Colon-specific Drug Delivery System Based On In Situ Crosslinking Of Pectin And Calcium

The in-situ crosslinking effect and mechanism between pectin and calcium ions were investigated. The factors that influenced the crosslinking interaction between pectin and calcium, thereby drug release from matrix tablets were also investigated. Enteric-coated pectin/calcium chloride matrix tablets and pectin/calcium chloride compression-coated tablets were studies as potential oral colon-specific drug delivery system incorporating non-steroid anti-inflammatory indomethacin as a model drug. 1 Sigmoidal release of indomethacin from pectin matrix tablets: effect of in situ crosslinking by calcium cationsIn order to elucidate the effect of in situ crosslinking of pectin and calcium ions, indomethacin release and matrix erosion characteristics of pectin/calcium chloride matrix tablet were investigated and compared with those of pectin and pectin/sodium chloride. The results indicated that the large amount of calcium chloride in pectin matrix tablets was able to slow down the initial drug release and retard matrix erosion. Release profiles of indomethacin from pectin/calcium chloride matrix tablets were of typical sigmoidal release pattern. Power law equation was used to estimate the sigmoidal release profiles, and exponent n values, up to 1.20 when calcium chloride content kept increasing, were observed, which was exceptional for matrix systems. Erosion correlated well with drug release indicating erosion-controlled release. A "crosslinking intensity relaxation" was assumed to be the inherent mechanism controlling matrix erosion and drug release simultaneously.Proof-of-concept study was performed to find evidence of "intensity relaxation" of the hydrated pectin/calcium matrix. Calcium release and methylene blue binding measurement estimating the crosslinking density indicated that not only the crosslinking interaction but also the high calcium ions concentration within the matrix affected the drug release. Pectin, under the action of calcium ions, formed open network microstructure in distilled water observed under emission gun environment scanning electron microscopy, and the network microstructure underwent gradual change to less intense texture at various release time point. According to the results of texture analysis, the gel structure of pectin/calcium matrix showed obvious signs of relaxation. Adding calcium ions to the pectin solution produced higher apparent viscosity than that of pure pectin solution, and the apparent viscosity changed little when the calcium chloride contents reached to some extent such as form 4.0g to 8.0g.The crosslinking interaction between pectin and calcium ions was related to the physicochemical properties of calcium salts, thus affected the drug release profiles. For example, when freely water-soluble calcium salts such as calcium chloride or calcium acetate was used, the effect of retarding on drug release was much stronger. The results suggested that freely dissociated calcium ions could interact with pectin easily. The methoxylated degree of pectin also influenced the in-situ crosslinking effect, thus affected the drug release from matrix.2 The studies on enteric-coated pectin/calcium chloride matrix tabletsA new colon-specific drug delivery system which takes advantage of the combined approaches of a specifically colon-biodegradable pectin/calcium matrix with a pH-sensitive Eudragit^? S100 polymeric coating was developed. Tablets with 8% coating weight gain showed good acid resistance and timed-release in dissolution media like 0.1M HC1 and pH 6.8 citrate buffer salts. The performance that polymeric coating dissolved slowly in pH 7.4 citrate buffer salts could reduce the percent drug release in distal small intestine and assure more reliable colon-specificity. Both Pectinex Ultra SP-L, Pectinex XXL and Pectinex Smash XXL could trigger drug release form matrix tablets through enzyme-induced degradation of pectin, and the enzymatic degradation activity of Pectinex Smash XXL was relative powerful.The indomethacin concentration in Beagle dog plasma was analyzed by HPLC. Pharmacokinetic parameters such as AUC, T_1/2, T_lag, and C_max were determined. T_max and T_1/2 of indomethacin power and enteric-coated pectin/calcium chloride matrix tablets were 1.15 h vs. 6.6 h and 3.26 h vs. 6.23 h, respectively. T_lag of enteric-coated pectin/calcium chloride matrix tablets had obvious difference among individual Beagle dogs, and the mean T_lag was 1.9 h. The enteric-coated pectin/calcium chloride matrix tablets showed delayed T_max and decreased C_max compared to indomethacin power. This phenomenon was related to the fact that indomethacin power started to be absorbed form stomach, while enteric-coated pectin/calcium chloride matrix tablets from distal small intestine.3 The studies on compression-coated pectin/calcium chloride tabletsThe rapidly disintegrated core tablets were optimized by a central composite design/response surface methodology, and the compression-coated tablets with pectin/calcium chloride granules were prepared. The results of release studies in vitro showed that the lag time became longer with increasing amount of calcium chloride in compression coat. At pectin/calcium chloride ratio as 1/1, the lag time was 6-7 h at thecoat weight of 400 or 500 mg. Release studies in pH 6.8 citrate buffer salts containing pectinases or rat caecal contents demonstrated that the lag time was becoming shorter with larger amount calcium chloride in compression coat, the possible reason was that many pectinases were supposed to be stimulated by or have an absolute requirement for calcium ions for their activity. The compression coat erosion was accelerated when adding pectinases to medium, as a result, the water uptake was decreased. In vitro drug release studies demonstrated that suitable amount of pectin and calcium chloride, when applied as compression coat, proved capable of protecting core tablet during conditions mimicking mouth to colon transit, and was susceptible to enzymatic attack.Pharmacokinetic parameters of core and compression-coated pectin/calcium chloride tablets such as AUC, T_1/2, T_lag, and C_max were determined. T_max and T_1/2 of core and compression-coated pectin/calcium chloride tablets were 1.4 h vs. 5.4 h and 3.14 h vs. 6.79 h, respectively. T_lag of compression-coated pectin/calcium chloride tablets had obvious difference among individual Beagle dogs, and the mean T_lag was 3.0 h. The compression-coated pectin/calcium chloride tablets showed delayed T_max and decreased C_max compared to core tablets. This phenomenon was relevant with the beginning absorbing site core tablets disintegrated in stomach and started to be absorbed, while compression-coated pectin/calcium chloride tablets from ascending colon.Rapidly disintegrating core tablets containing ^99m-Tc were prepared and compressed coating with 500 mg granules which pectin/calcium chloride ratio was 1/1. Preliminary gamma scintigraphic studies were carried out in two healthy male volunteers to observe the gastrointestinal transit of compression-coated pectin/calcium chloride tablets in vivo. In one volunteer, the compression-coated pectin/calcium chloride tablet remained intact during its transit through the upper gastrointestinal tract, and disintegrated in ascending colon with a further spread into the transverse, descending and sigmoidal colon. The results indicated the site-specificity had been achieved and established that pectin with calcium chloride, in form of compression coat, is a potential carrier for drug targeting to colon.The compression-coated pectin/calcium chloride tablets could protect the drug from being released in the physiological environment of stomach and small intestine through the in-situ crosslinking effect and the relative high calcium ions concentration around the tablets, which could inhibit the pectin swelling and erosion. On enteringthe ascending colon, the pectin coat was broken down by the enzymatic action of colonic bacteria, so the drug released. Besides, the calcium ions in formulation could stimulate or had an absolute requirement for some pectinase activity, thereby, facilitated the drug release further. The characteristic of this formulation was rational for colon-specific drug delivery system.