Colonic Release Research Articles

Development of novel pH–responsive dual crosslinked hydrogel beads based on Portulaca oleracea polysaccharide-alginate-borax for colon specific delivery of 5-fluorouracil

This study aimed to explore the colon targeting potential of novel polymeric beads encapsulating the anticancer drug 5-fluorouracil (5-FU) prepared utilizing Portulaca plant mucilage. Polysaccharide gel matrix was prepared by using ionotropically gelled mixture of biopolymers sodium alginate and Portulaca polysaccharide, which was isolated from leaves of Portulaca oleracea and was then cross-linked with borax for effective control of drug release in colon. Size and morphology of the prepared beads were characterized using scanning electron microscope (SEM). Other parameters evaluated were drug encapsulation efficiency and cumulative in vitro drug release using rat caecal content and different pH media to simulate the gastrointestinal tract. This novel pH responsive biopolymer provides an option to use plant-based mucilage for colon-specific drug delivery. These natural polysaccharides can form hydrogels and they have an added advantage of being categorized under GRAS (generally recognised as safe) with additional benefits of biocompatibility, biodegradability and specificity towards drug targeting to colon.

Protection against Clostridium difficile infection in a hamster model by oral vaccination using flagellin FliC-loaded pectin beads

Clostridium difficile flagellin FliC is a highly immunogenic pathogen-associated molecular pattern playing a key role in C. difficile pathogenesis and gut colonization. Here, we designed an oral vaccine against C. difficile with FliC encapsulated into pectin beads for colonic release. Bead stability and FliC retention was confirmed in vitro using simulated intestinal media (SIM), while bead degradation and FliC release was observed upon incubation in simulated colonic media (SCM). The importance of FliC encapsulation into pectin beads for protection against C. difficile was assessed in a vaccination assay using a lethal hamster model of C. difficile infection. Three groups of hamsters orally received either FliC-loaded beads or unloaded beads in gastro-resistant capsule to limit gastric degradation or free FliC. Two other groups were immunized with free FliC, one intra-rectally and the other intra-peritoneally. Hamsters were then challenged with a lethal dose of C. difficile VPI 10463. Fifty percent of hamsters orally immunized with FliC-loaded beads survived whereas all hamsters orally immunized with free FliC died within 7 days post challenge. No significant protection was observed in the other groups. Only intra-peritoneally immunized hamsters presented anti-FliC IgG antibodies in sera after immunizations. These results suggest that an oral immunization with FliC-loaded beads probably induced a mucosal immune response, therefore providing a protective effect. This study confirms the importance of FliC encapsulation into pectin beads for a protective oral vaccine against C. difficile.

Optimizing pH-sensitive and time-dependent polymer formula of colonic pH-responsive pellets to achieve precise drug release

Time-sensitive and pH-dependent polymers are generally employed to prepare colon-site delivery system, and their coating thickness and order are very important in controlling the drug release. The traditional colon-site delivery systems consist of time-dependent polymers as inner layer and pH-sensitive polymers as outer layer. However, they suffer from low drug-loading rate and immature drug release. In this study, total alkaloids of sophora alopecuroides(TASA)-loaded pellets were prepared by extrusion-spheronization method and coated with Eudragit RS30D and Eudragit S100. Pellets using Eudragit RS30D as inner layer and Eudragit S100 as outer layer were named as ERS-ES100 TCO, while pellets with Eudragit S100 as inner layer and Eudragit RS30D as outer layer were ES100-ERS NCO. Both types of formulations with varying coating ratios and orders of Eudragit S100 and Eudragit RS30D were designed and prepared. The following in vitro drug release and SEM studies indicated that ERS-ES100 TCO(F2) with 12.8% Eudragit RS30D as inner layer and 21% Eudragit S100 as outer layer released up to 42% drug in 5 h. Interestingly, ES100-ERS NCO (F4) coated with 12.8% Eudragit S100 and 14.8% Eudragit RS30D showed optimal drug release in colon. In conclusion, ES100-ERS NCO colonic delivery system achieved reduced coating thickness and improved colonic targeting compared with traditional delivery system (ERS-ES100 TCO). In addition, the similarity factors (f2) value of sophoridine and matrine for investigated formulation were within 50–100 and > 80, demonstrating that sophoridine and matrine in all formulations achieved a synchronous release.

