Colonic Drug Delivery Research Articles

Film Coatings Based on Aqueous Shellac Ammonium Salt"Swanlac®ASL 10"and Inulin for Colon Targeting.

Over the past decades, increasing interests took place in the realm of drug delivery systems. Beyond treating intestinal diseases such as inflammatory bowel disease, colon targeting can provide possible applications for oral administration of proteins as well as vaccines due to the lower enzymatic activity in the distal part of GIT. To date, many strategies are employed to reach the colon. This article encompasses different biomaterials tested as film coatings and highlights appropriate formulations for colonic drug delivery. A comparison of different films was made to display the most interesting drug release profiles. These films contained ethylcellulose, as a thermoplastic polymer, blended with an aqueous shellac ammonium salt solution. Different blend ratios were selected as well for thin films as for coated mini-tablets, mainly varying as follows: (80:20); (75:25); (60:40). The impact of blend ratio and coating level was examined as well as the addition of natural polysaccharide "inulin" to target the colon. In vitro drug release was measured in 0.1M HCl for 2h followed by phosphate buffer saline pH 6.8 to simulate gastric and intestinal fluids, respectively. Coated mini-tablets were exposed to fresh fecal samples of humans in order to simulate roughly colonic content. Several formulations were able to fully protect theophylline as a model drug up to 8h in the upper GIT, but allowing for prolonged release kinetics in the colon. These very interesting colonic release profiles were related to the amount of the natural polysaccharide added into the system.

Challenges, opportunities, and future prospects of polysaccharide-based nanoparticles for colon targeting: A comprehensive review

Polysaccharides have attracted considerable attention as potential vehicles for drug delivery because of their unique and versatile characteristics. The biodegradability, biocompatibility, mucoadhesive characteristics, and tunable properties of polysaccharide make them attractive carriers for formulating of colon-targeted drug delivery systems. This review article encompasses the research on nanoparticles (NPs) based on polysaccharides (e. g. pectin, sodium alginate and chitosan) for targeted drug delivery to the colon. Various strategies such as microbially triggered, enzymatic degradation, and pH responsive systems have been discussed. Furthermore, ligand-based active targeting of therapeutics to colon has also been highlighted. The review also covers the various characterization and evaluation techniques used in the development of polysaccharide-based NPs. The importance of morphology, particle size (PS), surface charge of the NPs on performance of the delivery system has also been given due consideration. The challenges and future perspectives associated with colon drug delivery have been summarized. The information presented will be helpful to the scientific community when working with polysaccharides and will pave the way for improved therapeutic outcomes.

3D printed pH-responsive tablets containing N-acetylglucosamine-loaded methylcellulose hydrogel for colon drug delivery applications

The pH-responsive drug release approach in combination with three-dimensional (3D) printing for colon-specific oral drug administration can address the limitations of current treatments such as orally administered solid tablets. Such existing treatments fail to effectively deliver the right drug dosage to the colon. In order to achieve targeted drug release profiles, this work aimed at designing and producing 3D printed tablet shells using Eudragit® FS100 and polylactic acid (PLA) where the core was filled with 100 µl of N-acetylglucosamine (GlcNAc)-loaded methyl cellulose (MC) hydrogel. To meet the requirements of such tablets, the effects of polymer blending ratios and MC concentrations on physical, thermal, and material properties of various components of the tablets and most importantly in vitro drug release kinetics were investigated. The tablets with 80/20 wt% of Eudragit® FS100/PLA and the drug-loaded hydrogel with 30 mg/ml GlcNAc and 3% w/v MC showed the most promising results having the best printability, processability, and drug release kinetics besides being non-cytotoxic. Manufacturing of these tablets will be the first milestone in shifting from the conventional “one size fits all” approach to personalized medicine where different dosages and various combinations of drugs can be effectively delivered to the inflammation site.

