Colonic Drug Delivery Research Articles

Formulation and evaluation of deflazacort loaded mucoadhesive microsphere for colon drug delivery system

Irritable bowel disease is very common colon disease. Deflazacort is one of the best drug with clinical activity against Irritable bowel disease. Microsphere system are effectively protect drugs against premature degradation, to localize drug molecules at the target site of action and to control the time and rate of release. Mucoadhesive microspheres enhance the bioavailability of orally given drugs by lengthened contact time of drug with the intestinal mucosa. The main disadvantage of these microspheres is adherence to the substrate by non-specific interaction. To overcome this limitation, microspheres are prepared by emulsification method to treat irritable bowel disease. Chitosan microspheres were prepared by Ionotropic Gelation method. Microspheres were coated with Eudragil S using solvent evaporation method.
 Keywords: Deflazacort, Mucoadhesive, Microspheres, Irritable bowel disease

Advances in orally targeted drug delivery to colon.

Colon-specific drug delivery is critical for treating diseases of colon, such as colon cancer, amoebiasis, irritable bowel syndrome, and inflammatory bowel disease. This study reviews the effects of targeted oral drug delivery on patient by measuring the accurate administration of the drug to specific disease spot, thus enhancing the therapeutic efficacy and provides better therapeutic outcomes. Medically targeted delivery to colon produces local effect on the diseases and hinders the systemic toxic effects of drugs. The delivery of therapeutics to the specific diseased part of colon has its merits over systemic drug delivery, albeit has some obstacles and problems. Colon drug delivery can be used to create both systemic and local effects. Many advanced approaches are used, such as conventional methods for drug release to colon, delayed release dosage forms, nanoparticles, carbon nanotubes, dendrimers, and alginate coated microparticles. This concise review summarizes and elaborates the details of different techniques and strategies on targeted oral drug delivery to colon as well as studies the advantages, disadvantages, and limitations to improve the application of drug in the part of the affected colon.

Preparation and Evaluation of Hydrogel Nanoparticles as Drug Delivery System

Hydrogel nanoparticles (NPs) can be used for colon drug delivery, utilizing Methotrexate (MTX) as a model drug. MTX loaded hydrogel NPs were prepared using Poly-acrylamide-grafted- gum ghatti (PAAm-g-Gg), which is pH sensitive. PAAm-g-Gg was synthesized by free radical polymerization. MTX loaded hydrogel NPs was prepared from PAAm-g-Gg by using nanoemulsification polymer crosslinking method. FT-IR and DSC studies of the prepared NPs indicated no chemical change of MTX in the hydrogel NPs. The prepared hydrogel NPs showed mean diameters in the range of 238 ± 0.57 nm to 1064 ± 0.99 nm. The encapsulation efficiency of the drug was found to be 39.11% to 48.84%. The suitability of the polyacrylamide grafted gum ghatti hydrogel NPs for the release of Methotrexate was studied by in vitro release at pH 1.2 and 7.4. It was observed that, there was no significant amount of drug release in gastric pH and 97.28% of drug release at pH 7.4 for formulation F6 at the end of 12 hrs. Based on result formulation F6 was considered as the best formulation and further evaluated for stability studies and characterized for surface morphology using SEM. SEM photographs have shown that the hydrogel NPs are spherical in shape and the stability study data indicated no significant change in the drug content.

In vitro drug release from acetylated high amylose starch-zein films for oral colon-specific drug delivery

This study describes the preparation of free films of zein with and without acetylated high amylose maize starch (HAS) and their corresponding coated tablets as a novel approach to colonic drug delivery. We hypothesise that the embedding of a digestible starch component within the inert zein would allow the film to remain intact until the large intestine is reached. Free films of zein alone and starch/zein were prepared and characterized. SEM and AFM images of film surface showed that films were morphologically inhomogeneous, particularly at lower HAS/Zein ratios; however, nanothermal analysis data suggested that these differences in appearance within the same film are not compositional differences. Moreover, FT-IR could detect no molecular interaction between the two polymers. Paracetamol tablets were coated with HAS/Zein aqueous based coatings of different compositions to a TWG of 20%. Drug release from zein alone and 1:5 HAS/Zein coated tablets under upper gastrointestinal conditions (pH 1.2, pH 6.8 with pepsin and pancreatin included) was very similar (for example approximately 12% and 14% of the drug was released, respectively, after 6 h in a sequential in vitro test), suggesting that release in this region is limited and is not influenced by the presence of HAS in the ratio to zein under study. Studies using an in vitro colon model showed that under simulated colonic conditions, the drug release was significantly (p < 0.05) more rapid from 1:5 HAS/Zein, compared to the zein alone coating formulation. These data therefore support the potential use of zein-starch mixed films for colonic targeting purposes.