Gamma radiative fabrication of semi interpenetrating network film: Optimization, characterization and investigation as colon, intestine specific drug release device

Presented work was fabrication of colon and intestine specific drugs release device using gamma radiations as initiators. Semi-interpenetrating network (Semi-IPN) film was castoff as drug delivery device to investigate release profile of diethyl carbamazine citrate and amoxicillin in 9.2, 7.0 and 2.2 pH media. Optimized reaction parameters for semi-IPN film were: gamma dose 2.5 kGy/h; solvent 25 ml; AA 4.6 mol/L; MBA 5.1 × 10−3 mol/L and pH 9.0. Sample was characterized by X-RD; SEM; FT-IR and TGA studies. Semi-IPN film was thermally more stable than backbone showing 6400% water uptake efficacy. Sample degraded upto 80.3% and 81.7% at a degradation rate of 1.147(mg/min) and 1.167(mg/min) in vermi-composting and bio-composting degradations, respectively. Release behavior of diethyl carbamazine citrate was found to be non-Fickian in 9.2, 7.0 pH and Fickian in 2.2 pH solutions. In amoxicillin case II diffusion was found in 9.2 pH, non-Fickian in 7.0 and 2.2 pH solutions. Both drugs showed their maximum release in 9.2 pH media with higher values of Di than DL, thus can be used as colon and intestine specific release device where, drug released rate should be fast in the beginning followed by sustain release.

Degradation studies of modified inulin as potential encapsulation material for colon targeting and release of mesalamine

Due to the potential to treat colon specific diseases with reduced side effects, colon targeting has become of high interest over the last decades. Chemical modified inulin was investigated for its potential as encapsulation material regarding its enzymatic degradability and its drug release behavior. Different degrees of acetylated inulin (degree of substitution, DS, 0.3–2.1) were synthesized. The chemical modification leads to a reduction in enzymatic degradability by inulinase and esterase, enzymes which can be expressed by the colon microbiota. Acetylated inulin was only hydrolyzed to fructose units up to DS of 1.3. Microparticles made of native inulin and acetylated inulin (DS 1.8) were loaded with the colon-specific drug mesalamine by spray drying. Compared to the burst release of mesalamine by inulin particles within 6 h, acetylated inulin particles showed less burst release followed by a continuous drug release phase caused by diffusion up to 30% mesalamine after 52 h.

DESIGN AND EVALUATION OF COLON TARGETED DELIVERY OF TEGASEROD MALEATE FOR IRRITABLE BOWEL SYNDROME

The colon is being extensively investigated as a drug delivery site. Colonic drug delivery is a relatively recent approach for the treatment of diseases like ulcerative colitis, Crohn’s disease, and irritable bowel syndrome. To achieve successful colon targeted drug delivery, a drug needs to be protected from degradation, release and /or absorption in upper portion of GI tract and then ensure abrupt or controlled release in proximal colon. The purpose of this research is to develop and evaluate the polysaccharide based compression coated tablets of Tegaserod maleate for the treatment of irritable bowel syndrome. Core tablets of Tegaserod maleate were compression coated with various proportions of Galactosol, xanthan gum and chitosan. This work aimed to prepare compression coated tablets by direct compression method using single polymer and combination of polymers. And to evaluate prepared tablets parameters like hardness, friability, thickness, diameter, weight variation, drug content, swelling index, in vitro drug release. Keywords: Colon, Tegaserod maleate, Galactosol, xanthan gum and chitosanÂ

Formulation, preparation and in vitro - in vivo evaluation of compression-coated tablets for the colonic-specific release of ketoprofen