Amelioration of experimental colitis by a site-specific novel plant polysaccharide (Opuntia ficusindica) based macroparticles contains probiotic biomass and mesalazine

The availability of therapeutic substances at colonic regions is always challenging for researchers. In this work, we aimed to evaluate the colon-targeting ability of mesalazine and probiotic biomass using Opuntia ficusindica polysaccharide. The present work will explore the application of novel plant polysaccharides as a rate-controlling polymer for colon drug delivery. Opuntia ficusindica polysaccharide was extracted and evaluated for the in-vitro toxicity study on HT-29 cell lines. Drug-loaded macroparticles were prepared and compressed into the tablet. In-vitro drug release was determined in simulated gastric fluid. Disease models were developed in Sprague Dawley rats to determine the efficacy of prepared formulation in the presence of probiotic biomass. Colon targeting efficiency of 99mTc-pertechnetate labeled mesalazine was monitored in human volunteers. Investigation of the polysaccharide's in-vitro toxicity revealed that the polysaccharide was safe for colon applications. Drug release data increased (p < 0.05) in the presence of rat cecal material at 6 h. The study also revealed that drug release from the different batches was directly proportional to polysaccharide concentration. In-vivo animal study confirms the better prevention of the disease in the presence of probiotic mass and drug. Gamma scintigraphy further supports the minimal drug release from the radiolabeled formulation in the upper gastrointestinal tract (GIT), despite the fact that it started drug release after 360 min, which was then disseminated during the subsequent 720–960 min in the colon. The study shows that Opuntia ficusindica polysaccharide can be used to deliver mesalazine to the colon.

A review on fungal pullulan as a natural polymer focusing on targeted therapy for colon cancer and other pharmaceutical applications

AbstractColon cancer is the second most invasive cancer and fourth most common malignant neoplasm worldwide. Targeted oral colonic drug delivery systems have attracted considerable attention in the treatment of colon cancer due to their superior properties. However, the delivery of drugs safely and effectively to the target site of the colon tumor is a hindrance due to the complexity of the gastrointestinal structure. Herein, to achieve an effective delivery system specifically targeting the colon, we have taken concern by using natural polymer such as pullulan, signifying its flexibility and relevance in biomaterials science to design antineoplastic approaches. Here, we summarize the physicochemical properties, different pullulan derivatives and their biomedical application, several colon cancer‐related treatment, and pullulan and its derivatives‐based delivery systems towards colonic tissue.

Developing 3D-network gels from polysaccharide gums for biomedical applications

Keeping in view the recent advancements in polysaccharide materials, gum acacia (GA) - tragacanth gum (TG) was investigated for designing polymeric network structures impregnated with cephalexin antibiotics for drug delivery (DD). Grafted product of polyvinylimidazole [poly(VIm)] and GA-TG was characterized by field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermo-gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Change in mesh size (from 17.73 to 32.98 nm) and crosslinking density (between 1.64 × 10−5 to 5.06 × 10−5 mol cm−3) was found with change in poly(VIm), gum and crosslinker NNMBA content which revealed that these parameters can be tailored made as per requirement and applications. Swelling properties illustrated pH sensitivity in copolymers because of composition which is useful for colon or site-specific DD of cephalexin. FESEM and AFM demonstrated heterogeneous morphology with the rough surface topology of grafted product. XPS and FTIR confirmed the grafting of poly(VIm) onto polysaccharide chains. Drug diffusion was non-Fickian and release was fitted in Higuchi kinetic model from copolymers. The release was slow and prolonged due to drug-polymer interactions. Copolymers exhibited 31.29% scavenging ability in DPPH assay and haemolysis was less than 2% that inferred biocompatible nature. Bio-surface interactions with intestinal membrane indicated the muco-adhesive nature of copolymers. Antimicrobial properties of hydrogel were evaluated against E. coli, P. aeruginosa and S. aureus. All observations revealed that GA-TG crosslinked copolymers could be explored for colon DD of antibiotic drugs with tailored crosslinking density.

