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.

Camptothecin (CPT), a natural plant alkaloid, has indicated potent antitumor activities via targeting intracellular topoisomerase I. The promise that CPT holds in therapies is restricted through factors that include lactone ring instability and water insolubility, which limits the drug oral solubility and bioavailability in blood plasma. Novel strategies involving CPT pharmacological and low doses combined with nanoparticles have indicated potent anticancer activity in vitro and in vivo. This systematic review aims to provide a comprehensive and critical evaluation of the anticancer ability of nano-CPT in various cancers as a novel and more efficient natural compound for drug development. Studies were identified through systematic searches of PubMed, Scopus, and ScienceDirect. Eligibility checks were performed based on predefined selection criteria. Eighty-two papers were included in this systematic review. There was strong evidence for the association between antitumor activity and CPT treatment. Furthermore, studies indicated that CPT nano-formulations have higher antitumor activity in comparison to free CPT, which results in enhanced efficacy for cancer treatment. The results of our study indicate that CPT nano-formulations are a potent candidate for cancer treatment and may provide further support for the clinical application of natural antitumor agents with passive targeting of tumors in the future.

The canonical Wnt pathway is one of the key cellular signaling cascades that regulates, via the transcriptional co-activator β-catenin, numerous embryogenic developmental processes, as well as tissue homeostasis. It is therefore not surprising that misregulation of the Wnt/β-catenin pathway has been implicated in carcinogenesis. Aberrant Wnt signaling has been reported in a variety of malignancies, and its role in both hereditary and sporadic colorectal cancer (CRC), has been the subject of intensive study. Interestingly, the vast majority of colorectal tumors harbor mutations in the tumor suppressor gene adenomatous polyposis coli (APC). The Wnt pathway is complex, and despite decades of research, the mechanisms that underlie its functions are not completely known. Thus, although the Wnt cascade is an attractive target for therapeutic intervention against CRC, one of the malignancies with the highest morbidity and mortality rates, achieving efficacy and safety is yet extremely challenging. Here, we review the current knowledge of the Wnt different epistatic signaling components and the mechanism/s by which the signal is transduced in both health and disease, focusing on CRC. We address some of the important questions in the field and describe various therapeutic strategies designed to combat unregulated Wnt signaling, the development of targeted therapy approaches and the emerging challenges that are associated with these advanced methods.

In this study, amphipathic chitosan derivative (ACS) and cell-penetrating peptide (CPP) co-modified colon-specific nanoparticles (CS-CPP NPs) were prepared and evaluated to improve the oral bioavailability of protein and peptide drugs. ACS modification was harnessed to protect CPPs from degradation in the stomach and small intestine after oral administration and achieve colon-specific drug delivery. After CS-CPP NPs reached the colon, ACSs on the surface of the NPs were gradually degraded and CPPs were exposed to bring into play the penetration efficacy in the colon epithelium. Herein, we synthesized four types of ACSs (TOCS, TDCS, TPCS and TSCS) and adopted three types of CPPs (Tat, Penetratin and R8) to prepare NPs (TOCS-Tat NPs, TDCS-Tat NPs, TPCS-Tat NPs, TSCS-Tat NPs, TDCS-Pen NPs and TDCS-R8 NPs). The study of the protective effects of ACS upon Tat showed that the modification of ACS exerted favourable protection upon Tat in the stomach and small intestine. ACS degradation in the colon was indirectly determined in the viscosity method, which indicated that ACS could be gradually degraded in the colon. Using Caco-2 cell monolayers as cell models, it was found that the cellular uptake amount and transcellular transportation performance of CS-CPP NPs were much enhanced compared with those of TDCS NPs and PVA NPs. With Bama mini-pigs as animal models, the pharmacodynamic study demonstrated that the hypoglycemic effect for insulin-loaded TDCS-Tat NPs was more significant than that for TDCS NPs, lowering the blood glucose by 40%. The pharmacokinetic study indicated that the AUC and Cmax for TDCS-Tat NPs were respectively increased by 1.45 times and 1.82 times compared with those of TDCS NPs. In conclusion, CS-CPP NPs as vehicles for colon-specific drug delivery systems may be an efficient approach to improve the oral absorption of protein and peptide drugs.

