccharides display enormous potential for colon-specific targeting mainly owing to their resistance to upper GI tract environments along with pH sensitivity, rather easy digestion by colonic microbial enzymes, and the possibility of mucoadhesion. Natural plant-based polymers offer added advantages of excellent biocompatibility, and reduced toxicity compared to synthetic and/or semisynthetic counterparts. A number of plant polysaccharides and their analogs have been successful to achieve colon-specific targeting. The fact that most of them are approved pharmaceutical excipients makes them more desirable among the multiple approaches to colon targeting. Plant polysaccharide-based formulations and coatings are widely utilized to deliver drug(s) distinctly to the colonic region.
Next-generation biomaterials are expected to possess both desirable mechanical features and unique biological functions. Recently, two plant-derived glucomannans (GMs)-Konjac glucomannan (KGM) and the polysaccharide of Bletilla striata (BSP)-have emerged as new sources for development of biomaterials. They have been fabricated into drug delivery vehicles and wound healing dressings in varying shapes and sizes, and demonstrated strong gelling properties, high biocompatibility and remarkable convenience for processing and modification. Notably, they demonstrate bioactivities such as response to enzymes produced in special biological niches and/or affinity for carbohydrate receptors on specific cells. All these mechanical and biological advantages suggest these two GMs have great potential for future development and broader application in various biomedical and pharmaceutical fields.
The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented. In this study, we prepared a new capped mesoporous silica nanoparticle as a potential material for colon-specific drug delivery. This material consisted of nanoscopic mesoporous MCM-41 supports loaded with ibuprofen and capped with a bridged silsesquioxane with azo groups. X-ray diffraction, N2 sorption analysis, transmission electron microscopy, UV–vis diffusion reflectance spectroscopy, and 29Si magic angle spinning nuclear magnetic resonance were used to verify the well-ordered mesostructure and the successful grafting of bridged silsesquioxane on the surface of the mesoporous material. The material showed “zero release” in simulated gastric fluid and simulated intestinal fluid. The opening and release of cargo occurred in simulated colonic fluid with azo-reductase due to the reductive cleavage of the azo bonds. However, no release of ibuprofen was observed in phosphate-buffered saline without enzyme. These results indicated that the capped mesoporous material showed excellent behavior for colon specificity and could be a potential material for colon-specific drug delivery.
The objective of the present study is to develop a colon targeted drug delivery systems for Aceclofenac using xanthan gum as a carrier. In this study, multilayer coated system that is resistant to gastric and small intestinal conditions but can be easily degraded by colonic bacterial enzymes was designed to achieve effective colon delivery of Aceclofenac. The xanthan gum, the drug and the physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). All the formulations were evaluated for hardness, drug content uniformity and other physical properties. Release aspects of Aceclofenac in simulated gastrointestinal fluid and colonic fluid with enzymes were investigated. From these results, Eudragit coated system exhibited gastric and small intestinal resistance to the release of Aceclofenac. The rapid increase in release of Aceclofenac in SCF was revealed as due to the degradation of the xanthan gum membrane by bacterial enzymes. The designed system could be used potentially as a carrier for colon delivery of Aceclofenac by regulating drug release in stomach and the small intestine.
The aim of the present study was to develop a single unit, site-specific matrix tablets of aceclofenac allowing targeted drug release in the colon with a microbially degradable polymeric carrier, chondroitin suphate (CS) and to coat the optimized batches with a pH dependent polymeric. The tablets were prepared by wet granulation method using starch mucilage as a binding agent and HPMC K-100 as a swellable polymer. Chondroitin Sulphate and drug and physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The tablets were tested for their in-vitro dissolution characteristics in various simulated gastric fluids for their suitability as a colon-specific drug delivery system and also the tablets were evaluated for physicochemical properties, drug content, water percentage swelling and erosion characteristics. The dissolution data demonstrates that the 10% w/w increase in coating level of the pH dependent polymer (Eudragit L-100 and Eudragit S-100 in a ratio of 1 : 4 prevented the drug release in the simulated gastric fluid (pH 1.2-SGF) and the simulated intestinal fluid (pH 7.4-SIF). The dissolution rate of the tablet is dependent upon the concentration of Chondroitin sulphate in the simulated colonic fluid (SCF). The rapid increase in release of aceclofenac in SCF was revealed as due to the degradation of the Chondroitin sulphate membrane by bacterial enzymes. The studies confirmed that, the designed system could be used potentially as a carrier for colon delivery of aceclofenac by regulating drug release in stomach and the small intestine.
Hyaluronic acid (HA) is a high molecular weight biopolysacharide, discovered in 1934, by Karl Meyer and his assistant, John Palmer in the vitreous of bovine eyes. Hyaluronic acid is a naturally occurring biopolymer, which has important biological functions in bacteria and higher animals including humans. It is found in most connective tissues and is particularly concentrated in synovial fluid, the vitreous fluid of the eye, umbilical cords and chicken combs. It is naturally synthesized by a class of integral membrane protein s called hyaluronan synthases, and degraded by a family of enzymes called hyaluronidases. This review describes metabolisms, different physi - ological and pathological functions, basic pharmacological properties, and the clinical use of hyaluronic acid.