The aim of this study was to formulate and prepare compression-coated tablets for colonic release (CR-tablets), and to evaluate the bioavailability of ketoprofen following the administration of a single dose from mini-tablets with immediate release (IR-tablets) compared to CR-tablets. CR-tablets were prepared based on time-controlled hydroxypropylmethylcellulose K100M inner compression-coating and pH-sensitive Eudragit® L 30D-55 outer film-coating. The clinical bioavailability study consisted of two periods, in which two formulations were administered to 6 volunteers, according to a randomized cross-over design. The apparent cumulative absorption amount of ketoprofen was estimated by plasma profile deconvolution. CR-tablets were able to delay ketoprofen’s release. Compared to IR-tablets used as reference, for the CR-tablets the maximum plasma concentration (Cmax) was lower (4920.33±1626.71 ng/mL vs. 9549.50±2156.12 ng/mL for IR-tablets) and the time needed to reach Cmax (tmax) was 5.33±1.63 h for CR-tablets vs. 1.33±0.88 h for IR-tablets. In vitro-in vivo comparison of the apparent cumulative absorption amount of ketoprofen showed similar values for the two formulations. Therefore, the obtained pharmacokinetic parameters and the in vitro-in vivo comparison demonstrated the reliability of the developed pharmaceutical system and the fact that it is able to avoid the release of ketoprofen in the first part of the digestive tract.

Inhibitory effects of patchouli alcohol on stress-induced diarrhea-predominant irritable bowel syndrome.

AIMTo elucidate the mechanism of patchouli alcohol (PA) in treatment of rat models of diarrhea-predominant irritable bowel syndrome (IBS-D).METHODSWe studied the effects of PA on colonic spontaneous motility using its cumulative log concentration (3 × 10−7 mol/L to 1 × 10−4 mol/L). We then determined the responses of the proximal and distal colon segments of rats to the following stimuli: (1) carbachol (1 × 10−9 mol/L to 1 × 10−5 mol/L); (2) neurotransmitter antagonists including Nω-nitro-L-arginine methyl ester hydrochloride (10 μmol/L) and (1R*, 2S*)-4-[2-Iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt (1 μmol/L); (3) agonist α,β-methyleneadenosine 5′-triphosphate trisodium salt (100 μmol/L); and (4) single KCl doses (120 mmol/L). The effects of blockers against antagonist responses were also assessed by pretreatment with PA (100 μmol/L) for 1 min. Electrical-field stimulation (40 V, 2-30 Hz, 0.5 ms pulse duration, and 10 s) was performed to observe nonadrenergic, noncholinergic neurotransmitter release in IBS-D rat colon. The ATP level of Kreb’s solution was also determined.RESULTSPA exerted a concentration-dependent inhibitory effect on the spontaneous contraction of the colonic longitudinal smooth muscle, and the half maximal effective concentration (EC50) was 41.9 μmol/L. In comparison with the KCl-treated IBS-D group, the contractile response (mg contractions) in the PA + KCl-treated IBS-D group (11.87 ± 3.34) was significantly decreased in the peak tension (P < 0.01). Compared with CCh-treated IBS-D rat colon, the cholinergic contractile response of IBS-D rat colonic smooth muscle (EC50 = 0.94 μmol/L) was significantly decreased by PA (EC50 = 37.43 μmol/L) (P < 0.05). Lack of nitrergic neurotransmitter release in stress-induced IBS-D rats showed contraction effects on colonic smooth muscle. Pretreatment with PA resulted in inhibitory effect on L-NAME-induced (10 μmol/L) contraction (P < 0.05). ATP might not be the main neurotransmitter involved in inhibitory effects of PA in the colonic relaxation of stress-induced IBS-D rats.CONCLUSIONPA application may serve as a new therapeutic approach for IBS-D.

Formulation and Evaluation of Pulsatile Drug Delivery of Lovastatin

In the present study, an attempt was made to develop the pulsatile drug delivery of Lovastatin to reduce plasma cholesterol levels and to prevent cardiovascular diseases. Formaldehyde treated Capsule bodies were used for the preparation of pulsincaps. It was sealed with unhardened cap of the capsule. The microspheres were prepared by emulsion solvent evaporation technique. Hydrogel plug (karaya gum and lactose in 1:1 ratio) having 4.5kg/cm2 hardness and 100 mg weight was placed in the capsule opening and found that it was satisfactory to retard the drug release in small intestinal fluid and to eject out the plug in colonic fluid and releasing the microspheres into colonic fluid after a lag time criterion of 5 hours. The sealed capsules were completely coated by dip coating method with 5% cellulose acetate phthalate to prevent variable gastric emptying. Optimized microsphere formulations were selected based on dissolution studies. Dissolution studies of pulsatile capsule device in media with different pH (1.2, 7.4 and6.8) showed that drug release in colon could be modulated by optimizing the concentration of polymers in the microspheres. Drug–polymer interaction studies indicated no interaction in between the drug and the polymer. Among all the formulations Lovastatin microspheres prepared with Ethyl cellulose, in 1:3 ratio shown prolonged release for a period of 11 hours. The obtained results showed the capability of the system in delaying drug release for a programmable period of time and to deliver the drug in the early morning hours when cholesterol synthesis are more prevalent.