PH-sensitive carboxymethyl starch-gelatin coated COF/5-Fu for colon cancer therapy

Owing to the desired structure, recently covalent organic frameworks (COFs) have emerged as one of the more efficient drug-loading platforms. Therefore, in the current study, we constructed COF with a spherical structure as a platform for 5-fluorouracil (5-Fu) loading. The as-synthesized COF showed a larger pore size (∼30.42 nm) than the 5-Fu dimension and a surface area of 230.58 m2/g. With these advantages, the 5-Fu loading percentage on COFs was achieved at ∼93.33 % (COF/5-Fu). However, their imine bond is relatively unstable in harsh acidic conditions. Hence, to prevent the fast drug release at pH 1.2, and considering that the key objective of the frontier work was to construct an oral site-definite controlled drug delivery system, there is an urgent and strong need to cap COF/5-Fu into carboxymethyl starch-gelatin (CMS-Gel) coat (COF/5-Fu@CMS-Gel). Drug release tests showed that the loaded 5-Fu was released highly at pH 7.4, but only 14.11 % of 5-Fu releases occurred at pH 1.2. The structural analyses supported the hypothesis of the successful formation of the prepared samples. The MTT assay showed the biocompatible nature of neat COF@CMS-Gel and its cytotoxic potential after drug loading. All these good properties can guarantee that the COF/5-Fu@CMS-Gel is promising for controlled colon drug delivery.

PH-sensitive HPMCP-chitosan nanoparticles containing 5-aminosalicylic acid and berberine for oral colon delivery in a rat model of ulcerative colitis

Ulcerative colitis (UC) with continuous and extensive inflammation is limited to the colon mucosa and can lead to abdominal pain, diarrhea, and rectal bleeding. Conventional therapies are associated with several limitations, such as systemic side effects, drug degradation, inactivation, and limited drug uptake, leading to poor bioavailability. These restrictions necessitate drug delivery to the colon so that the drug passes through the stomach unchanged and has selective access to the colon. The present study aimed to formulate 5-aminosalicylic acid (5-ASA) and berberine (BBR) in chitosan nanoparticles cross-linked by HPMCP (hydroxypropyl methylcellulose phthalate) as a colon drug delivery system for UC. Spherical nanoparticles were prepared. They showed appropriate drug release in the simulated intestinal fluid (SIF), while the release did not occur in the simulated gastric fluid (SGF). They improved disease activity parameters (DAI) and ulcer index, increased the length of the colon, and decreased the wet weight of the colon. Furthermore, histopathological colon studies showed an improved therapeutic effect of 5-ASA/HPMCP/CSNPs and BBR/HPMCP/CSNPs. In conclusion, although 5-ASA/HPMCP/CSNPs showed the best effect in the treatment of UC, BBR/HPMCP/CSNPs, and 5-ASA/BBR/HPMCP/CSNPs were also effective in vivo study, and this study anticipated they could be helpful in future clinical applications for the management of UC.

Efficient colonic drug delivery in domestic pigs employing a tablet formulation with dual control concept.

Efficient and reproducible colonic drug delivery remains elusive. The aim of this study was to demonstrate specific colonic delivery in vivo in domestic pigs with a novel tablet formulation based on a dual release control concept using 5-aminosalicylic acid (5-ASA) and caffeine as drug substances. The developed controlled colonic release (CCR) tablet formulation employs a pH-sensitive coating based on Eudragit® FS 30 D to prevent drug release in the upper gastrointestinal tract, and a xyloglucan-based matrix to inhibit drug release after coating removal in the small intestine and to allow microbiome-triggered drug release by enzymatic action in the colon. CCR tablets were administered to domestic pigs and plasma concentration data was analyzed by physiologically based pharmacokinetic modeling to estimate absorbed amounts from small and large intestine and in vivo drug release rates by model-dependent deconvolution using immediate release (IR) tablets and intravenous solutions as reference. Peak concentration times (tmax) and values (cmax) of CCR 5-ASA and caffeine tablets indicated strongly delayed drug absorption and the deduced absorbed amount as a function of time confirmed absorption overwhelmingly from the large intestine. The microbially cleaved marker molecule sulfasalazine administered alone or together with caffeine in CCR tablets reported, in combination with telemetry measurements, gastrointestinal transit times and site of absorption. Drug release from CCR tablets was inferred to take place predominantly at the site of absorption at a release rate of caffeine that was much larger in the colon than in the small intestine indicating enzymatically triggered release by the colonic microbiome. Xyloglucanase activity in rectal and cecal samples was consistent with release data and compound recovery in fecal droppings was consistent with 5-ASA bioavailability. The results provide evidence that the developed formulation can prevent premature drug release and provide targeted colonic drug delivery. Clinical relevance based on the comparability between pig and man is discussed.