Synthesis and characterization of a new hydrogel were carried out using a chemically modified starch (starch-M) consisting of coupling CC bounds coming from glycidil methacrylate (GMA) onto the polysaccharide structure. 13C NMR, 1H NMR, and FT-IR spectroscopies were used to confirm the incorporation of such groups onto the starch-M. The hydrogel was prepared by a crosslinking polymerization of starch-M using sodium persulfate as an initiating agent. The starch-M hydrogel shows morphology clearly different from that of the raw starch film due to the presence of voids on its surface. The swelling process of the starch-M hydrogel was not significantly affected by changes on the temperature or on pH of the surrounding liquid, indicating the such behavior can be then understood by a diffusional process, resulting from its physical–chemical interactions with the solvent. The values of the diffusional exponent n were on the order of 0.45–0.49 for the range of pHs investigated, demonstrating that the water transport mechanism of starch-M hydrogel is more dependent on Fickian diffusion, that is, controlled by water diffusion. Such starch-M hydrogel is a promising candidate to be used in transporting and in preserving acid-responsive drugs, such as corticoids, for the treatment of colon-specific diseases, for example, Crohn's disease. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2567–2574, 2008
Amylose-ethylcellulose film coatings obtained from organic-based solvents were investigated as potential vehicles for colonic
drug delivery. Amylose, in the form of an amylose-butan-1-ol dispersion, and ethylcellulose, dissolved in either ethyl lactate,
ethanol, or propanol and plasticized with dibutyl sebacate, were mixed in various proportions and applied using a fluidized
bed coater to achieve a range of film thicknesses on 5-aminosalicylic acid pellets. Drug release from the coated pellets was
assessed under gastric and small intestinal conditions in the presence and absence of pepsin and pancreatin using dissolution
methodology, and also within a simulated colonic environment involving fermentation testing with human feces in the form of
a slurry. Under upper gastrointestinal tract conditions, the rate and extent of drug release were found to be related to the
thickness of the coating and the ratio of amylose to ethylcellulose within the film. Modeling of the drug release data revealed
that the ratio was more important than coat thickness in controlling drug release, irrespective of the solvent used for coating.
Coatings with a thick film and/or low amylose content were relatively impermeable and able to delay drug release under conditions
mimicking the upper gastrointestinal tract. Furthermore, drug release was unaffected by the presence of pepsin and pancreatin
and by long-term storage. Under simulated colonic conditions, drug release was more pronounced from coating formulations containing
higher proportions of amylose. Colon-specificity can therefore be achieved using such systems by judicious choice of the appropriate
ratio of amylose to ethylcellulose and coat thickness.
Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.
To investigate the colon specificity of novel natural polymer khaya gum and compare with guar gum. Release profile of tablets was carried out in presence and absence of rat cecal contents. The fast disintegrating core tablets of budesonide, were initially prepared by direct compression technique. Later, these tablets were coated with khaya gum or guar gum. After suitable pre compression and post compression evaluation, these tablets were further coated using Eudragit L-100 by dip coating technique. X-ray images were taken to investigate the movement, location and the integrity of the tablets in different parts of gastro intestinal tract in rabbits. The release profiles revealed that khaya gum or guar gum, when used as compression coating, protected the drug from being released in the upper parts of the gastro intestinal tract to some extent but the enteric coated formulations completely protected the drug from being released in the upper parts of the gastro intestinal tract, and released the drug in the colon by bacterial degradation of gums. It was found that both the polysaccharide polymers exhibited different release profiles in presence and absence of rat cecal contents. However, further enteric coat helped in targeting the drug to colon very effectively. Better dissolution models revealed the colon specificity of polysaccharides and alone can not be used either for targeting the drug to the colon or for sustaining or controlling the release of drug.
A novel colon targeted tablet formulation was developed using pectin as carrier and diltiazem HCl and indomethacin as model drugs. The tablets were coated with inulin followed by shellac and were evaluated for average weight, hardness and coat thickness. In vitro release studies for prepared tablets were carried out for 2 h in pH 1.2 HCl buffer, 3 h in pH 7.4 phosphate buffer and 6 h in simulated colonic fluid. The drug release from the coated systems was monitored using UV/Vis spectroscopy. In vitro studies revealed that the tablets coated with inulin and shellac have limited the drug release in stomach and small intestinal environment and released maximum amount of drug in the colonic environment. The study revealed that polysaccharides as carriers and inulin and shellac as a coating material can be used effectively for colon targeting of both water soluble and insoluble drugs.
Colon specific delivery of drugs are of interest for the treatment of colonic diseases, so as to maximize the effectiveness of these drugs. Oral delivery of peptides and proteins are possible because colon provides a more friendly environment than the upper gastrointestinal tract. Colon is also rich in lymphoid tissue so uptake of antigens into the mast cells of the colonic mucosa produces rapid local production of antibodies thus helping in vaccine delivery. This review deals with the anatomy and physiology of colon and various aspects of formulations by which colon targeting of drugs can be achieved.
Degradation of guar gum by colonic microorganisms has been extensively exploited to design colon specific drug delivery systems. Most of these designs suffer from the drawback of very high polymer proportion, need for enteric coating, use of other polysaccharides having better colon specific delivery tendency or compromised therapeutic efficacy due to variation in gastric transit time. In the present investigation, an attempt was made to first understand and rationalize important findings of earlier reports and then identify mechanisms that can be better suited for colonic delivery systems. It was concluded that a pH and transit time dependent mechanism of release preceding colonic microorganism mediated trigger for drug release will provide systems that are having biphasic release profile ideal for colonic delivery. In this study, controlled release colon specific formulations of indomethacin were designed with pH and transit time dependent release profile using combination of responsive polymers Eudragit (L100 or S100) and guar gum in matrix bases. In vitro drug release studies indicated a high burst release from matrix tablets with only guar gum as release retarding polymer, thereby confirming non-suitability of such matrix for colon specific release. The inclusion of pH responsive polymers Eudragit (L100 and S100) in the matrix base significantly reduced the drug released in the initial phase (0-6 h) followed with controlled release upto 14-16 h. A sigmoidal release pattern was observed from the designed formulations suitable for colonic delivery. This formulation design is expected to show a combined pH and swelling controlled release behavior with potential of a better performance when compared to coated systems and/only guar gum based matrix tablets.