PLGA nanoparticles are effective to control the colonic release and absorption on ibuprofen

The oral controlled release (CR) formulations have become more important in recent years. Among them, the polymeric nanoparticles have been thoroughly studied during the last decades, consequently they are extensively employed for a broad range of applications and drugs. The objective of this research was to develop polymeric nanoparticles (NPs) of ibuprofen with poly(lactic-co-glycolic) acid (PLGA) as polymer, and to test their applicability for oral CR formulations development. Different proportions of drug/polymer were employed to develop the ibuprofen NPs and their in vitro release profiles were analysed. The in situ segmental permeability of ibuprofen was tested in Wistar rat and demonstrated the high permeability of ibuprofen in rat colon. In addition, in vivo assays were performed to study the plasma concentration-time profiles of encapsulated versus non-encapsulated ibuprofen. The results showed that ibuprofen release from the NPs was pH-dependent and consequently higher at colonic pH. Moreover, the plasma concentration-time profiles reveal a controlled release from the ibuprofen NP. Therefore, the ibuprofen PLGA-NPs will be a good CR formulation to achieve a controlled release targeted to the colon, where the release rate of the drug from the NPs will be the limiting factor for the absorption process.

COLON SPECIFIC DRUG DELIVERY SYSTEMS: CURRENT TRENDS AND APPROACHES

The colon is a site where both local and systemic delivery of drugs can take place. The colon targeted drug delivery system is used for the treatment of various diseases related to colon like Crohn’s disease, ulcerative colitis, etc and systemic delivery of therapeutic peptides and proteins. It can be possible to target disease site thus lowers the requirement of higher doses of drug and reducing the dosage frequency and cost of the drugs. It also lowers the systemic side effects. For successful colon targeted drug delivery, a drug needs to be protected from degradation, release and absorption in the upper portion of the gastric intestinal tract and then to be ensured abrupt or controlled release in the proximal colon. This article gives detail description on anatomy and physiology of the colon and approaches utilized for colon specific drug delivery like prodrugs, pH and time dependent, prodrug, osmotic pressure controlled drug delivery. Peer Review History: Received 19 August; Revised 28 August; Accepted 5 September, Available online 15 September 2017 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main of purpose it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 4.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewer(s) detail: Prof. Dr. Syamsudin Abdillah, Pancasila University, Indonesia, syamsudin.abdillah@gmail.com Dr. Masoomeh S Ghahfarokhi, University of Benin, Nigeria, mshamsgh@yahoo.com Similar Articles: DEVELOPMENT AND EVALUATION OF ALBENDAZOLE MICROCAPSULE FOR COLONIC DRUG DELIVERY SYSTEM FORMULATION AND EVALUATION OF COLON TARGETED MATRIX TABLETS CONTAINING EXTRACT OF SOLENOSTEMMA ARGEL (HARGEL)

Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages.