New insights on the effects of blend composition on the biodegradation and permeability of Inulin-Eudragit RS film coatings for colon drug delivery

Inulin has been applied in Inulin-Eudragit RS (Inu-ERS) coatings as the component responsible for degradation by human microbiota. However, studies on how bacterial enzymes can degrade polysaccharides like inulin imbedded in water insoluble polymers like Eudragit RS are still elusive. The present work aims at elucidating the complex process of enzyme triggered biodegradation of inulin with various molecular weights in isolated films with Eudragit RS. The ratio of inulin to Eudragit RS was varied to create films with different degree of hydrophilicity. The phase behavior study revealed that blends of inulin and Eudragit RS are phase separated systems. The film permeability was studied by determination of the permeability coefficient of caffeine and the fraction of inulin that was released from the films in a buffer solution with or without inulinase was quantified. Together with the morphology characterization of the Inu-ERS films with and without incubation in the enzyme solution, these results suggest that the action of the enzyme was only limited to the fraction of inulin released in the buffer solution. Inulin fully embedded in the Eudragit RS matrix was not degraded. The permeation of the model drug caffeine occurred in the phase-separated film as a result of pores formed as a consequence of inulin release. The inulin to Eudragit RS blend ratio and the molecular weight of inulin affected the percolation threshold, the release of inulin, the morphology of the film formed thereafter and the connectivity of the formed water channels, thus influencing the drug permeation properties.

Development of almond gum based copolymeric hydrogels for use in effectual colon-drug delivery

Development of almond gum based copolymeric hydrogels for use in effectual colon-drug delivery

Design and Evaluation of Controlled Onset Extended-Release System for Chronotherapeutic Delivery of Aceclofenac

The purpose of this research is to design and test Aceclofenac-containing capsule dosage type, which may be intended for the treatment of early morning stiffness and symptomatic pain relief in patients with rheumatoid arthritis. Immediate release tablets were prepared by wet granulation method using crospovidone, SSG, Lycoat, and Ludiflash. Enteric coated Microspheres were prepared using Eudragit L100 and Eudragit R100 by oil-in-oil solvent evaporation method. Both IR tablets and microspheres of aceclofenac have been tested for pre-compression, post-compression and findings find to be appropriate in our trials. Chemical reactions between the drug and the polymeric substance have been tested using FTIR. There was no disparity between the IR patterns of Aceclofenac, the physical mixture of Aceclofenac and polymers. Based on the results obtained IR tablet (AI12) containing Crospovidone as super disintegrant was considered as the optimum powder blend for fabrication of capsule system. Among the enteric coated microspheres AC9 was considered as optimized formulation for colonic drug delivery. As our aim of work is to maintain a chronotherapeutic drug delivery, now we combine the optimized IR tablets and optimized enteric coated microspheres in a single capsule. Based on the drug release studies, it shows drug released up to 20hrs and follows zero order release kinetics with non-ficikian diffusion mechanism.

Design, Development, and Optimisation of Smart Linker Chemistry for Targeted Colonic Delivery-In Vitro Evaluation.

