Oral Colon-specific Drug Delivery System Based On Guar Gum Coating

Oral colon-specific drug delivery system has received considerable interest in recent 20 years. Efforts in this area have been done because of the need to better treat local disorders of the colon and the potential to improve absorption of protein and peptide drugs. 5-Fluorouracil (5-FU) is still the first-line chemotherapeutic agent to treat colorectal cancer. Due to erratic oral bioavailability of 5-FU, the clinical fundamental administration is intravenous injection, which causes severe systemic toxic effects, poor compliance and failed therapy. Indomethacin (IDM) inhibits cell proliferation and induces apoptosis by the way of cycloxygenase, hence can prevent and treat colorectal cancer to some degree. However, non-steroid anti-inflammatory drugs do harm and irritation to gastrointestinal tract, which limits its chronical use in prophylaxis of colorectal cancer. Therefore, oral targeted delivery of 5-FU and IDM to the colon would ensure direct treatment at the disease sites, lower dosing and less systemic side-effect.The aim of this study is to achieve a reliable method to prepare colon-specific drug delivery system. Hence pellets, considered as optimal dosage form for colonic drug delivery, and guar gum, the biodegradable material, were chosen to develop colonic drug delivery systems of 5-FU and IDM based on enzyme-triggered drug release combined other mechanism, which offers a novel dosage form of 5-FU/IDM to treat/prevent colorectal cancer with lower side-effects and better therapeutical effect.Drug-loaded cores were respectively coated with a colonic microflora-degradable polysaccharide, guar gum, as an inner coat, and a pH-sensitive polymer, Eudragit FS30D, as an outer coat in fluidized bed to prepare pH-, enzyme-double controlled colon-targeted pellets. Factors influencing drug release were investigated. As a result, Eudragit FS30D with 30% coat weight gain and without plasticizer can protect drug intact in 0.1mol/L HCl and pH6.8PBS, but film coat dissolved fastly and drug released rapidly once the Eudragit FS30D coated pellets came into pH7.4PBS. Eudragit FS30D, as a pH-sensitive polymer, able to response to the pH of the environment rapidly, can protect drug from mouth to ileum where the lumen pH of over 7 ignites the dissolution of the enteric polymer and drug release. On exposure to dissolution fluids, guar gum becomes hydrated and forms a viscous gel layer that can delaythe drug release and this capability of delaying drug release is increased with increase of the viscosity of guar gum. For water-soluble drug 5-FU, the coat weight of guar gum with viscosity of 5200～5500 cps amounting to 550% or so can lower the drug release from 100% to 10% within 1 h compared with instant release drug loaded pellets. On the other hand, for water-insoluble drug IDM, the guar gum coating with only 44% coat weight gain can achieve the same protective effect. In consecutive gradient pH condition, double-coated pellets (30%FS30D, 580%GG) of 5-FU began to release drug after 5 h and completed release within 4h under action by galactomannanase. Without enzyme, the drug release was not completed until the 12^th h after lag time. Double coated pellets (30%FS30D, 44%GG) of IDM began to release drug after 4.5 h and all drug was released out at the 8^th h attacked by enzyme, or the drug release continued to the 18^th h. In a word, Eudragit FS30D/guar gum doubled coated pellets of the model drugs with different characteristic of solubility shows the good ability of targeting drugs to the colon.After blending guar gum with ethylcellulose, the mixture was spayed onto the drug loaded cores in fluidized bed coater to prepare the time-, enzyme-double controlled colon-targeted pellets. The aim to specifically deliver drug to the colon can be achieved by adjusting the ratio of guar to ethylcellulose and the coat weight gain, which controls the delayed drug release time to about 5 h. The effect of delayed drug release was more obvious with increasing the proportion of ethylcellulose and coat weight. Factorial design and response surface methodology was used to optimize guar gum-ethylcellulose mix-coated pellets. As a result, for 5-FU, when the ratio of guar to ethylcellulose is 1/2 and coat weight gain is 405%, the delayed drug release time was about 5 h and after that all drug was released within 5 h presence of enzyme, or the drug release would last 7 h. For IDM, when the ratio of guar to ethylcellulose is 1/1 and coat weight gain is 105%, the drug release was less than 5% within 5 h. After that, the entire drug was released within 19 h in presence of enzyme, or the drug release would be 65% within the same time in absence of enzyme. It was suggested that the sensitivity of drug release triggered by colonic enzyme was diminished due to much ethylxellulose occupied on mixed coating.The efficacy of the Eudragit FS30D/guar gum double coated pellets of 5-FU/IDM and the guar gum-ethylcellulose mix-coated pellets in targeting drugslocally to the colon were assessed by subjecting them to pharmacokinetic evaluation in beagle dogs against Eudragit FS30D coated pellets and/or uncoated drug-loaded pellets. The results show that four kinds of colon-targeted pellets all can delay drug release in vivo and the lag time in vivo of them is closed to that of in vitro, except Eudragit FS30D/guar gum double coated pellets of /IDM that has delayed absorption time in vivo of 2.84 h, less than the delayed release time in vitro of 4.5 h. It is suggested that Eudragit FS30D/guar gum double coating and guar gum-ethylcellulose mixed coating both achieve targeting drug to the colon, which can improve the efficiency and safely of 5FU/IDM on treat/prevent colorectal cancer.