A New 5-Fluorouracil Compression-Coated Tablet For Colon Delivery

5-Fluorouracil(5-FU) is a metabolic antagonist,which is used clinically as an effective chemotherapeutic drug for the treatment of colorectal cancer.However, 5-FU shows low biological availability,great toxicity and side-effects in addition to its incomplete absorption after oral administration.Now,intravenous administration has been used clinically.In order to increase the local concentration in colon,avoid the systemic absorption and reduce the side effects,we designed a new zein/pectin compression-coated tablets containing 5-FU for colon delivery.This system has the initiate release in the proximal colon.We studied the physicochemical properties,in vitro drug release of the tablets and the characters of colon-specific delivery in rats.Firstly,preformulation was investigated.The ultraviolet spectrophotometry method was applied to determine the content of 5-FU.The results showed that the UV method is convenient,accurate,and has a high specificity.The method of 5-FU drug release was established.The core tablets of 5-FU were prepared by direct compression of the powder mixture.The effects of filler and disintegrant on the drug release of core tablet were studied using disintegration time as a reference.The effect of lubricant on the flowability of powder was also examined using angle of repose. The orthogonal design was used to determine filler,type and amount of disintegrant in formulation of core tablet.The results showed that the dual wavelength spectrophotometry and K-ratio spectrophotometry for determining in vitro drug release of 5-FU were convenient and sensitive.And the disturbance of enzymes could be effectively avoided during UV measurement.The results of the preformulation indicated that the ratio of MCC and lactose,type and amount of disintegrant were the major influence factors.The optimal formulation of core tablet was:5-FU content in core tablet was 50 mg,the ratio and amount of MCC and lactose were 2:1 and 43.2 mg.The disintegrant and lubricant were CMS-Na(4.8 mg) and talc(2 mg).Another formulation of core tablet which included 5-FU(50 mg),MCC(48 mg) and talc(2 mg) was studied as an alternative.In additon,the effect of ratio and quantity of coating material on in vitro drug release were also studied.When the ratio of pectin and zein was 1:2 and the quantity of coating material was 300 mg,The coated tablets released only 2.70±0.61%and 0.54±0.09%of 5-FU in the first 5 h,then released 89.8±7.7%and 2.35±0.47%continuously at 12 h with and without enzymes.It was found that pectin/zein mixture were cross-linked in gastro-intestinal fluid(GIF) at 37℃, which could effectively prevent premature 5-FU release in GIF from polymer degradation by enzymes.Secondly,TLC,swelling,erosion and SEM studies were carried out to examine the mechanism of drug release.Moreover,stability of coated tablets was also studied. The spots of zein and coating layer(pectin/zein 1:2) showed different colors,while there was no spot of pectin on the plate.Flow rate(R_f) of spots for zein and coating layer were 0.72 and 0.32,repectively.This means that zein and pectin could have an interaction,for example by cross-linking reaction in GIF at 37℃.The swelling and erosion of the tablets were modeled using Ritger-Peppas equation.Curve fitting for erosion(%) and t^0.89(h) of time was performed.And curve fitting for swelling distances (mm,radial and axial direction) and t^0.45(h) of time was also performed.The curves were in linearity.This indicated that the erosion of the coated tablet linearly increase with t^0.89(h) of time and the swelling distances linearly increased with t^0.45(h) of time, the liquid uptake was drived by diffusion mechanism.SEM images showed that the coating layer gelated and swelling in 2 h;there were small pores in the surface of the tablet at 5 h,and the solvent penetrated into the interior core through the pores,then the drug released;At 12 h,the pores and channels were more obvious,and the size of the channels became bigger.The Ritger-peppas equation indicated that the release of coated tablets were drived by diffusion and erosion mechanism.The n value was 0.88.Finally,in vivo study of 5-FU coated tablets was investigated in rats. High-performance liquid chromatograph(HPLC) was used for the determination of 5-FU in rat plasma,colon content and tissue.And the methodolgy was validated.The method was simple,sensitive and specific.After 15 min of oral administration of uncoated tablets,the 5-FU could be detected in the plasma,and the maximum plasma concentration was 1111.6ng·ml^-1 at 0.5 h.The maximum plasma concentration of 5-FU was 146.2 ng·ml^-1 at 5 h after oral administration of coated tablets.The results showed that 5-FU did not release in the colon during 2 h after oral administration,and during 5～16 h,5-FU was detected in colon content.The maximum concentration of 5-FU in colon content was 25.03μg·g^-1,however,the drug content in colon was low. The results of residual drug content showed that drug release was relatively slow during 6～10 h.At 12 h,the residual drug content was above 60%.The 5-FU could be detected in colon tissue during 5～10 h,and the maximum concentration of 5-FU in colon tissue was 1.95μg·g^-1.At 12 h,there was no drug in colon tissue.The in vitro study indicated that drug release was drived by both diffusion and erosion.The 5-FU almost did not release in the GI tract and released quickly after getting into colon.The in vivo experiments verified that drug was almost not released in the stomach,and there was little drug released in the small intestine,and drug release was relatively slow during 6～10 h.The relative distribution of 5-FU in rat was mainly in the colon content,and the purpose of colon-specific drug delivery was completed.These provide experimental and theoretical bases for further study.