Guar gum is a natural, low water-soluble polysaccharide which is widely used as a thickening agent in the food and pharmaceutical industries. As a pharmaceutical adjuvant, it may be used for colon-specific purposes because of its reported degradation in the human large intestine. In this work, guar gum is used as a model in which we examined whether its fluid uptake properties could be increased by a chemical modification to enhance its enzymatic degradation. The guar gum was reacted with increasing amounts of borax, and the properties of the new polymers were characterized by viscosity measurements prior to drying, atomic absorption, Fourier transform infrared spectroscopy, water solubility measurements, and equilibrium water uptake measurements. It was found that, despite the reaction with borate, solid guar gum (either in film form or compressed tablets) maintained its ability to degrade by galactomannanase. The modified products were found to possess better swelling properties and, as a result, better enzymatic degradation. The increase in the polymer biodegradation was directly proportional to the increase in their fluid uptake characteristics.
The present study objective was to develop novel colon specific drug delivery systems for aceclofenac using chitosan as a microbially degradable polymeric carrier and to coat the optimized batches with a pH dependent polymeric coating solution containing Eudragit L 100 and S 100 (1:4). Tablets containing four proportions of chitosan were prepared. The tablets were evaluated for physicochemical properties, drug content, dissolution, water uptake & erosion characteristics, in vitro drug release studies. The amount of aceclofenac released from the chitosan tablets at different time intervals was estimated by UV spectrophotometric method at 275nm. Eudragit coated Chitosan tablets prevented release of the aceclofenac in the physiological environment of stomach and small intestine depending on the proportion of chitosan used in the formulation. The dissolution profile and in vitro release kinetics showed that chitosan tablets were promising for controlled delivery of the drug. The findings of the present study conclusively state that chitosan tablets are promising for colon targeting of aceclofenac to synchronize the chronobiological symptoms for effective treatment of rheumatoid arthritis.
The spreading of enema solutions has been monitored in four normal subjects using gamma scintigraphy. Two volumes, 50 ml and 200 ml, were administered on separate occasions. Enema dispersion was greater with the 200 ml dose but there was considerable variability. Enema administration and eating stimulated intraluminal colonic motility, but food taken 1 h after enema dosing did not affect spreading. Aboral movement of the colon contents appears to inhibit dispersion. It is concluded that 100 ml is the optimum enema solution volume for the delivery of topically active drugs to the descending colon.
Konjac glucomannan (KGM) exhibited liquid crystalline (LC) behaviour in aqueous solutions above 7% (w/w) concentrations as was determined by polarized optical microscopy and circular dichroism. The rheological properties of the concentrated LC solutions of KGM exhibited pseudoplastic behaviour. The fibrous extrudates retained a significant degree of flow-induced orientation as was determined by wide angle X-ray scattering, thereby indicating potential applications of KGM as fibres and films. Differential scanning calorimetry experiments showed that a significant degree of interaction occurred between KGM and water and that the KGM gels produced in our study cannot be classified as thermoreversible.
The gastrointestinal transit and disintegration characteristics of an enteric coated timed release formulation were investigated in a group of six healthy volunteers using the technique of gamma scintigraphy. The mean in vivo tablet disintegration time was approx. 10 h post-dose and 7.5 h after gastric emptying which was in excellent agreement with that predicted from in vitro methodology. The anatomical site of release ranged from the caecum to the descending colon and once the onset of disintegration had been detected by scintigraphy, the time for complete break up was typically in the region of 45–60 min. The enteric coated Time Clock® system therefore provides for a pharmaceutical preparation capable of drug delivery to the colon.
Chitosan, a polycationic polymer and waste product from the sea food processing industry, is an abundant natural resource that has, as yet, not been fully utilized. Advantages of this polymer include availability, low cost, high biocompatibility, biodegradability and ease of chemical modification. In this paper, the physicochemical properties of chitosan, as well as its numerous applications, are reviewed with particular emphasis on its use in water treat ment, pharmaceutics, agriculture and membrane formation.
Various procedures for preparation of the biopolymers chitin and chitosan have been developed over the years. Preparation methodology and analysis of physicochemical properties of these biopolymers are reviewed in terms of crustacean species and diverse characterization methodology. Such properties influence biopolymer functionality differing with crustacean species and preparation methods. Monitoring of the relationship between process conditions and chitin/chitosan products is needed to insure uniformity and proper product quality control. Research with chitosan derived from crawfish processing operations indicates the need for a more integrated approach for total resource utilization. Examples of value-added processing by-products, coupled with chitosan recovery, are noted.
Abstract The development of delivery systems which enable selective release of drugs in the large intestine has gained much interest during the past decade. Two important therapeutic applications which can be found for oral colon-specific drug delivery are the treatment of local disorders of the colon and the delivery of protein and peptide drugs via the oral route. With the explosion of new peptide and protein products under development in the biotechnology industry, there has been increasing interest in utilizing the colon as site for drug absorption. Indeed, the large intestine may be the best site for peptide delivery because of the high residence time and the low digestive enzymatic activity. Due to the localization of the colon, it is difficult to reach. However, using different approaches, several potential colonic targeting systems have been developed. Among these, the most promissing are coating drugs with pH-sensitive and bacterial degradable polymers; delivery of drugs through bacterial degradable hydrogels or matrix systems; and delivery of drugs via bacterial degradable prodrugs. A major advantage of delivery systems based upon colon-specific enzymes from bacterial origin is the site-specificity. Therefore, other enzyme systems of bacterial origin may be explored in the future.