Oral colon-specific delivery systems emerged as the main therapeutic cargos by making a significant impact in the field of modern medicine for local drug delivery in intestinal inflammation. The site-specific delivery of therapeutics (aminosalicylates, glucocorticoids, biologics) to the ulcerative mucus tissue can provide prominent advantages in mucosal healing (MH). Attaining gut mucosal healing and anti-fibrosis are main treatment outcomes in inflammatory bowel disease (IBD). The pharmaceutical strategies that are commonly used to achieve a colon-specific drug delivery system include time, pH-dependent polymer coating, prodrug, colonic microbiota-activated delivery systems and a combination of these approaches. Amongst the different approaches reported, the use of biodegradable polysaccharide coated systems holds great promise in delivering drugs to the ulcerative regions. The present review focuses on major physiological gastro-intestinal tract challenges involved in altering the pharmacokinetics of delivery systems, pathophysiology of MH and fibrosis, reported drug-polysaccharide cargos and focusing on conventional to advanced disease responsive delivery strategies, highlighting their limitations and future perspectives in intestinal inflammation therapy.

A myriad of pathologies affect the gastrointestinal tract, citing this affected area as a significant target for therapeutic intervention. One group of therapeutic agents, antisense and oligonucleotides and small interfering RNAs, offer a promising platform for treating a wide variety of diseases ranging from cancer to auto-immune diseases. Current delivery methods are carried out either systemically or locally into diseased areas, both of which involve needles. The challenge in orally administering this type of treatment lies in the complications that arise due to the vast environmental extremes found within the gastrointestinal tract, owing to the fact that, as the drug travels down the gastrointestinal tract, it is subjected to pH changes and interactions with bacteria and a variety of digestive and protective enzymes including proteases, DNAses, and RNAses. Overcoming these challenges to allow the practical application of these drugs is a priority that has invoked a multitude of research in the chemical, biological, and material sciences. In this review, we will address common gastrointestinal pathologies, the barriers to oral-based therapies and antisense-interfering technologies, the approaches that have already been applied for their delivery, and the current status of antisense drug therapy clinical trials for gastrointestinal-related disorders.

In the present study, Eudragit S100 coated Citrus Pectin Nanoparticles (E-CPNs) were prepared for the colon targeting of 5-Fluorouracil (5-FU). Citrus pectin also acts as a ligand for galectin-3 receptors that are over expressed on colorectal cancer cells. Nanoparticles (CPNs and E-CPNs) were characterized for various physical parameters such as particle size, size distribution, and shape etc. In vitro drug release studies revealed selective drug release in the colonic region in the case of E-CPNs of more than 70% after 24 h. In vitro cytoxicity assay (Sulphorhodamine B assay) was performed against HT-29 cancer cells and exhibited 1.5 fold greater cytotoxicity potential of nanoparticles compared to 5-FU solution. In vivo data clearly depicted that Eudragit S100 successfully guarded nanoparticles to reach the colonic region wherein nanoparticles were taken up and showed drug release for an extended period of time. Therefore, a multifaceted strategy is introduced here in terms of receptor mediated uptake and pH-dependent release using E-CPNs for effective chemotherapy of colorectal cancer with uncompromised safety and efficacy.

Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.

Several curcumin derivatives are now becoming increasingly of interest because of their bioactive attributes, especially their action as antioxidants and anti-carcinogenic activities. Tetrahydrocurcumin (THC), an active metabolite of curcumin, was selected to be a proper starting material for the work presented here as it is stable in physiological pH and has the typical pharmacological properties of curcumin. We have now reported that novel synthesized water-soluble polymeric macromolecule prodrugs can specifically deliver the drug to the colon. To study the drug loading and drug release, THC was conjugated with a hydrophilic polymer, carboxymethylcellulose (CMC) with the degree of substitution (DS) values of 0.7 and 1.2. THC was also attached to two different spacers including p-aminobenzoic acid (PABA) and p-aminohippuric acid (PAH) via an azo bond that was cleaved by the azoreductase activities of colonic bacteria. The novel active molecule, 4-amino-THC, was readily released from the conjugates in the colon (>62% within 24h) with only very small amounts released in the upper GI tract (<12% over 12h). The polymer conjugates showed chemical stability at various pH values along the gastrointestinal tract and increased water solubility of up to 5mg/mL. 4-Amino-THC demonstrated cytotoxic ability against the human colon adenocarcinoma cell lines (HT-29) with an IC50 of 28.67 ± 1.01 μg/mL, and even greater selectivity (∼ 4 folds) to inhibit HT-29 cells than to normal human colon epithelial cell lines while curcumin was a non-selective agent against both cell lines. Our study has demonstrated that the use of THC-CMC conjugates may be a promising colon-specific drug delivery system with its sustained release in the colon to be an effective treatment for colonic cancer.