Ulcerative colitis (UC) is characterized by a functional dysregulation of alternatively activated macrophage (AAM) and intestinal epithelial cells (IECs) homeostasis. Chromogranin-A (CHGA) secreted by neuroendocrine cells is implicated in intestinal inflammation and immune dysregulation. CHGA undergoes proteolytic processing to generate CHGA-derived peptides. Chromofungin (CHR: CHGA47–66) is a short CHGA-derived peptide encoded by CHGA Exon-IV and is involved in innate immune regulation, but the basis is poorly investigated. We investigated the expression of CHR in colonic tissue of patients with active UC and assessed the effects of the CHR in dextran sulfate sodium (DSS) colitis in mice and on macrophages and human colonic epithelial cells. We found that mRNA expression of CHR correlated positively with mRNA levels of AAM markers and gene expression of tight junction (TJ) proteins and negatively with mRNA levels of interleukin (IL)-8, IL-18, and collagen in patients with active UC. Moreover, AAM markers correlated positively with gene expression of TJ proteins and negatively with IL-8, IL-18, and collagen gene expression. Experimentally, intracolonic administration of CHR protected against DSS-induced colitis by priming macrophages into AAM, reducing colonic collagen deposition, and maintaining IECs homeostasis. This effect was associated with a significant increase of AAM markers, reduction of colonic IL-18 release and conservation of gene expression of TJ proteins. In vitro, CHR enhanced AAM polarization and increased the production of anti-inflammatory mediators. CHR-treated AAM conditioned medium increased Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins, and decreased oxidative stress-induced apoptosis and proinflammatory cytokines release. Direct CHR treatments had the same effect. In conclusion, CHR treatment reduces the severity of colitis and the inflammatory process via enhancing AAM functions and maintaining IECs homeostasis. CHR is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of colonic inflammation and could lead to new therapeutic strategies for UC.

Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells.

Bile acids and epithelial-derived human β-defensins (HβDs) are known to be important factors in the regulation of colonic mucosal barrier function and inflammation. We hypothesized that bile acids regulate colonic HβD expression and aimed to test this by investigating the effects of deoxycholic acid (DCA) and ursodeoxycholic acid on the expression and release of HβD1 and HβD2 from colonic epithelial cells and mucosal tissues. DCA (10-150 µM) stimulated the release of both HβD1 and HβD2 from epithelial cell monolayers and human colonic mucosal tissue in vitro In contrast, ursodeoxycholic acid (50-200 µM) inhibited both basal and DCA-induced defensin release. Effects of DCA were mimicked by the Takeda GPCR 5 agonist, INT-777 (50 μM), but not by the farnesoid X receptor agonist, GW4064 (10 μM). INT-777 also stimulated colonic HβD1 and HβD2 release from wild-type, but not Takeda GPCR 5-/-, mice. DCA stimulated phosphorylation of the p65 subunit of NF-κB, an effect that was attenuated by ursodeoxycholic acid, whereas an NF-κB inhibitor, BMS-345541 (25 μM), inhibited DCA-induced HβD2, but not HβD1, release. We conclude that bile acids can differentially regulate colonic epithelial HβD expression and secretion and discuss the implications of our findings for intestinal health and disease.-Lajczak, N. K., Saint-Criq, V., O'Dwyer, A. M., Perino, A., Adorini, L., Schoonjans, K., Keely, S. J. Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β-defensin-1 and -2 secretion by colonic epithelial cells.

Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice

Susceptibility of gastrointestinal dysmotility increases with age-associated colonic degeneration. A paucity of remedies reversing colonic degeneration per se hinders the fundamental relief of symptoms. Here we discovered the correlation between colon degeneration and altered nicotinamide adenine dinucleotide (NAD) level in aged mice. Compared to 3-month-old young controls, 2-year-old mice showed a spectrum of degenerative colonic phenotypes and exhibited a significant elongated transit time and slowed stool frequency in the context of Lomotil-induced slow-transit constipation. Despite upregulated colonic tryptophan hydroxylases expression, serotonin release and expression of colon-predominant type IV serotonin receptor, reduced viability of interstitial cells of Cajal while enhanced aquaporins (Aqp1, 3 and 11) led to a less colonic motility and increased luminal dehydration in aged mice. Notably, this colonic degeneration was accompanied with reduced key NAD+-generating enzyme expression and lowered NAD+/NADH ratio in aged colon. Three-month continuous administration of beta nicotinamide mononucleotide, a NAD+ precursor, elevated colonic NAD+ level and improved defecation in aged mice. In contrast, pharmacological inhibition of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme for NAD+ biosynthesis, induced a reduction in colonic NAD content and impaired gastrointestinal function in young mice. Taken together, these findings suggest the beneficial effect of NAD+ in maintaining colonic homoeostasis and reactivating NAD+ biosynthesis may represent a promising strategy to counteract age-related gastrointestinal degeneration.