Drug targeting is necessary to deliver drugs to a specific site of action at a rate dictated by therapeutic requirements. The pharmacological action of a drug can thereby be optimised while minimising adverse effects. Numerous colonic drug delivery systems have been developed to avoid such undesirable side effects; however, these systems lack site specificity, leaving room for further improvement. The objective of the present study was to explore the potential of amino-alkoxycarbonyloxymethyl (amino-AOCOM) ether prodrugs as a general approach for future colonic delivery. To circumvent inter- and intra-subject variabilities in enzyme activities, these prodrugs do not rely on enzymes but rather are activated via a pH-triggered intramolecular cyclisation−elimination reaction. As proof of concept, model compounds were synthesised and evaluated under various pH conditions, simulating various regions of the gastrointestinal tract (GIT). Probe 15 demonstrated excellent stability under simulated stomach- and duodenum-like conditions and protected 60% of the payload in a small intestine-like environment. Moreover, 15 displayed sustained release at colonic pH, delivering >90% of the payload over 38 h. Mesalamine (Msl) prodrugs 21 and 22 were also synthesised and showed better stability than probe 15 in the simulated upper GIT but relatively slower release at colonic pH (61−68% of Msl over 48 h). For both prodrugs, the extent of release was comparable to that of the commercial product Asacol. This study provides initial proof of concept regarding the use of a cyclisation-activated prodrug for colon delivery and suggests that release characteristics still vary on a case-by-case basis.

AN OVERVIEW: DEVELOPMENT OF COLON DRUG DELIVERY SYSTEM AND ITS APPLICATION AND LIMITATIONS

There are various routes of drug administration. Oral administration is considered the most preferred route in drug administration for systemic effects, but the oral administration is not suitable for people with ulcerative colitis, crohn's disease, bowel cancer, diarrhea, treatment of diseases that sensitive to circadian rhythms such as asthma and angina, as well as for steroids administration. The delivery of targeted drugs has the goal of achieving the desired therapeutic profile by delivering the drug to the target site. This study conducted by reviewing related articles based on specify keywords on Science Direct database that has been published for the last 10 y. In recent decades, research has been conducted to develop methods that can target drugs to specific organs. The focusing on targeted drug delivery system to the colon, the various ways that were carried out for its approach, as well as the evaluation. By this study, some challenges in the colon drug delivery system could be overcome along with new approaches.

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics.

Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro, in vivo, and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics.

Tablet formulation with dual control concept for efficient colonic drug delivery

Aim of this study was to develop a tablet formulation for targeted colonic drug release by implementing two control mechanisms: A pH-sensitive coating layer based on Eudragit® FS 30 D to prevent drug release in the upper gastrointestinal tract, combined with a matrix based on plant-derived polysaccharide xyloglucan to inhibit drug release after coating removal in the small intestine and to allow microbiome triggered drug release in the colon. In vitro dissolution tests simulated the passage through the entire gastrointestinal tract with a four-stage protocol, including microbial xyloglucanase addition in physiologically relevant concentrations as microbiome surrogate to the colonic dissolution medium. Matrix erosion was monitored in parallel to drug release by measurement of reducing sugar equivalents resulting from xyloglucan hydrolysis. Limited drug release in gastric and small intestinal test stages and predominant release in the colonic stage was achieved. The xyloglucan matrix controlled drug release after dissolution of the enteric coating through the formation of a gummy polysaccharide layer at the tablet surface. Matrix degradation was dependent on enzyme concentration in the colonic medium and significantly accelerated drug release resulting in erosion-controlled release process. Drug release at physiologically relevant enzyme concentration was completed within the bounds of colonic transit time. The dual control concept was applicable to two drug substances with different solubility, providing similar release rates in colonic environment containing xyloglucanase. Drug solubility mechanistically affected release, with diffusion of caffeine, but not of 5-ASA, contributing to the overall release rate out of the matrix tablet.

Time-Based Formulation Strategies for Colon Drug Delivery.