To overcome the undesirable side-effects of metronidazole (MTZ), ethylene glycol dimethacrylate is used as the cross-linker, and a series of poly(methacrylic acid) (PMAA) nanogels were prepared to load the MTZ. We investigated the morphology, size, in vitro release property in the simulated gastrointestinal medium, long-term antibacterial performance against Bacteroides fragilis, cytotoxicity, stability and activity of this novel MTZ/PMAA nanogel. The results indicate that the MTZ/PMAA nanogel sustained the release of MTZ in long-term antibacterial activity in the simulated gastrointestinal medium. This MTZ/PMAA nanogel exhibits less cytotoxicity than MTZ alone, suggesting that MTZ/PMAA nanogel is a more useful dosage form than MTZ for mild-to-moderate Clostridium difficile infections. The novel aspects of this study include the synthesis of a nanogel and the three-phase study of the release profile, which might be useful for other researchers in this field.

Pulsatile delivery is generally intended as a release of the active ingredient that is delayed for a programmable period of time to meet particular chronotherapeutic needs and, in the case of oral administration, also target distal intestinal regions, such as the colon. Most oral pulsatile delivery platforms consist in coated formulations wherein the applied polymer serves as the release-controlling agent. When exposed to aqueous media, the coating initially performs as a protective barrier and, subsequently, undergoes a timely failure based on diverse mechanisms depending on its physico-chemical and formulation characteristics. Indeed, it may be ruptured because of the gradual expansion of the core, swell and/or erode due to the glassy-rubbery polymer transition or become permeable thus allowing the drug molecules to diffuse outwards. Otherwise, when the coating is a semipermeable membrane provided with one or more orifices, the drug is released through the latter as a result of an osmotic water influx. The vast majority of pulsatile delivery systems described so far have been prepared by spray-coating, which offers important versatility and feasibility advantages over other techniques such as press- and dip-coating. In the present article, the design, manufacturing and performance of spray-coated pulsatile delivery platforms is thus reviewed.

In order to adapt a previously described swellable/erodible pulsatile delivery system to a multiple-unit configuration, insoluble films with adequate permeability and flexibility were proposed for application to its functional hydroxypropyl methylcellulose (HPMC) layer. By slowing down the penetration of water into the system, such films would be expected to improve the relevant effectiveness in delaying the onset of release without possibly impacting on the mechanism involved. Free films of Eudragit(®)NE containing differing amounts (10-20%) of a superdisintegrant, i.e. Explotab(®)V17, Ac-Di-Sol(®), Kollidon(®)CL or Kollidon(®)CL-M, were prepared by spraying technique and evaluated for hydration, permeability and tensile properties. The hydration and permeability characteristics were enhanced by the addition of the superdisintegrants, generally as a function of their concentration. Explotab(®)V17 was shown particularly useful to increase the film permeability. Moreover, it exerted a minor impact on the advantageous tensile properties of the acrylic polymer, especially in the wet state. Based on these results and on a preliminary release study performed with two-layer devices, the Eudragit(®)NE film with Explotab(®)V17 at the highest investigated percentage was identified as a potential formulation candidate for being applied to HPMC-coated cores thus allowing the onset of release to effectively be delayed by coatings of reduced thickness.

Oral colon delivery is currently considered of importance not only for the treatment of local pathologies, such as primarily inflammatory bowel disease (IBD), but also as a means of accomplishing systemic therapeutic goals. Although the large bowel fails to be ideally suited for absorption processes, it may indeed offer a number of advantages over the small intestine, including a long transit time, lower levels of peptidases and higher responsiveness to permeation enhancers. Accordingly, it has been under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Because of a strong underlying rationale, most of these studies have focused on insulin. In the present review, the impact of key anatomical and physiological characteristics of the colon on its viability as a protein release site is discussed. Moreover, the main formulation approaches to oral colon targeting are outlined along with the design features and performance of insulin-based devices.