A highly deacetylated chitosan from shrimp with a degree of deacetylation of 95.28 ± 3.03% was prepared and spun into a monofilament fiber using a solution of 4% (w/v) chitosan in 4% (v/v) aqueous acetic acid. Samples of the spun fibers were immersed in aqueous solutions containing glutaraldehyde and glyoxal, and subsequently washed and dried. When the concentration of crosslinking agent was varied at room temperature over a constant time of 1 h, dry mechanical properties improved up to a point after which increasing concentrations resulted in degradation. Immersion time was also varied between 1 and 60 min at 25.8°C, and temperature was varied between 25.8 and 70.0°C, at fixed concentrations of both glyoxal and glutaraldehyde. It was demonstrated that mechanical improvements might be rendered at higher temperatures over lesser times. However, it was also shown that at higher temperatures, fiber mechanical properties would begin to diminish. Chitosan films were subjected to similar treatments in aqueous crosslinking solutions. Fourier transform infrared data (FTIR) on the films suggest that some interaction is occurring between the glutaraldehyde or glyoxal and the amine group on the chitosan backbone. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 1079–1094, 1999
Cooking and processing of starch-containing foodstuffs results in a portion of the starch becoming resistant to hydrolytic enzymes secreted in the small intestine of man. In order to determine whether this resistant starch (RS) was degraded in the colon, samples of RS and readily digestible starch (RDS) for comparisons were incubated with (a) cell-free supernatants from faecal suspensions and (b) washed faecal bacterial cell suspensions. The data obtained showed that, whereas pancreatic amylase and faecal supernatants hydrolysed RDS, with the production of oligosaccharides, RS totally resisted breakdown. In contrast, both RS and RDS were completely degraded by the washed bacterial cells with the generation of volatile fatty acids (VFA) and organic acids. Hydrolysis and fermentation of RDS was extremely rapid and, as a consequence, oligosaccharides and lactate initially accumulated in the culture medium. RS was broken down more slowly, howevér, and oligosaccharides and lactate never accumulated. The rate of polysaccharide hydrolysis had a significant effect on the quantities of VFA produced, in that 54% of carbohydrate was fermented to VFA in cultures incubated with RDS as sole carbon source as compared to only 30% in cultures incubated with RS. However no qualitative difference was observed in the VFA produced by fermentation of RDS or RS.
Dilute solution properties of Karaya gum from Sterculia urens were studied using size-exclusion chromatography, static and dynamic light scattering and viscosity experiments in 0·1 m aq. NaCl.Solubility in water was found to be strongly dependent on the degree of acetylation. The native acetylated Karaya gum assumes a rather compact and branched conformation in aqueous solution, as evidenced by the low values of power-law exponents. In contrast, the fully deacetylated Karaya gum assumes a more expanded conformation and behaves as a random coil.
Inulin hydrogels have been developed as potential new carriers for colonic drug targeting. Since site-specific drug release of this delivery system is based on its bacterial degradation in the colon, the enzymatic digestibility of the prepared inulin hydrogels was assessed by performing an in vitro study using an inulinase preparation derived from Aspergillus niger. The amount of fructose liberated from the inulin hydrogels by the action of inulinase was quantified using the anthrone method. The equilibrium swelling ratio as well as the mechanical strength of the hydrogels were studied before and after incubation in inulinase solutions. The data obtained by these different methods indicate that enzymatic digestion of the inulin hydrogels appeared to be enhanced by a prolonged degradation time, a higher inulinase concentration and a lower degree of substitution and feed concentration of the hydrogel polymer. The inulin hydrogels exhibited an increase in equilibrium swelling after degradation compared to the swelling before degradation, suggesting that inulinase enzymes are able to diffuse into the inulin hydrogel networks causing bulk degradation.
The human gastrointestinal tract consists of a highly complex ecosystem of aerobic and anaerobic microorganisms that plays a significant role in the metabolism of nutrients as well as drugs. In the colon, bacteria ferment various types of substrates that are not susceptible to digestion in the small intestine. This arouses interest in specific drugs, drug delivery systems, and prodrugs that escape small bowel digestion, arrive intact, and are absorbed or degraded in the large bowel. For the past forty years, experience has been gained with the azo prodrug of 5-amino salicylic acid, salazopyrine, which is cleaved by colonic bacteria to its parent drug. Some laxative drugs were also reported to degrade into active metabolites in the colon. Lately equally interesting and more sophisticated microbial controlled delivery systems, have been developed based on similar principles.
Purpose:
(a) To reduce the swelling properties of guar gum (GG) by crosslinking it with glutaraldehyde (GA), while maintaining its degradation properties in the presence of typical colonic enzymes, (b) to characterize the modified GG and to examine its degradation properties in vitro and in vivo, and (c) to assess, by drug probes with different water solubilities, the potential of the crosslinked GG to serve as a colon-specific drug carrier.
Methods:
GG was crosslinked with increasing amounts of GA under acidic conditions to obtain different products with increasing crosslinking densities. These products were characterized by measuring (a) their swelling properties in simulated gastric and intestinal fluids, (b) their crosslinking densities, (c) the release kinetics of three different drugs: sodium salicylate (SS), indomethacin (Indo) and budesonide (Bud) from the crosslinked products into buffer solutions, with or without a mixture of galactomannanase and alpha-galactosidase, and (d) their in vivo degradation in the cecum of conscious rats with and without antibiotic treatment.
Results:
Significant reduction in GG swelling properties, in both simulated gastric and intestinal fluids, was accomplished by its crosslinking with GA. The crosslinking density of the modified GG products was GA concentration-dependent. The release of SS from crosslinked GG discs was completed within 120 minutes. During the same period of time and for more than 10 hours the release of Indo and Bud was negligible. The release rate of the latter two drugs was enhanced when galactomannanase and alpha-galactosidase were added to the dissolution media. Discs made of the crosslinked GG were implanted in the cecum of rats and their degradation was assessed after 4 days. The extent of degradation was dependent on the amount of GA used for the crosslinking. After 4 days the same discs were recovered intact from rats exposed to antibiotic treatment and from simulated gastric and intestinal fluids.