Despite poor absorption properties, delivery to the colon of bioactive compounds administered by the oral route has become a focus of pharmaceutical research over the last few decades. In particular, the high prevalence of Inflammatory Bowel Disease has driven interest because of the need for improved pharmacological treatments, which may provide high local drug concentrations and low systemic exposure. Colonic release has also been explored to deliver orally biologics having gut stability and permeability issues. For colon delivery, various technologies have been proposed, among which time-dependent systems rely on relatively constant small intestine transit time. Drug delivery platforms exploiting this physiological feature provide a lag time programmed to cover the entire small intestine transit and control the onset of release. Functional polymer coatings or capsule plugs are mainly used for this purpose, working through different mechanisms, such as swelling, dissolution/erosion, rupturing and/or increasing permeability, all activated by aqueous fluids. In addition, enteric coating is generally required to protect time-controlled formulations during their stay in the stomach and rule out the influence of variable gastric emptying. In this review, the rationale and main delivery technologies for oral colon delivery based on the time-dependent strategy are presented and discussed.

Advancement in Therapeutic Intervention of Prebiotic-Based Nanoparticles for Colonic Diseases.

Intestinal flora has become a therapeutic target for the intervention of colonic diseases (CDs) with better understanding of the interplay between microbiota and CDs. Depending on unique properties and prominent ability of regulating the intestinal flora, prebiotics can not only achieve a colon-specific drug delivery but also maintain the intestinal homeostasis, thus playing a positive role in the intervention of CDs. Currently, different studies on prebiotic-based nanoparticles have been contrived for colonic drug delivery and have shown great potential in curing various CDs, such as colitis and colorectal cancer. Nevertheless, there is a lack of systematic survey on the use of prebiotic nanoparticles for the treatment of CDs. This review aims to generalize the state-of-the-art of prebiotic nanomedicines specific for CDs. The species and function of intestinal flora and various kinds of prebiotics available as well as their regulating effects on intestinal flora were expounded. A variety of prebiotic nanoparticles pertinent to colon-targeted drug delivery systems were illustrated with particular emphasis on their curative activities on CDs. The efficacy and safety of prebiotic-based colonic drug delivery systems (p-CDDs) were also analyzed. In conclusion, the synergy between prebiotic nanoparticles and their cargos may hold promise for the treatment and intervention of CDs.

Colon Targeting: A Novel Drug Delivery System

The oral route is considered to be the most preferred route for administration of drugs for systemic effect, but the oral route is not suitable to the administration of drug for lower gastrointestinal (GI) diseases, this happened due to their release at upper GI tract (stomach, small intestine), which further minimizes the accessibility of drugs at the lower GI tract. To overcome this difficulty, colon-specific drug delivery systems have been broadly analyzed during the last two decades. Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon like Crohn’s disease, ulcerative colitis, etc. but also for the systemic delivery of proteins, therapeutic peptides, anti-asthmatic drugs, antihypertensive drugs, and anti-diabetic agents. This review article discusses, in brief, the introduction of the colon, factor affecting the colonic transition, colonic diseases and the novel and emerging technologies for colon targeting.

Dual stimuli-responsive hydrogels for colon targeted drug delivery.

Colon targeted drug deliverysystems are promising for the treatment of local diseases. The colon possessesa diverse microbiome that secretes a number of biomolecules, such as enzymes,that can be exploited for targeted drug delivery. Here, we report the synthesisof 2-hydroxyethyl methacrylate and methacrylic acid &amp;nbsp;copolymer hydrogels crosslinked with an enzyme-sensitivecrosslinking agent. The swelling and drug release properties of hydrogels were observedin pH 1.2, pH 6.5 and pH 7.4, and in the presence of rat cecal content. Swellingstudies revealed pH responsivity of the hydrogels while the release kinetics ofmetronidazole from hydrogels containing an enzyme-labile crosslinker were fasterin the presence of rat cecal content. The results show that dual responsive hydrogelscould provide a promising platform for colonic drug delivery