An oral colon-targeting controlled release system based on resistant starch acetate (RSA) as a film-coating material was developed. The RSA was successfully synthesized, and its digestion resistibility could be improved by increasing the degree of substitution (DS), which was favorable for the colon-targeting purpose. As a delivery carrier material, the characteristics of RSA were investigated by polarized light microscopy, FTIR spectroscopy, and X-ray diffraction. The results revealed a decrease of the crystallinity of RSA and a change of its crystalline structure from B + V hydrid type to V type. To evaluate the colon-targeting release performance, the RSA film-coated pellets loaded with different bioactive components were prepared by extrusion-spheronization and then by fluid bed coating. The effects of the DS, plasticizer content, and coating thickness of the RSA film and those of the content and molecular weight of the loaded bioactive component on the colon-targeting release performance of the resulting delivery system were investigated. By adjusting the DS, the coating thickness, and the plasticizer content of the RSA film, either the pellets loaded with a small molecular bioactive component such as 5-aminosalicylic acid or those with a macromolecular bioactive peptide or protein such as bovine serum albumin, hepatocyte growth-promoting factor, or insulin showed a desirable colon-targeting release performance. The release percentage was less than 12% in simulated upper gastrointestinal tract and went up to 70% over a period of 40 h in simulated colonic fluid. This suggests that the delivery system based on RSA film has an excellent colon-targeting release performance and the universality for a wide range of bioactive components.

The feasibility of injection molding was explored in the preparation of a novel capsular device for oral pulsatile/delayed delivery based on swellable/erodible polymers. For this purpose, a mold intended to be coupled with a bench-top injection-molding press was designed. This was expected to enable the preparation of matching capsule cap and body items within a single manufacturing cycle and the selection of differing shell thicknesses (300, 600, and 900 μm). Hydroxypropylcellulose (Klucel(®) EF, LF, and GF) was employed as the release-controlling polymer in admixture with polyethylene glycol 1500 (10%, w/w) as the plasticizer. After preliminary trials aimed at the setup of operating conditions, Klucel(®) EF and LF capsule shells with satisfactory technological properties were manufactured. The performance of capsular devices filled with a tracer drug powder was studied by means of a modified USP31 disintegration apparatus. Typical in vitro delayed release patterns were thereby obtained, with lag time increasing as a function of the wall thickness. A good correlation was found between the latter parameter and t (10%), i.e., the time to 10% release, for both polymer grades employed. On the basis of the overall results, the investigated technique was proven suitable for the manufacturing of an innovative pulsatile release platform.

The therapeutic management of inflammatory bowel disease (IBD) represents the perfect scenario for drug targeting to the site(s) of action. While existing formulation-based targeting strategies include rectal dosage forms and oral systems that target the colon by pH-, time-, microflora- and pressure-triggered drug release, novel approaches for site-specific delivery in IBD therapy will target the inflamed intestine per se rather than intestinal region. The purpose of this article is to present a mechanistic update on the strategies employed to achieve minimal systemic exposure accompanied by maximal drug levels in the inflamed intestinal tissue. The introduction of biological agents, micro/nanoparticulate carriers including liposomes, transgenic bacteria, and gene therapy opportunities are discussed, as well as the challenges remaining to be achieved in the targeted treatment of IBD.

The design of a film coating technology which allows a tablet to deliver the drug in the ileocolonic segment would offer new treatment possibilities. The objective is to develop a platform technology that is suitable for a broad range of drug compounds. We developed a coated tablet with a delayed, pulsatile release profile based on a pH-sensitive coating technology (ColoPulse). The production process was validated, and the effect of core composition on the in vitro release and water uptake investigated. The release profile of the standard tablet core composition, based on the use of cellulose as a filler, was independent of the coat thickness in a range of 9.0-13.2 mg/cm(2). The release profile of a coated tablet was strongly influenced when cellulose was partly replaced by the model substance glucose (loss of sigmoidal release), citric acid (stabilization), sodium bicarbonate (destabilization) or sodium benzoate (destabilization). The film coating takes up water when below the pH-threshold. However, this did not cause early disintegration of the coating. The ColoPulse technology is successfully applied on tablets. The in vitro release characteristics of the coated tablets are influenced by the composition of the core.