A systematic review of nano formulation of natural products for the treatment of inflammatory bowel disease: drug delivery and pharmacological targets.

Inflammatory bowel diseases (IBD), which is classified into Crohn’s disease and ulcerative colitis, are among chronic gastrointestinal diseases with unknown pathogenesis. Diverse strategies have been applied for the treatment of this chronic disease. However, selective and site-specific routes of drug delivery to the inflamed location of the colon remain of high importance. Consequently, the application and effects of natural products in the form of nanoformulation and stimuli responsive nanoparticles as a novel strategy for the treatment of IBD are discussed in this review article. This approach may potentially overcome some complications that are associated with conventional means of colon drug delivery. Meanwhile, in vitro and in vivo studies pave the way for understanding of the mechanism that lies behind this chronic relapsing disease and potentially more effective treatment. Graphical abstractᅟ

Design and Development of Mucoadhesive Thiolated Chitosan Microspheres for Colonic Drug Delivery

Design and Development of Mucoadhesive Thiolated Chitosan Microspheres for Colonic Drug Delivery

A Micellar-Hydrogel Nanogrid from a UV Crosslinked Inulin Derivative for the Simultaneous Delivery of Hydrophobic and Hydrophilic Drugs.

Hydrogels are among the most common materials used in drug delivery, as polymeric micelles are too. They, preferentially, load hydrophilic and hydrophobic drugs, respectively. In this paper, we thought to combine the favorable behaviors of both hydrogels and polymeric micelles with the specific aim of delivering hydrophilic and hydrophobic drugs for dual delivery in combination therapy, in particular for colon drug delivery. Thus, we developed a hydrogel by UV crosslinking of a methacrylated (MA) amphiphilic derivative from inulin (INU) (as known INU is specifically degraded into the colon) and vitamin E (VITE), called INVITEMA. The methacrylated micelles were physicochemically characterized and subjected to UV irradiation to form what we called the “nanogrids”. The INVITEMA nanogrids were characterized by DSC, SEM, TEM, water uptake and beclomethasone dipropionate (BDP) release. In particular, the release of the hydrophobic drug was specifically assessed to verify that it can spread along the hydrophilic portions and, therefore, effectively released. These systems can open new pharmaceutical applications for known hydrogels or micelle systems, considering that in literature only few examples are present.

Controlled drug release behavior of 5-aminosalicylic acid using polyacrylamide grafted oatmeal (OAT-g-PAM): a pH-sensitive drug carrier

In the present investigation, we have evaluated the in vitro drug release of 5-aminosalicylic acid (5-ASA) using polyacrylamide grafted oatmeal (OAT-g-PAM). The graft co-polymer was synthesized by following free radical co-polymerization pathway using acrylamide as a monomer and ceric ammonium nitrate as a free radical initiator in the presence of microwave. The matrix tablet was prepared using the different grades of developed graft co-polymers following standard protocol. In vitro release phenomena of 5-ASA from the prepared matrix tablet up to 12 h in different buffer solution, i.e., pH 2.0, 7.0 and 7.4, an ideal condition for colon specific drug delivery was studied. The release rate of 5-ASA can be controlled efficiently by tuning the pH value. The drug release kinetic of 5-ASA from different matrix tablet was evaluated on the basis of in vitro controlled drug release results. The result indicates that the novel pH-sensitive matrices under study showing Fickian diffusion mechanism and potentially constructive for colonic drug delivery system.

Smart gated magnetic silica mesoporous particles for targeted colon drug delivery: New approaches for inflammatory bowel diseases treatment

Magnetic mesoporous silica microparticles were loaded with safranin O (S1) and with hydrocortisone (S2) and the outer surface functionalized with a bulky azo derivative bearing urea moieties. Aqueous suspensions of both solids at pH 7.4 showed negligible payload release whereas a marked delivery was observed in the presence of sodium dithionite due to the rupture of the azo bonds. Besides, a moderate cargo release was observed at acidic pH due to the hydrolysis of the urea bonds that linked the azo derivative onto the external surface of the inorganic scaffolds. In vitro digestion models showed that S1 and S2 microparticles could be used for the controlled release of payload in the reducing colon environment (in which azoreductase enzymes are present). On the other hand, in vivo pharmacokinetic studies in rats showed that safranine O release from S1 microparticles was concentrated in colon. The performance of S2 microparticles for the treatment of colitis in rats (induced by oral administration of a 2,4,6-trinitrobenzenesulfonic acid solution) was tested. The controlled release of hydrocortisone from S2 in the colon of injured rats induced marked reduction in colon/body weight ratio and in clinical activity score. Also, histological studies showed a marked decrease in inflammation followed by intensive regeneration and almost normal mucosal structure of the individuals treated with S2. Besides, the use of a magnetic belt increased the therapeutic performances of S2 due to an enhanced retention time of the particles in the colon.