Investigating Drug Repositioning Approach to Design Novel Prodrugs for Colon-specific Release of Fexofenadine for Ulcerative Colitis.

Recent immunologic data implicates involvement of mucosal immune cells of the intestine like eosinophils and mast cells to be functionally involved in the pathogenesis of UC. Mast cell activation is followed by increased secretion and elevated tissue concentration of histamine. Inhibition of mucosal histamine release in colon may be an effective therapeutic approach to treat UC. Some studies report that intestinal inflammation associated with acute and chronic colitis has been ameliorated by fexofenadine in mice. In the present work, we investigated the effect of colon- specific prodrugs of antihistaminic fexofenadine on TNBS- induced colitis in Wistar rats, applying the principle of drug repositioning. Amino acid- appended amide prodrugs of fexofenadine were designed and characterized spectrally. In vitro kinetics and protective effect of prodrugs were studied on TNBS-induced colitis in Wistar rats. Conjugation with amino acids improved the hydrophilicity of fexofenadine (log P: 0.037 to 0.082) to enable efficient delivery to colon. Prodrugs were chemically and enzymatically stable in aqueous buffers (pH 1.2 and7.4) and stomach homogenates/intestinal homogenates, respectively. Prodrugs were substantially cleaved to release 60-70% of fexofenadine in homogenates of colon in 12 h. Prodrug of fexofenadine with L-glutamine additively and significantly suppressed TNBS-induced colitis showing comparable effects to orally administered 5-aminosalicylic acid. The outcome of this preliminary work emphasizes involvement of mast cells that release histamine as one of the important pathological inducers of UC. These promising, dual acting, colontargeting fexofenadine prodrugs could be explored further for repositioning fexofenadine in the treatment of UC and its relapse.

Cellulose-polysaccharide film-coating of cyclodextrin based pellets for controlled drug release

An oral controlled release system based on blends of ethylcellulose and pectin as film-coating material for pellets was developed. Triamcinolone acetonide (TA) as drug useful in intestinal inflammatory disorders was loaded into cyclodextrin-based pellets. The combination of pectin and ethylcellulose as coating materials was investigated in terms of mechanical analysis, viscosimetry, DSC and TGA, water vapor permeability and TA diffusivity using membranes prepared at different ratios. The coating process by fluid bed coating system was used to obtain different thicknesses of coating for pellets previously fabricated by extrusion-spheronization. To investigate the influence of coating on controlled release properties, the microstructure, specific surface area, porosity and TA release profile from pellets were also assayed.The versatility of the system has been proven by selecting different combinations of blends of polymers. Further, by the reduction in the proportion of pectin in the ethlycellulose:pectin membrane and increasing the thickness of coating, it was possible to achieve a prolonged release over pH 6. These results suggest that the delivery system based on pectin:ethylcellulose coating for pellets has an excellent colon release performance for TA providing protection for drugs that are unstable at acidic pH.

Molecular and biopharmaceutical investigation of alginate–inulin synbiotic coencapsulation of probiotic to target the colon

Colon targeting, as a site-specific delivery for oral formulation, remains a major challenge, especially for sensitive bioactive components such as therapeutic forms of phages, live attenuated virus and prebiotics–probiotics association. Synbiotics could be used to protect encapsulated probiotics during the gastrointestinal tract and control their release in the colon. To achieve these goals, effective prebiotics, such as inulin, could be combined with alginate – the most exploited polymer used for probiotic encapsulation – in the form of beads. This work aimed to study the biopharmaceutical behaviour of alginate beads (A) and inulin–alginate beads of different inulin concentrations (5 or 20%) in 2% alginate (AI5, AI20). Beads were loaded with three probiotic strains (Pediococcus acidilactici Ul5, Lactobacillus reuteri and Lactobacillus salivarius). Dissolution of beads was studied by USP4 under conditions simulating the gastrointestinal condition. The survival rates of the bacterial strains were measured by a specific qPCR bacterial count. Mucoadhesiveness of beads was studied by an ex vivo method using intestinal mucosa. To understand the behaviour of each formulation, the ultrastructure of the polymeric network was studied using scanning electron microscopy (SEM). Molecular interactions between alginate and inulin were studied by Fourier transform infra-red spectroscopy (FTIR). Dissolution results suggested that the presence of inulin in beads provided more protection for the tested bacterial strains against the acidic pH. AI5 was the most effective formulation to deliver probiotics to the colon simulation conditions. FTIR and SEM investigations explained the differences in behaviour of each formula. The developed symbiotic form provided a promising matrix for the development of colonic controlled release systems.