Novel azo polymers were prepared for colonic drug delivery with a release mechanism based on structural features of azo derivatives designed for rapid bacterial degradation leading to soluble polymers. Two Salicylazo derivatives were prepared and conjugated as side chains at different ratios to methacrylic acid-methyl methacrylate copolymers (Eudragits). The azo compounds were designed to have a hydrophilic and a hydrophobic part on opposite sides of the azo bond. Upon reduction of the azo bonds, the hydrophobic part is released, resulting in a more water soluble polymer. The solubility of the polymeric films was studied relative to Eudragit S known to dissolve toward the end of the small intestine. One of the two azo derivatives prepared gave rise to polymers, which showed reduced solubility relative to Eudragit S. These polymers were subjected to reduction tests in anaerobic rat cecal suspensions by following the release of the hydrophobic product. Reduction rate was found to be rapid, comparable to that of Sulfasalazine. Studies on the azopolymeric films in anaerobic rat cecal suspensions, showed that these polymers dissolve faster than in sterilized suspensions. Solid dosage forms may be coated with these polymers to provide an efficient delivery system to the colon with a rapid release mechanism.

The enzyme-dependent conjugates of indomethacin and amylose (Am-IND) were synthesized at room temperature using N,N'-dicyclohexylcarbodiimide (DCC) as a coupling agent and 4-(N,N'-dimethylamino) pyridine (DMAP) as a catalyst. Their structures were characterized by FTIR and (1)H NMR analyses, and the results indicated that the IND residues were conjugated with amylose backbones through ester bonds. For the conjugate with a lower IND content, the better water absorption property was advantageous for enzymes diffusing into the swollen conjugate, resulting in biodegradation of the conjugates and release of IND. In vitro biodegradation evaluation indicated that the Am-IND conjugates were biodegraded in the simulated media of the intestines. In vitro drug release experiments showed that the Am-IND conjugates exhibited a sustained release behavior in the simulated media of the intestines, while IND was hardly released in the simulated gastric fluid. These features provide a great opportunity to use the conjugates as a prodrug for intestinally targeted and controlled release of IND through oral administration. This study may lead to the development of effective methods for utilizing amylose as a new drug delivery carrier.

A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable drugs across the intestinal epithelium. To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository. Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be co-released in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. An advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C(10)), a compound already approved as a food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level as well as in vitro and in vivo efficacy and safety studies. In specific clinical examples, we review how C(10)-based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for antisense oligonucleotides (ISIS Pharmaceuticals, USA).

Water soluble cellulose ethers, including methylcellulose and two hydroxyethylcelluloses with different molecular weights, were conjugate with indomethacin at room temperature. The chemical structures of the conjugates were characterized by FTIR, (1)H NMR and UV-vis spectroscopy. The results confirmed that different amounts of IND residues were covalently bonded to cellulose ether backbones through ester linkages. Their anaerobic biodegradation in colonic fermentation was investigated by gel permeation chromatography, gas chromatography and UV-vis spectroscopy. These conjugates were found to have different biodegradabilities, depending on the cellulose ether used and the amount of conjugated indomethacin residues. In vitro release experiments showed that hydroxyethylcellulose-based conjugates with low IND residues content could exhibit a sustained drug release behavior in colonic fermentation and were stable in the simulated media of the stomach and small intestine. Therefore, they are promising candidates for future applications in colon-specific drug delivery.

The aim of the present study was to define in-vitro and in-vivo characteristics of pectin/ethylcellulose-film-coated pellets of 5-fluorouracil (5-FU) for colonic targeting. The pellet cores were coated to different film thicknesses with three different pectin/ethylcellulose formulations using a fluidized bed coater. The gastrointestinal (GI) transit of coated pellets was determined by counting the percentage of coated pellets in the GI lumen by celiotomy at certain times after oral administration. 5FU was administered to rats at a dose of 15 mg kg(-1). The toxicity of 5-FU in the GI tract was evaluated using histological examination. The 1:2 ratio pectin:ethylcellulose-coated pellets with 30% total weight gain (TWG-30%) produced more satisfactory drug-release profiles in the simulated gastric, intestinal and colonic fluids. Most of the coated pellets were eliminated from the stomach in 2 h, moved into the small intestine after 2-4 h, and reached the large intestine after 4 h. After oral administration of coated pellets, 5-FU started appearing in the plasma at 7 h, and reached peak plasma concentration (Cmax) of 3.21+/-2.01 microg mL(-1) at 16 h (Tmax); the Cmax for uncoated pellets was 22.21+/-2.60 microg mL(-1) at Tmax 0.75 h. The TWG-30% formulation showed delayed Tmax, decreased Cmax and prolonged mean residence time compared with uncoated pellets. Marked pathological features in the colon were seen in rats given coated pellets, but no injuries were observed in the upper GI tract. The formulation of TWG-30% could deliver 5-FU to the colon for local action.