Zein as a Pharmaceutical Excipient in Oral Solid Dosage Forms: State of the Art and Future Perspectives.

Zein is the main storage protein of corn and it has several industrial applications. Mainly in the last 10-15years, zein has emerged as a potential pharmaceutical excipient with unique features. Zein is a natural, biocompatible and biodegradable material produced from renewable sources. It is insoluble, yet due to its amphiphilic nature, it has self-assembling properties, which have been exploited for the formation of micromicroparticle and nanoparticle and films. Moreover, zein can hydrate so it has been used in swellable matrices for controlled drug release. Other pharmaceutical applications of zein in oral drug delivery include its incorporation in solid dispersions of poorly soluble drugs and in colonic drug delivery systems. This review describes the features of zein significant for its use as a pharmaceutical excipient for oral drug delivery, and it summaries the literature relevant to macroscopic zein-based oral dosage forms, i.e. tablets, capsules, beads and powders. Particular attention is paid to the most novel formulations and applications of zein. Moreover, gaps of knowledge as well as possible venues for future investigations on zein are highlighted.

De-Esterified Tragacanth Microspheres Loaded into Eudragit S-100 Coated Capsules for Colon-Targeted Delivery.

The objective of this study was to develop a novel bacterially-triggered micro-particular system of de-esterified tragacanth (DET) in combination with Eudragit S-100 coated capsules for colon drug delivery of 5-fluorouracil (5-FU) using microemulsion method. The loading study was conducted at different drug-to-polymer ratios and cross-linker concentrations. The maximum loading efficiency was achieved, 44.1% at 1:5 drug-to-polymer ratio and 0.7% cross-linker concentration. The FTIR results also confirmed the encapsulation of 5-FU in microspheres. The release profile was dependent on the cross-linker concentration, environmental pH, and presence of pectinase enzyme. Microspheres inserted into Eudragit S-100 coated capsules released less than 5% of the drug at stomach and small intestine pH levels, whereas 70% of the drug was released at colon pH levels, and about 25% of the drug did not release unless in the presence of pectinase enzyme. To omit burst release, microspheres were washed with water, and the release became pH independent, and was just achieved in the presence of pectinase enzyme. 5-FU loaded microspheres with an IC50 value of 80 µg/mL were as effective as the free drug on HT-29. Generally, the results demonstrated that drug-loaded microspheres inserted into Eudragit S-100 coated capsules can be effective for colon-targeted delivery.

Encapsulation of Curcumin-Loaded Liposomes for Colonic Drug Delivery in a pH-Responsive Polymer Cluster Using a pH-Driven and Organic Solvent-Free Process.

The present study aimed to develop and optimize liposome formulation for the colonic delivery of biologically active compounds. A strategy to facilitate such targeting is to formulate liposomes with a polymer coating sensitive to the pH shifts in the gastrointestinal tract. To this end, liposomes encapsulating curcumin—chosen as the biologically active compound model—and coated with the pH-responsive polymer Eudragit S100 were prepared and characterized. Curcumin was encapsulated into small unilamellar vesicles (SUVs) by the micelle-to-vesicle transition method (MVT) in a simple and organic solvent-free way. Curcumin-loaded liposomes were coated with Eudragit S100 by a fast and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and curcumin antioxidant activity. In particular, curcumin-loaded liposomes displayed size lower than 100 nm, encapsulation efficiency of 98%, high stability at both 4 °C and 25 °C, high in vitro antioxidant activity, and a cumulative release that was completed within 200 min. A good Eudragit S100 coating which did not alter the properties of the curcumin-loaded liposomes was obtained. The present work therefore provides a fast and solvent-free method to prepare pH-responsive polymer-coated liposomes for the colonic delivery of biologically active compounds.

