Recent research advances on oral colon-specific delivery system of nature bioactive components: A review.

Oral colon-specific delivery system (OCDS) is a targeted approach that aims to directly deliver bioactive compounds directly to the colon following oral administration, thereby enhancing the colonic release of bioactive substances and minimizing adverse reactions. The effectiveness of bioactive substances in the colon hinges on the degree of release, which are affected by various factors including pH, mucosal barrier, delivery time and so on. Therefore, this review provides a comprehensive overview of the key factors affecting oral colon-specific release of bioactive components firstly. Considering the oral safety, this review then mainly focuses on the types of carriers with edible OCDS and preparation strategies for OCDS. Finally, several preparation strategies for loading typical natural bioactive ingredients into oral safe OCDS are reviewed, along with future development prospects.

Research on Preparation of 5-ASA Colon-Specific Hydrogel Delivery System without Crosslinking Agent by Mechanochemical Method.

PURPOSE: This study aims to overcome the challenges of the current oral targeted drug delivery system, such as the complex preparation process, poor biocompatibility, and delayed drug release. METHODS: Here, a non-covalent polymer hydrogel was prepared using the mechanochemical method, and the solid phase loading of 5-amino salicylic acid (5-ASA) was realized. RESULTS: The results obtained from the thermodynamics study, particle size analysis, and electron microscopy show that chitosan (CS) and sodium alginate (SA) form a pH-sensitive hydrogel under the mechanochemical force and also maintain good stability in aqueous solution. Fluorescent tracers study showed that the pH-sensitive hydrogel could achieve the targeted drug release in the colon and the retention time was over 12 h. Next, in vivo efficacy studies, change in mice body weight, DAI (disease activity index) score, thymus, and spleen index, and the diseased state of the mice colon revealed that the pH-sensitive hydrogel is an improved drug delivery system over 5-ASA API commercial preparations as observed in the efficacy and toxicological studies. CONCLUSION: This method uses an innovative preparation technology that without the need of cross-linking agent to produce an efficient colon-targeted drug delivery system for the treatment of ulcerative colitis.

Design of polysaccharidic nano-in-micro soft agglomerates as primary oral drug delivery vehicle for colon-specific targeting.

Microencapsulation of polysaccharidic nanoparticles is met with nanoscale and biological performance changes. This study designs soft agglomerates as nanoparticle vehicle without nanoparticles undergoing physical processes that alter their geometry. The nanoparticles were made of high molecular weight chitosan/pectin with covalent 5-fluorouracil/folate. Nanoparticle aggregation vehicle was prepared from low molecular weight chitosan. The nanoparticles and aggregation vehicle were blended in specific weight ratios to produce soft agglomerates. Nanoparticles alone are unable to agglomerate. Adding aggregation vehicle (< 2 µm) promoted soft agglomeration with nanoparticles deposited onto its surfaces with minimal binary coalescence. The large and rough-surfaced aggregation vehicle promoted nanoparticles deposition and agglomeration. A rounder vehicle allowed assembly of nanoparticles-on-aggregation vehicle into agglomerates through interspersing smaller between larger populations. Soft agglomeration reduced early drug release, and was responsive to intracapsular sodium alginate coat to further sustain drug release. The soft agglomerates can serve as a primary oral colon-specific vehicle.

Solid dispersion-based pellet for colon delivery of tacrolimus through time- and pH-dependent layer coating: preparation, in vitro and in vivo studies

The intent of the present investigation is to develop and evaluate colon-specific coated tacrolimus solid dispersion pellet (SDP) that retards drug release in the stomach and small intestine but progressively releases in the colon. Tacrolimus-SDP was prepared by extrusion-spheronization technology and optimized by the micromeritic properties including flowability, friability, yields and dissolution rate. Subsequently, the pH-dependent layer (Eudragit L30D55) and time-dependent layer (Eudragit NE30D and L30D55) were coated on the SDP to form tacrolimus colon-specific pellets (CSP) using a fluidized bed coater. Under in vitro gradient pH environment, tacrolimus only released from CSP after changing pH to 6.8 and then quickly released in the phosphate buffer solution of pH 7.2. The Cmax of CSP was 195.68 ± 3.14 ng/mL at Tmax 4.5 ± 0.24 h where as in case of SDP, the Cmax was 646.16 ± 8.15 ng/mL at Tmax 0.5 ± 0.03 h, indicating the ability of CSP targeted to colon. The highest area under the curve was achieved 2479.58 ± 183.33 ng·h/mL for SDP, which was 2.27-fold higher than tacrolimus suspension. However, the best biodistribution performance was achieved from CSP. In conclusion, SDP combining of pH- and time-dependent approaches was suitable for targeted delivery of tacrolimus to colon.

Design and evaluation of rhubarb total free anthraquinones oral colon-specific drug delivery granules to improve the purgative effect

Rhubarb is commonly used as a cathartic in Asian countries. However, researchers have devotedextensive concerns to the quality control and safety of rhubarb and traditional Chinese preparations composed of rhubarb due to the instable purgative effect and potential nephrotoxicity of anthraquinones. In this study, we aimed to prepare rhubarb total free anthraquinones (RTFA) oral colon-specific drug delivery granules (RTFA-OCDD-GN) to delivery anthraquinones to colon to produce purgative effect. RTFA-OCDD-GN were prepared using chitosan and Eudragit S100 through a double-layer coating process and the formulation was optimized. Continuous release studies were performed in a simulated gastric fluid (pH 1.2), followed by a small-intestinal fluid (pH 6.8) and a colonic fluid (pH 7.4, containing rat cecal contents). The purgative effect test was performed in rats. The dissolution profile of RTFA-OCDD-GN showed that the accumulative dissolution rate of RTFA was about 83.0% in the simulated colonic fluid containing rat cecal contents and only about 9.0% in the simulated gastrointestinal fluids. And the RTFA-OCDD-GN could produce the comparative purgative activity as rhubarb, suggesting it could deliver the free AQs to the colon. The RTFA-OCDD-GN was a useful media to enhance the purgative activity of free anthraquinones after administered orally.