Conclusions:
Reducing the enormous swelling of GG by crosslinking it with GA resulted in a biodegradable hydrogel which was able to retain poorly water soluble drugs, such as Indo and BUD, but not highly water soluble drugs, such as SS, in artificial gastrointestinal fluids. A variety of hydrogels with increasing crosslinking densities were produced and tested for their potential use as colon-specific drug platforms in vitro and in vivo. Their performance did not depend on creating physical barriers by means of compression.
Calcium pectinate (CaP)—the insoluble salt of pectin—can potentially be used as a colon-specific drug delivery system. The use of CaP as a carrier was based on the assumption that, like pectin, it can be decomposed by specific pectinolytic enzymes in the colon but that it retains its integrity in the physiological environment of the small bowel. The biodegradation of the carrier was characterized by monitoring the percent cumulative release of the insoluble drug indomethacin, incorporated into pectin or CaP matrices. Compressed tablets of pectin and indomethacin were analyzed for degradation in the presence of Pectinex 3XL, a typical pectinolytic enzyme mixture, and in the presence of the human colonic bacterium Bacteroides ovatus. The degradation of CaP-indomethacin tablets was assessed in the presence of Pectinex 3XL and in rat cecal contents. The release of indomethacin was significantly increased (end-time percentage cumulative release vs control) in the presence of Pectinex 3XL (89 20 vs 16 2 for CaP tablets), Bacteroides ovatus (12 and 22 vs 5.2 for pectin tablets), and rat cecal contents (61 16 vs 4.9 1.1 for CaP tablets). The weight loss of tablet mass was significantly higher (end-time dry weight vs control) in the presence of Pectinex 3XL (0 vs 75 6% of initial weight for CaP tablets). These findings indicate the potential of CaP, compressed into tablets with insoluble drug, to serve as a specific drug delivery system to the colon.
Compression coated tablets for oral colon specific delivery systems were developed with a mixture polysaccharide of konjac
glucomannan (KGM) and xanthan gum (XG) as the compression coat. Diffusion of cimetidine from compression coated tablets was
investigated by release experiment in Vitro. 0.22U/mL β-mannanase was applied in the mimic colon solution. The structure of the mixture polysaccharide was studied by an atomic force
microscope (AFM). The experimental results indicate that a KGM70 tablet with a 0.4 g coat is of good design, due to a less
than 5% drug loss in the mimic upper gastrointestinal solution by the synergistic interaction between XG and KGM, and due
to about 50% cumulative release in the mimic colon solution by degradation after 24 hours. The release mechanism and model
are discussed based on different periods of drug release including the delay of the drug, the constant release without an
enzyme and the delay of degradation. Under hydrolysis by β-mannanase, drug release from the tablet with KGM coat shows an exponential increase, while that from the dosage with the
mixture polysaccharide coat is an approximately zero-order process in which the constant release rate relates to the release
velocity of a non-degraded system, the content of KGM within the coat and the average molecular weight ratio of KGM to XG.
It was found that XG was the framework of the polysaccharide mixtures by AFM, which is similar to the analysis results from
experiments on drug release.
The reciprocating cylinder dissolution apparatus (USP Dissolution Apparatus III) was used to evaluate performance of several colonic delivery systems. Its dissolution tubes move between successive rows of vessels, allowing delivery systems to release drug in different media sequentially, i.e. simulated gastric fluids, simulated intestinal fluids, and simulated colonic fluids (SCF). The objective of this study was to assess USP dissolution apparatus III using formulations based on guar gum, a galactomannan polysaccharide. Drug (dexamethasone or budesonide) release in SCF was markedly increased at galactomannanase concentrations >0.01 mg/ml. The galactomannanase concentration and dipping speeds in the SCF were adjusted to produce dexamethasone release profiles similar to those estimated from absorption data in vivo. Thus, this dissolution setup may have predictive value for in vivo colonic delivery using guar gum-based colonic dosage forms.
We have produced cores containing theophylline, calcium acetate and microcrystalline cellulose by extrusion-spheronization and then applied a coating of calcium pectinate by interfacial complexation. After drying, the coatings were observed by scanning electron microspcopy to be 50–80 μm thick. The type of pectin used, the core size and the coating time all influenced the yield of theophylline in the coated cores. Theophylline release from the uncoated cores was rapid and linear with the square root of time. The in-vitro release of theophylline from the coated cores was tested in water, simulated gastric fluid USP minus pepsin (SGF) and a Tris buffer (pH 7.4). In general, release was essentially constant until 75–80% of the drug was released. The large coated cores released over a period of about 4 h and the small coated cores released over a period of 2 h. Although the coatings swelled more when they were rehydrated in the Tris buffer compared to water and SGF, theophylline release was similar in all the dissolution media. In particular, release was not increased by SGF as may have been expected from studies using a similar polysaccharide sodium alginate. Calcium pectinate coatings are easy to apply, do not require harsh conditions and may yield release profiles which are relatively independent of pH.
Novel hydrogels based on dextran crosslinked with diisocyanate have been proposed for colon-specific drug delivery. The hydrogels have been characterized by equilibrium degree of swelling and mechanical strength. Degradation of the hydrogels has been studied in vitro using dextranase, in vivo in rats and in a human fermentation model. It was found that by changing the chemical composition of the hydrogels it is possible to control the equilibrium degree of swelling, mechanical strength and degradability. The dextran hydrogels were degraded in vivo in the cecum of rats but not in the stomach. Furthermore, the dextran hydrogels were degraded in a human colonic fermentation model, indicating that dextranases are indeed present in human colonic contents. Finally, release of hydrocortisone from the hydrogels was evaluated. It was found to depend on the presence of dextranases in the release medium. The results suggest that the dextran hydrogels are promising as drug carriers for colon-specific drug delivery.