Pectin beads containing beta-lactamases were designed for the hydrolysis of colonic residual antibiotics responsible for the emergence of resistance. Beads were prepared by ionotropic gelation in CaCl2 and stabilized by coating with polyethylenimine (PEI) to resist disintegration in the upper GI tract. Particle characterization showed that dried beads had a diameter around 1 mm independently of the presence of PEI. Seven to ten percent (w/w) of PEI was located on bead surface forming a coating layer as observed by scanning electron microscopy. PEI improved considerably bead stability in simulated intestinal medium while affecting slightly the encapsulation efficiency of active beta-lactamases. Coated beads were able to preserve beta-lactamases from premature leakage in the upper GIT whereas, in simulated colonic medium, pectinases induced matrix degradation and reduction of beta-lactamase content especially in beads coated in a 0.8% PEI solution. Finally, the pharmacokinetics of amoxicillin in rat after oral administration was not modified by the co-administration of beads containing beta-lactamases. In conclusion, PEI-coated beads are stable in the upper GIT but remain sensitive to the action of pectinolytic enzymes allowing release of beta-lactamases in a colonic medium without modification of the absorption of a beta-lactam antibiotic when co-administered with loaded beads.

To quantitate and predict colon-specific 9-aminocamptothecin (9-AC) release from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-9-AC conjugate and its absorption behavior after oral administration in rats.

Drug distribution in the gastrointestinal (GI) tract and the plasma concentration-time profile of 9-AC released from the HPMA copolymer conjugate were predicted using the degradation, transit, and absorption rate constants in cecum. The fate of 9-AC in cecum and liver was measured by in-situ cecum absorption and liver perfusion.

Following oral administration of the conjugate, 9-AC was released rapidly in cecum. Based on the pharmacokinetic model, up to 60% of the dose was in the cecum at ~6 h, and 7% of the dose still remained there at 24 h. The predicted plasma concentration curve for released 9-AC after an oral dose of 3 mg/kg of 9-AC equivalent increased gradually and reached a peak of 98 nM at 7 h, then started decreasing slowly to 16 nM at 24 h. The bioavailability value was estimated as 0.31 after the first-pass elimination.

A pharmacokinetic model delineated the impact of GI transit, drug absorption rate, and first-pass metabolism on drug disposition following oral administration of HPMA copolymer-9-AC conjugate in rats.

The quest to eliminate the needle from insulin delivery and to replace it with non- or less-invasive alternative routes has driven rigorous pharmaceutical research to replace the injectable forms of insulin. Recently, various approaches have been studied involving many strategies using various technologies that have shown success in delivering insulin, which are designed to overcome the inherent barriers for insulin uptake across the gastrointestinal tract, mucosal membranes and skin. This review examines some of the many attempts made to develop alternative, more convenient routes for insulin delivery to avoid existing long-term dependence on multiple subcutaneous injections and to improve the pharmacodynamic properties of insulin. In addition, this article concentrates on the successes in this new millennium in developing potential non-invasive technologies and devices, and on major new milestones in modern insulin delivery for the effective treatment of diabetes.

Absorption enhancement of poorly absorbed hydrophilic compounds from various mucosal sites by co-administration of a mucolytic agent and a non-ionic surfactant was examined in rats. Fluorescein isothiocyanate-labeled dextran with average molecular weight of ca. 4.4kDa (FD-4), and salmon calcitonin (SCT) were used as model compounds. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100) were selected as a mucolytic agent and a non-ionic surfactant, respectively. Dosing solutions containing these agents were administered into various mucosal sites including the nose, the lung and the large intestine, and the bioavailabilities were determined. The combination of 5% NAC and 5% TX-100 significantly enhanced the nasal, the pulmonary and the large intestinal absorption of FD-4 compared to the control, and the enhancement ratios relative to the control were 7.2-, 2.8- and 4.5-fold, respectively. The different enhancement ratio among the administration sites explored indicates that the absorption enhancing effect of the combination of NAC and TX-100 is site-dependent. This combination also improved the nasal and the pulmonary absorption of SCT, and the enhancement ratios relative to the control were 6.1- and 8.1-fold, respectively. All these results suggest that the combination strategy of a mucolytic agent and a non-ionic surfactant may be widely applicable to various mucosal deliveries of poorly absorbed hydrophilic compounds.