Starch film-coated microparticles for oral colon-specific drug delivery.

The aim of this study was to prepare and characterize a novel type of starch-coated microparticles (MPs) allowing site-specific delivery of bioactives to the colon. An oral colon-specific controlled-release system was developed in the form of MPs coated with a resistant starch (RS2/RS3) film (RS@MPs) through an aqueous suspension coating process. The RS2 was chosen from a high-amylose cornstarch with 88.5% digestion resistibility. The RS3 was prepared by a high-temperature/pressure (HTP) treatment, with the following of enzymatic debranching, and retrogradation, resulting in a dramatic increase in enzymatic resistance (RS3 content: 76.6%). RS@MPs showed 40.7% of 5-aminosalicylic acid release within 8 h. The in vivo study of fluorescein-loaded RS@MPs indicated the high acidic and enzymatic resistibility of RS@MPs and a restrained release in the upper GIT. Therefore, RS@MPs has revealed to be a high potential system for accurately targeting bioactive compound delivery to the colon.

Oral colon-specific drug delivery system reduces the nephrotoxicity of rhubarb anthraquinones when they produce purgative efficacy.

Rhubarb is commonly used to treat constipation in China and anthraquinones (AQs) are the active components present in rhubarb. However, an increasing number of studies have reported that AQs induce nephrotoxicity. In the present study, rhubarb total free anthraquinones (RTFA) oral colon-specific drug delivery granules (RTFA-OCDD-GN) were prepared to determine whether RTFA-OCDD-GN could reduce the nephrotoxicity that occurs when AQs produce purgative efficacy. RTFA-OCDD-GN were prepared using pH-enzyme double-layer coating technology and the cumulative release rate of RTFA in RTFA-OCDD-GN was assessed. The first black stool time, the number and state of feces over 8 h were observed to measure the purgative efficacy. In the nephrotoxicity test, biochemical and histopathological examinations were performed following 20 and 40 days administration, and 20 days convalescence. The cumulative release rate of RTFA in RTFA-OCDD-GN was >80% in simulated colonic fluid. RTFA-OCDD-GN produced considerable purgative efficacy compared with rhubarb medical material samples (RMMS). Following 40 days RMMS administration, blood urea nitrogen, creatinine and urine ß2-microglobulin levels in the high-dosage group were significantly increased compared with the control and RTFA-OCDD-GN groups (P<0.05). All specimens from the high-dosage RMMS group exhibited swelling/degeneration of renal proximal convoluted tubule epithelial cells. No difference in pathological conditions and biochemical indicators was detected between the RTFA-OCDD-GN groups and the control group. The nephrotoxicity of AQs was significantly reduced following RTFA-OCDD-GN administration, which produced considerable purgative efficacy compared with RMMS.

Advances of new excipients and technique in colon-specific preparations / 中国药科大学学报

The oral colon-specific drug delivery system (OCDDS) has gained more attention from investigators in recent years since it can increase local drug concentration and reduce dosage and side effects.The type of colonspecific drug delivery system consists of enzyme dependent,pH dependent,time dependent,pressure dependent system and CODEDSTM.The development of many new materials and technology is very important for the preparation of new type of precise positioning colon-specific preparation.This article summarizes the advances in excipients and technique for oral colon-specific drug delivery system in recent years.It may provide a reference and a basis for the researchers concerned.

The pharmacokinetic study on the mechanism of toxicity attenuation of rhubarb total free anthraquinone oral colon-specific drug delivery system.

Rhubarb is commonly used as laxatives in Asian countries, of which anthraquinones are the major active ingredients, but there are an increased number of concerns regarding the nephrotoxicity of anthraquinones. In this study, we compared the pharmacokinetic characteristics of rhubarb anthraquinones in rats after orally administered with rhubarb and rhubarb total free anthraquinone oral colon-specific drug delivery granules (RTFA-OCDD-GN), and then explained why these granules could reduce the nephrotoxicity of anthraquinones when they produced purgative efficacy. A sensitive and reliable high performance liquid chromatography (HPLC) method has been fully validated for simultaneous determination of the five active components of rhubarb, and successfully applied to investigate and compare the remarkable differences in pharmacokinetic study of rhubarb anthraquinones after orally administered with rhubarb and RTFA-OCDD-GN. The results showed that, compared with rhubarb group, the AUC, Cmax, t1/2z and Vz/F of aloe-emodin, rhein, emodin and chrysophanol in rats receiving the RTFA-OCDD-GN were significantly decreased, and the Tmax of the four analytes was prolonged. Moreover, the Tmax of rhein, the Cmax of chrysophanol and emodin all have significant differences (P<0.05). Simultaneously, anthraquinone prototype excretion rates in urine and feces of aloe-emodin, rhein, emodin, chrysophanol and physcion were all increased. These findings suggested that oral colon-specific drug delivery technology made anthraquinone aglycone to colon-specific release after oral administration. This allowed anthraquinones to not only play the corresponding purgative effect but also avoid intestinal absorption and promote excretion. And thereby greatly reduced the nephrotoxicity of rhubarb. The result is a new breakthrough in rhubarb toxicity attenuated research.