Manufactured by the process of injection moulding, starch capsules have been shown to be a very useful alternative delivery system for orally administered compounds. This review describes the starch capsule manufacturing and filling processes and provides an overview of the capsules’ physical characteristics. In addition, investigations supporting the development of novel delivery technologies based on the starch capsules are described. Particular emphasis is given to a technology that facilitates drug delivery to specific sites in the human gastrointestinal tract.
Colon-specific drug delivery may be possible by the application of dried amylose films to pharmaceutical formulations. Amylose, one of the major fractions of starch, possesses the ability to form films through gelation, when prepared under appropriate conditions. The microstructure of the film is potentially resistant to the action of pancreatic a-amylase but is digested by amylases of the colonic microflora. However, under simulated gastro-intestinal conditions, coatings made solely of amylose swell, become porous and allow drug release. Incorporation of insoluble polymers into the amylose film, to control amylose swelling, provides a solution to this problem. A range of cellulose and acrylate based copolymers were assessed, of which a commercially available ethylcellulose (Ethocel®) was found to control the swelling most effectively. The in vitro dissolution of various coated pellets under simulated gastric and small intestinal conditions, using commercially available pepsin and pancreatin, was determined and demonstrated the resistance of the amylose-Ethocel® coat ( 1:4 w/w ) to such conditions over a period of 12 h. With additional thermal treatment of the coat, in vitro drug release under simulated gastric and small intestinal conditions was prevented further, even after storage of the product for one year. Coated pellets were further evaluated in a batch culture fermenter, simulating colon conditions, containing an inoculum of mixed faecal bacteria. The in vitro release of 5-aminosalicylic acid from coated pellets in the fermenter system was shown to occur.
Dexamethasone-β-d-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent dexamethasone. To deliver dexamethasone selectively to the colon, the glycoside prodrug must be slowly absorbed from the alimentary canal and it must be chemically and enzymatically stable in the stomach and small intestine. Once the prodrug reaches the large intestine, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-β-d-glucoside for colon-specific delivery of dexamethasone was first assessed in the rat, and more recently in the guinea pig, an animal in which an inflammatory bowel disease (IBD) model had been developed. The hydrolytic activity of both the tissues and contents of the guinea pig stomach, proximal and distal portions of the small intestine, cecum, and colon were measured. For the tissues, β-d-glucosidase activity was greatest in the proximal small intestine while the contents of the cecum and colon showed the greatest β-d-glucosidase activity. The luminal contents retained their activity even after repeated centrifugation and resuspension in a buffer; the activity was also unaffected by homogenization. Movement and hydrolysis of dexamethasone-β-d-glucoside down the gastrointestinal tract (GIT) in the guinea pig was also examined. About 20 to 30% of an oral dose appeared to reach the guinea pig cecum. Here the prodrug was rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-β-d-glucoside is poorly absorbed in the GIT (bioavailability < 1%). There is a selective advantage for delivery of dexamethasone in cecal tissues of about 9 in the guinea pig under conditions of this experiment. In another study, degraded carrageenan was used to develop experimental IBD in the guinea pig. Following oral dosing of dexamethasone-β-d-glucoside (1.3 μmol/kg or 0.65 μmol/kg), dexamethasone (1.3 μmol/kg), or the dosing vehicle (H2O/EtOH, 0.95:0.05, v/v), the total number of ulcers in each group of animals was counted. Relative to control animals (dosing vehicle only), the drug and prodrug treatments significantly (P < 0.05) reduced the total number of ulcers. While there was no difference statistically between the drug and prodrug treatments, the results indicate that a lower dose of dexamethasone, administered as its glucoside prodrug, can be equally efficacious relative to higher dose of dexamethasone. This conclusion is consistent with the pharmacokinetic data obtained in normal guinea pigs and suggests there is a potential to decrease the usual dose of corticosteroids with a concomitant reduction in the systemic exposure.
A multiparticulate system with the potential for site-specific delivery to the colon has been investigated. Gelation of droplets of amidated pectin solutions in the presence of calcium is the basis of the method of preparation. Two drugs, indomethacin and sulphamethoxazole were successfully incorporated into the beads. Drug release from the beads was a function of media pH and drug loading. In simulated gastric and small intestinal conditions, drug release was greater with the more soluble sulphamethoxazole, but release of both drugs could be reduced to satisfactory levels by the formation of a chitosan polyelectrolyte complex around the beads. All the preparations released drug in simulated colonic conditions within 135 min.
Inulin is a naturally-occurring gluco-fructan, which can resist hydrolysis and digestion in the upper gastro-intestinal tract. In the colon it is fermented by the colonic microflora. Therefore inulinHP (inulin with a high degree of polymerization) was formulated as a biodegradable colon-specific coating by suspending it in Eudragit RS films. The in vitro degradability of the prepared isolated films was studied by incubating them in a faecal degradation medium. Measurements of the pH of the degradation medium and determination of the permeability coefficients of the incubated films as a function of time, indicated that inulinHP was indeed degraded by the faecal bacteria, even when it was suspended in Eudragit RS films. Films with different amounts of incorporated inulinHP and with different plasticizers were evaluated. The isolated films could also withstand gastric and intestinal fluid.
Azo-linked polymeric prodrugs of 5-aminosalicylic acid (5-ASA) were prepared and evaluated in simulated human intestinal microbial ecosystem. Release of 5-ASA was demonstrated. Polyamides containing azo groups in the backbone were prepared and tested in vitro in a reductive buffer or in the bioreactor medium. It was demonstrated that for the hydrophobic polymer reduction stops at the hydrazine stage whereas for a hydrophilic analogue reduction with formation of amines occurred.