Synthesis of Azopolymer for Colon Targeted Drug Release

Background: Colon specific drug delivery system has attracted considerable attention for the past few years to release drugs in a predictable and reproducible manner. To achieve successful drug delivery, a drug needs to be protected from degradation, release and absorption in the upper portion of the gastric intestinal tract and then to be ensured abrupt or controlled release in the proximal colon. Methods: A system for colonic targeting drug delivery was developed by coating the drug-containing capsules with azo aromatic, microbial degrading and pH-sensitive polymers that are prone to selective degradation in the colon environment. The azo aromatic polymers were synthesized by a bulk polymerization technique using different ratios of water-soluble and water-insoluble monomers. Result and conclusion: These polymers were characterized for physical attributes, namely film-forming properties, effect on colon bacterial flora, and pH. The systems were subjected to in vitro release and in vivo performance studies. The studies revealed that azo aromatic polymers are cleaved by the colonic microbiota and can be used successfully for colonic targeting drug release

Resistant starch/pectin free-standing films reinforced with nanocellulose intended for colonic methotrexate release

Although resistant starch/pectin (RS/P) films have previously displayed suitable properties for colon-specific drug delivery, nanocomposite films were developed aiming to enhance physicochemical, thermal, mechanical and barrier properties, as well as the low oral bioavailability of methotrexate (MTX). FEG-SEM micrographs of nanocomposite films showed different interaction patterns occurring among nanocellulose and RS/P. The nanofiller addition led to an increase in the thermal stability, probably due to its interaction with RS crystalline double helices. Results also displayed an improvement of the puncture strength, while barrier properties revealed a low water vapor permeability. Ex vivo bioadhesion test displayed the nanocomposites films to interact strongly with porcine gastrointestinal mucosa. In vitro drug release studies showed that the films developed enhanced the drug dissolution rates with approximately 80% of MTX release in 150min, suggesting the potential of these materials as a poor solubility drugs carrier, which constitutes an important tool for enhancing oral bioavailability.

Adeno-associated virus-mediated colonic secretory expression of HMGB1 A box attenuates experimental colitis in mice.

Extracellular high mobility group box 1 (HMGB1) is crucially implicated in the pathogenesis of inflammatory bowel diseases (IBDs). A box domain of HMGB1 has been identified as a specific antagonist of HMGB1. In the present study, we tested the effects of adeno-associated virus (AAV)-mediated colonic secretory expression of HMGB1 A box on murine experimental colitis. Self-complementary AAV-2 carrying mouse immunoglobin Gκ leader-human HMGB1 A box (AAV-HMGB1 A box) was constructed. The effects of intracolonically administered AAV-HMGB1 A box on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were assessed by the disease activity index (DAI), colon length, macroscopic and histological scoring, myeloperoxidase (MPO) activity, and epithelial apoptosis and complementary proliferation. Colonic immune cell infiltrates, mucosal malondialdehyde content and superoxide dismutase activity, colonic tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-10 levels, serum HMGB1 concentration, and colonic HMGB1 release were determined to investigate the underlying mechanisms. Intracolonically administered AAV-HMGB1 A box efficiently mediated secretory expression of HMGB1 A box and led to significant decreases in DAI, macroscopic and histological scores and colonic epithelial apoptosis in both DSS- and TNBS-treated mice. Modulating inflammation-associated cytokines, such as inhibiting colonic TNF-α and IL-1β expression, decreasing HMGB1 release, and restoring colonic IL-10 levels, and thereby inhibiting inflammatory cell infiltration and alleviating oxidant damage, might be the underlying mechanism. Intracolonic application of AAV-HMGB1 A box is effective in alleviating murine colitis and has therapeutic potential in human IBDs.