Enhanced solubility and self-assembly of amphiphilic sulfasalazine-PEG-OMe (S-PEG) conjugate into core-shell nanostructures useful for colonic drug delivery

Recently, several studies have been undertaken to formulate drugs in soluble state leading to enhanced bioavailability as well as to provide controlled drug release. Because of their distinct advantages, such systems have attracted increasing attention of the researchers. Here, sulfasalazine, a drug used to treat inflammatory bowel disease, was conjugated with a low molecular weight polyethylene glycol monomethyl ether (750 Da) to obtain amphiphilic sulfasalazine-polyethylene glycol (S-PEG) conjugate, which not only showed enhanced solubility but also, on self-assembly, generated core-shell type micellar nanostructures with hydrophobic core and hydrophilic shell. Post-physicochemical characterization, these micellar nanostructures were used to entrap hydrophobic drug molecules, ornidazole and sulfasalazine. The drug-entrapped S-PEG nanoformulations showed controlled release of drugs at pH 7.2 making these nanoformulations ideal for colon-targeted drug delivery. Further, azo-moiety bearing sulfasalazine conjugate showed responsiveness to a chemical reductant, sodium dithionite, which mimics azoreductase enzymes present in the colonic microflora. Drug release in the presence of sodium dithionite increased significantly ensuring the potential of these formulations for colon-targeted drug delivery.

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

Functional Magnetic Mesoporous Silica Microparticles Capped with an Azo-Derivative: A Promising Colon Drug Delivery Device.

Magnetic micro-sized mesoporous silica particles were used for the preparation of a gated material able to release an entrapped cargo in the presence of an azo-reducing agent and, to some extent, at acidic pH. The magnetic mesoporous microparticles were loaded with safranin O and the external surface was functionalized with an azo derivative 1 (bearing a carbamate linkage) yielding solid S1. Aqueous suspensions of S1 at pH 7.4 showed negligible safranin O release due to the presence of the bulky azo derivative attached onto the external surface of the inorganic scaffold. However, in the presence of sodium dithionite (azoreductive agent), a remarkable safranin O delivery was observed. At acidic pH, a certain safranin O release from S1 was also found. The pH-triggered safranin O delivery was ascribed to the acid-induced hydrolysis of the carbamate moiety that linked the bulky azo derivatives onto the mesoporous inorganic magnetic support. The controlled release behavior of S1 was also tested using a model that simulated the gastro intestinal tract.

Tetrandrine beads using alginate/polyvinyl alcohol and alginate-carboxymethyl cellulose: Not ideal as colon-targeted dosage form

Objectives: Colon drug delivery system should be able to maintain drug release until the system reaches its target. In this study, beads were selected as drug carrier system to deliver tetrandrine to colon using a combination of two polymers, alginate and polyvinyl alcohol (PVA) and also alginate and carboxymethyl cellulose (CMC). It was hypothesized that alginate/PVA beads and alginate-CMC beads may be able to protect the drug effectively while in the gastrointestinal tract and may deliver the drug at colon under the influence of colonic pH. Materials and Methods: Beads were formulated into six formulae with different concentrations of polymer. Beads were characterized and evaluated for in vitro drug release using dissolution method. Results: Beads' Formula 3 (alginate and PVA 2:1) and Formula 6 (alginate and CMC 2:1.5) were the best formulae with entrapment efficiency 32.12% and 39.83%, respectively. The drug release test was performed first in hydrochloric acid (HCl) medium for 2 h, then in phosphate-buffered pH 7.4 + 2% Tween 80 for 3 h, and finally in phosphate-buffered pH 6.8 + 2% Tween 80 medium for 3 h, successively. The results of drug release in HCl pH 1.2 were 84.13%, 73.12%, 66.57%, 85.59%, 78.26%, and 69.56%, for Formula 1, 2, 3, 4, 5, and 6, respectively. Conclusion: All type of beads showed the high release of tetrandrine in HCl; hence, it is not ideal yet as a colon-targeted dosage form.

Mesalamine-loaded mucoadhesive microsphere for colon drug delivery system: Effect of process variables and in vitro characterization