In the present study degradation of dextran hydrogels, potential drug carriers for colon-specific drug delivery, was studied in simulated small intestinal juices as well as in a human colonic fermentation model. Dextran hydrogels were shown to be stable when incubated at 37°C with the small intestinal enzymes amyloglucosidase, invertase and pancreatin. After a 24 h incubation, less than 3.3% of free glucose was released. However, the hydrogels were still intact as measured by the dry weight remaining. The fermentation of dextran hydrogels and several mono- and polysaccharides to short-chain fatty acids (SCFA) was investigated after anaerobic incubation in a human colonic fermentation model at 37°C for 0–72 h. In addition, the dextranase activity of the incubations was determined. The amounts and ratios of SCFA formed varied considerably in relation to the type of substrate fermented (glucose, maize starch, potato starch, cellulose, soluble dextran and dextran hydrogels). Detailed SCFA analysis demonstrated that fermentable saccharides resulted in an increased SCFA production, in contrast to the metabolic inert polysaccharide, cellulose. The hydrogels were found to be completely degraded in the human colonic fermentation model. An increased crosslinking density or a decreased degree of hydration resulted in a lower degradability. The pH of the incubations were found to be inversely proportional to the SCFA production as a result of the increased acid formation.
The chemical forms and resistance to hydrolysis in vitro of raw and gelatinised starch from peas, maize, wheat and potatoes were measured. Raw granular starch proved very resistant to amylolysis. Only wheat starch was fully degraded after 24 hours' incubation with amylase (20 units/mg polysaccharide) at 37°C. In contrast, hydrolysis of freshly gelatinised starches was essentially complete within 1 h. To investigate the onset of resistance to hydrolysis after gelation, dispersions of amylose and amylopectin were stored at 20°C prior to amylolysis. Retrogradation of amylose was rapid, and the resulting material was highly resistant to amylolysis. In contrast, amylopectin underwent retrogradation more slowly and was almost completely degraded by amylase after incubation for 24 h. The onset of resistance to starch-hydrolysis in an amylose-rich food (cooked peas) was confirmed using a simulated digestion technique.
The objective of this study was to investigate a novel hydrogel plug using isolated root mucilage of Sterculia urens to obtain a desired lag time for an oral chronotherapeutic colon-specific pulsatile drug delivery of indomethacin. Pulsatile drug delivery was developed using chemically treated hard gelatin capsule bodies filled with eudragit multiparticulates of indomethacin, and sealed with different hydrogel plugs (root mucilage of S. urens, xanthan gum, guar gum, HPMC K4M and combination of maltodextrin with guar gum). Indomethacin multiparticulates were prepared using extrusion spheronization, spray drying and solvent evaporation techniques with Eudragit® L-100 and S-100 (1:2) by varying drug-to-polymer ratio. After oral administration, the water-soluble cap of capsule dissolved in the intestinal fluid and the hydrogel plug swells. After a controlled time, the swollen plug subsequently ejected from the dosage form, releases the contents of the capsule. The formulation factors affecting the drug release were concentration and types of hydrogel plug used. In vivo gamma scintigraphy study in healthy rabbits proved the capability of the system to release drug in lower parts of the gastrointestinal tract after a programmed lag time. This study demonstrates that the indomethacin multiparticulates could be successfully colon-targeted by the design of time and pH-dependent modified chronopharmaceutical formulation. In conclusion, the investigated novel hydrogel plug could be a valuable tool for achieving desired lag time.
Anti-inflammatory drugs with high potency and low systemic adverse effects, such as budesonide, are drugs of choice for the treatment of ulcerative colitis (UC). Budesonide controlled-release formulations are now being used to induce and maintain clinical remission of Crohn's disease. Budesonide-dextran conjugates were synthesized as novel prodrugs of budesonide for oral controlled delivery of the major part of the drug to the colon without needing to coat the pellets of the drug. The aim of this study was to evaluate the in vivo efficacy of this conjugate against acetic acid-induced colitis in rats.
Experimental UC was induced by rectal instillation of 4% solution of acetic acid to rats. After induction of colitis, rats were treated with vehicle (dextran solution), mesalasine (120 mg/kg), budesonide suspension (300 microg/kg) and BSD-70 (equivalent to 300 microg/kg of budesonide), prednisolon (4 mg/kg), hydrocortisone acetate enema (20 mg/kg), and 5-ASA enema (Asacol) (400 mg/kg) for 5 days and then colon macroscopic and microscopic sections were examined for inflammatory response.
Vehicle-treated rats presented bloody diarrhoea and gross lesions. The effective formulations for attenuating the damage were BSD-70, oral prednisolon and hydrocortisone acetate enema. Rats treated with BSD-70 showed huge improvement in macroscopic and histological scores of colitis compared to the negative control group and mesalasine and budesonide suspension.
Data indicated that budesonide-dextran conjugate is effective in improving signs of inflammation in experimental model of colitis through selective delivery of the drug to the inflamed area.
Preventive and therapeutic efficacies of resveratrol on several lower gastrointestinal (GI) diseases (e.g., colorectal cancer, colitis) are well documented. To overcome the problems due to its rapid absorption and metabolism at the upper GI tract, a delayed release formulation of resveratrol was designed to treat these lower GI diseases. The current study aimed to develop a delayed release formulation of resveratrol as multiparticulate pectinate beads by varying different formulation parameters. Zinc-pectinate (Zn-pectinate) beads exhibited better delayed drug release pattern than calcium-pectinate (Ca-pectinate) beads. The effects of the formulation parameters were investigated on shape, size, Zn content, moisture content, drug encapsulation efficiency, swelling-erosion, and resveratrol retention pattern of the formulated beads. Upon optimization of the formulation parameters in relative to the drug release profiles, the optimized beads were further subjected to morphological, chemical interaction, enzymatic degradation, and stability studies. Almost all prepared beads were spherical with approximately 1 mm diameter and efficiently encapsulated resveratrol. The formulation parameters revealed great influence on resveratrol retention and swelling-erosion behavior. In most of the cases, the drug release data more appropriately fitted with zero-order equation. This study demonstrates that the optimized Zn-pectinate beads can encapsulate very high amount of resveratrol and can be used as delayed release formulation of resveratrol.