A water soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-9-aminocamptothecin (9-AC) conjugate was designed for oral colon-specific drug delivery in the treatment of colon cancer. Comparative studies between the polymer conjugate and free drug have been performed to assess their biodistribution and pharmacokinetics in mice. After oral administration of equal doses of the polymer conjugate or free 9-AC, the drug concentrations in major organs at fixed time points were determined using an HPLC-fluorescence assay. Only 2+/-1% of 9-AC released from the polymer conjugate was detected in the small intestine (SI), and the mean peak concentration of free 9-AC was 45-fold higher than that from released drug. Colon-specific release of 9-AC produced high local concentrations. The mean peak concentration of released 9-AC in cecal contents, feces, cecal tissue, and colon tissue were, respectively, 3.2-fold, 3.5-fold, 2.2-fold and 1.6-fold higher than that using free 9-AC. In plasma, the high and sharp drug concentration profile from free drug was in contrast to the relatively low and flat pharmacokinetic profile obtained from drug released from the HPMA copolymer. There was no significant difference between released and free drug for the area under the concentration-time curve (AUC) and bioavailability values. As a consequence of the colon-specific release of unmodified 9-AC from the polymer conjugate, antitumor efficacy can be anticipated to be enhanced due to prolonged colon tumor exposure to higher and more localized drug concentrations.

The bioactivity of beta-lactamases upon entrapment in calcium-pectinate beads was evaluated. Non-amidated (NAP) and amidated pectin (AP) beads were prepared according to the ionotropic gelation method using calcium chloride (CaCl(2)) as gelling agent, washed and dried at 37 degrees C in an oven for 2h. Both enzyme activity and protein content were determined as well as bead calcium content. NAP allowed a better encapsulation of the protein than AP. Increasing both CaCl(2) concentration and bead residence time in the gelation medium led to a significant loss of beta-lactamase activity. The drying process of beads also lowered the enzyme activity. Moreover, bead calcium content increased as the CaCl(2) concentration augmented. Being very hygroscopic, the excess of CaCl(2) correlates with an increase of moisture content in beads that affects enzyme activity. After elimination of free calcium from beads, it was shown that a small amount is needed to form the Ca-pectinate network and that the activity of beta-lactamases is preserved in these conditions. Therefore, the bioactivity of encapsulated beta-lactamases in pectin beads mainly depends on formulation parameters such as pectin type, CaCl(2) concentration, washing and drying processes.

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

Fifteen years of research in the area of colon-specific drug delivery has left us with a slim choice of viable techniques, not because of the lack of proofs of concept but because of the ambiguity regarding the therapeutic necessity of targeting the colon with drugs. Critical analysis of existing technologies as well as medically based novel ideas could lead to interesting prospects.:

Insulin-monomethoxypoly(ethylene glycol) derivatives were obtained by preparation of mono- and di-terbutyl carbonate insulin derivatives, reaction of available protein amino groups with activated 750 Da PEG and, finally, amino group de-protection. This procedure allowed for obtaining high yield of insulin-1PEG and insulin-2PEG. In vivo studies carried out by subcutaneous injection into diabetic mice demonstrated that the two bioconjugates maintained the native biological activity. In vitro, PEGylation was found to enhance the hormone stability towards proteases. After 1 h incubation with elastase, native insulin, insulin-1PEG and insulin-2PEG undergo about 70, 30 and 10% degradation, respectively, while in the presence of pepsin protein degradation was 100, 70 and 50%, respectively. The attachment of low molecular weight PEG did not significantly (P >0.05) alter insulin permeation behavior across the intestinal mucosa. Insulin-1PEG was formulated into mucoadhesive tablets constituted by the thiolated polymer poly(acrylic acid)-cysteine. The therapeutic agent was sustained released from these tablets within 5 h. In vivo, by oral administration to diabetic mice, the glucose levels were found to decrease of about 40% since the third hour from administration and the biological activity was maintained up to 30 h. According to these results, the combination of PEGylated insulin with a thiolated polymer used as drug carrier matrix might be a promising strategy for oral insulin administration.