Objective: The main objective of this study is to formulate mucoadhesive microspheres for colon drug delivery with sodium alginate (ALG) core enriched with drug. Methods: The core microspheres of ALG were prepared by modified emulsification method followed by cross-linking with different concentration of CaCl2 at different stirring speed with constant drug-to-polymer ratio (1:3). The core microspheres were further coated with Eudragit S-100 using the solvent evaporation technique. Results: The microspheres (core and coated) were characterized by shape, size, surface morphology, size distribution, entrapment efficiency, and in vitro drug release studies. In vitro drug release showed that the optimized batch of core microsphere and coated microspheres exhibited 99.53% ± 0.39% and 89.22% ± 0.26%, respectively. The drug release from all formulations of mesalamine microsphere followed Higuchian Kinetics. Moreover, drug release from core and Eudragit S-100-coated microspheres followed Korsmeyer–Peppas equation with anomalous and Fickian kinetics mechanism, respectively. Stability study suggests that the degradation rate constant of mesalamine from Eudragit S-100-coated microsphere was found to be minimum 2 years shelf life of the formulation. On the basis of scanning electron microscopy, the core microspheres were formed slightly irregular in shape due to surface-attached crystals of the drug and coated mesalamine microspheres showed smooth surface and a smaller number of pores due to coating. Conclusions: It can be concluded that the appropriate combination of a pH-dependent polymer (Eudragit S-100) with a pH-independent polymer sodium ALG) was suitably adequately sustained the drug release from mesalamine microspheres.

Formulation and evaluation of colon specific matrix tablet of metronidazole

Targeting of drug to the colon oral route the drug release is controlled by the gastrointestinal pH, transit times and intestinal flora. Metronidazole is only used antibiotics, which can be used, in colonic disease. Matrix formulations containing various proportions of Xanthan gum and HPMC E5LV were prepared by wet granulation technique using 10% starch paste. Six Matrix tablet formulation (1 to 6) of Metronidazole were prepared different mixture of Xanthan gum and HPMC-E5LV. All the formulations were evaluated for in-process quality control tests. The in-vitro drug release study first in 0.1N HCl followed by in pH 7.4 phosphate buffer, the formulation F3 show good drug release in control manner. Hence, synthetic polymer such as HPMCE5LV is most cheap and suitable for colonic drug delivery.

Design and Evaluation of Colon Targeted Dosage Form Containing Mesalazine Using pH Dependent Polymers

Colonic drug delivery has gained 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 and irritable bowel syndrome but also for the potential it holds for the systemic delivery of proteins and therapeutic peptides. The aim of the study was to develop colon targeted tablets of Mesalazine by wet granulation method using 33 response surface method with design of experiment software and HPMC K4M, Eudragit RL100, Ethyl cellulose and PVP K-30 used as pH dependent polymers. All the formulations (F1 to F27) were evaluated for the physicochemical parameters and were subjected to in vitro drug release studies. The amount of Mesalazine released from tablets at different time intervals was estimated by UV spectrophotometer. The formulation F26 released 98.16% of Mesalazine after 24 h. The results of the study showed that formulation F26 is the best formulation based on the evaluation parameters which provides targeting of Mesalazine for local action in the colon owing to its minimal release of the drug in the first 4 h. The pH dependent tablet system is a promising vehicle for preventing rapid hydrolysis in gastric environment and improving oral bioavailability of Mesalazine for the treatment of disease at colon region.

Sono-chemical synthesis and characterization of Fe3O4@mTiO2-GO nanocarriers for dual-targeted colon drug delivery

In this study, a kind of magnetic Fe3O4@mTiO2-GO (where m was shorted mesoporous) hybrids with core–shell nano-structure for controlled dual targeted drug delivery was synthesized using a facile sono-chemical method. The structure and chemical composition of the nanocarrier (NC), and its surface morphology, were studied by X-ray diffraction (XRD), scanning electron microscopy (SEM) with an energy dispersive X-ray (EDX), vibrating sample magnetometer (VSM) spectroscopy and Fourier transform infrared spectroscopy (FT-IR). Synthesis of Fe3O4@mTiO2-GO was proved by XRD and FT-IR. SEM showed that the particle size of this NC was in the range of ∼ 85–95 nm. EDX confirmed the presence of Ti, Fe, C and O in the nanocarrier. VSM analysis showed the magnetic behavior of the Fe3O4@mTiO2-GO nano-hybrids with saturation magnetization (M S) of 1.57 emu/g at room temperature. Curcumin (CUR) as a hydrophobic and an anti-tumor model drug was loaded on the NC. Drug loading capacity and encapsulation efficiency of this NC were as high as 17.85 and 72.45%, respectively. The drug release behavior was sustained and pH-responsive. MTT results demonstrated no significant cytotoxicity of the NC on Human Foreskin Fibroblast Normal cell line (HFF-2), indicating that this NC can be safe for use as a drug carrier for delivering anticancer drugs to tumor sites. The results of an MTT test on Caco-2 cancerous cells proved that CUR in nano-carriers has retained its anti-cancer properties.