Sterculia gum has been used as a therapeutic agent to cure diverticulitis. Hydrogels developed from sterculia gum to release the therapeutic agent will be double curing in action. Therefore, in the present study, an attempt has been made to synthesize novel hydrogels for the release of the model drug ciprofloxacin, a drug for diverticulitis. This paper discusses the synthesis, characterization, and in vitro release of ciprofloxacin from drug-loaded hydrogels in solutions of different pHs and simulated gastric and intestinal fluid. A non-Fickian diffusion mechanism has been observed for the release of the drug from drug-loaded hydrogels. This article also discusses the mechanistic implications of the cross-linking of sterculia gum with methacrylamide in the presence of N,N'-methylenebisacrylamide (N,N'-MBAAm) cross-linker.
The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via the colon, and the emerging data on the levels of cell membrane transporters and metabolic enzymes along the gut could prove advantageous for this. Often efflux transporters and metabolic enzyme levels are lower in the colon, suggesting a potential for improved bioavailability of drug substrates at this site. The locoregional distribution of multiple metabolic enzymes (including cytochromes), efflux transporters (including P-glycoprotein and breast cancer resistance proteins), and influx transporters (including the solute carrier family) along the intestine is summarized. Local delivery to the colonic mucosa remains a valuable therapeutic option. New therapies that target inflammatory mediators could improve the treatment of inflammatory bowel disease, and old and new anticancer molecules could, when delivered topically, prove to be beneficial adjuncts to the current systemic or surgical treatments. New issues such as pharmacogenomics, chronotherapeutics, and the delivery of prebiotics and probiotics are also discussed in this review. Targeting drugs to the colon utilizes various strategies, each with their advantages and flaws. The most promising systems are considered in the light of the physiological data which influence their in vivo behavior.
The different approaches for targeting orally administered drugs to the colon include coating with pH-dependent polymers, design of time-release dosage forms, and the utilization of carriers that are degraded exclusively by colonic bacteria. The aim of the present study was to develop a single unit, site-specific drug formulation allowing targeted drug release in the colon. Matrix tablets were prepared by wet granulation using cross-linked chitosan (ChI) and chondroitin sulfate (ChS) polysaccharides as binder and carrier. ChS was used to form polyelectrolyte complexes (PEC) with ChI, and its potential as a colon-targeted drug carrier was investigated. Indomethacin was used as a model drug. The ChI and ChS PEC was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction studies (XRD). The matrix tablets were tested in vitro for their suitability as colon-specific drug delivery systems. FTIR demonstrated that the PEC forms through an electrostatic interaction between the protonated amine (NH
3+) group of ChI with the free carboxylate (COO−) group and sulfate (SO
42−) group of ChS. DSC and XRD indicated that the PEC has different thermal characteristics from ChI or ChS. The dissolution data demonstrates that the dissolution rate of the tablet is dependent upon the concentration of polysaccharide used as binder and matrix and time of cross-linking. The study confirmed that selective delivery of indomethacin to the colon can be achieved using cross-linked ChI and ChS polysaccharides.
Unlabelled:
Hyaluronic acid-coupled chitosan nanoparticles bearing oxaliplatin (L-OHP) encapsulated in Eudragit S100-coated pellets were developed for effective delivery to colon tumors. The in vitro drug release was investigated using a USP dissolution rate test paddle-type apparatus in different simulated gastrointestinal tract fluids. In therapeutic experiments the pellets of free drug, and hyaluronic acid-coupled and uncoupled chitosan nanoparticles bearing L-OHP were administered orally at the dose of 10 mg L-OHP/kg body weight to tumor-bearing Balb/c mice. In vivo data showed that hyaluronic acid-coupled chitosan nanoparticles delivered 1.99 +/- 0.82 and 9.36 +/- 1.10 microg of L-OHP/g of tissue in the colon and tumor, respectively after 12 hours, reflecting its targeting potential to the colon and tumor. These drug delivery systems show relatively high local drug concentration in the colonic milieu and colonic tumors with prolonged exposure time, which provides a potential to enhance antitumor efficacy with low systemic toxicity for the treatment of colon cancer.
From the clinical editor:
In this study, a nanoparticle system was developed to deliver oxaliplatin to colorectal tumors. In murine models, the drug delivery system showed relatively high local drug concentration in colonic tumors with prolonged exposure time, which provides a potential for enhanced antitumor efficacy with low systematic toxicity.
The objective of this study is to utilize the pH sensitivity of modified carboxymethyl starch (CMS) for oral delivery of insulin. The chemical modification of natural polymers by grafting has received considerable attention in recent years because of the wide variety of monomers available. Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate) (PEGMA), and carboxymethyl starch (CMS) in the presence of bis-acrylamide as a cross-linking agent (CA) and persulfate as an initiator. The pH sensitive nature and ability to control gel permeability indicate that these materials have significant potential for drug delivery applications. Equilibrium swelling studies were carried out in enzyme-free simulated gastric and intestinal fluids (SGF and SIF, respectively). Insulin was entrapped in these gels, and the in vitro release profiles were established separately in both (SGF, pH 1) and (SIF, pH 7.4). Drug release studies showed that the increasing content of MAA in the copolymer enhances hydrolysis in SIF. In these cases, the biological activity of insulin was retained. These results were used to design and improve protein release behavior from these carriers.