Colchicine Oral Sustained And Controlled Release Formulations

Colchicine has been used for centuries in acute gout arthritis,its therapeutics index is very narrow(0.5～3ng·ml^-1),but it need frequent administration and usually shows side effects in gastrointestinal tract and poor patient-compliance.Common tablet is the only oral dosage form in market and there is no literature about oral drug delivery systems(DDS) till now.Fewer adverse reactions and better patient-compliance would be expected if we develop colchicine into oral sustained/controlled release system.Aims:Three new oral dosage forms of colchicine will be prepared by modern drug delivery technology,be compared and evaluated by in vitro and in vivo test,and one of them will be choosed to be the most preferred dosage form for colchicine.We hope to build foundation for new oral DDS development of colchicine and to offer reference for similar research.Methods:The drug release profile,pharmacokinetic parameters and bioavailability of three different dosage forms were compared and evaluated by drug release in vitro and pharmacokinetic parameters in vivo.1.Methods for sample assay and drug release test in vitro were established.2.Solubility and absorption properties of colchicine were studied by single-pass intestinal perfusion technique in rats.Viscosity,swelling and erosion properties of hydrophilic polymer commonly used were tested as the basis for formulation and process design.3.The formulations and process of three dosage forms were studied by single-factor test and optimized by orthogonal or uniform design.4.Drug relase profiles in vitro,key influencing factors and release mechanism of three preparations were studied.5.The pharmacokinetic parameters and bioavailability of common tablet and three different preparations in Beagle dogs were studied by LC-MS. Results:1.RP-HPLC methodology for analysis of colchicine samples was established with appropriate convenience and accuracy.The cup method in Chinese Pharmacopoeia(Edition 2005) was adopted for in vitro release test of colchicine preparations.2.Colchicine is sparingly soluble in water and its solubility changed markedly in solvents with different pH and osmotic pressure.Colchicine absorbed in whole rat intestinal and lactose improved its absorption,its absorption rate constant(K_a) were jejunum＞duodenum＞ileum＞colon,and were independent of the concentrations of colchicine in perfusion.Polymers with different units and polymerization degree differed in viscosity,swelling and erosion properties in water.3.Colchicine osmotically controlled release tablets with PEO as main core ingredients showed excellent zero-order release profile in vitro(2～16h,r=0.9942, F₁₆＞90%),and the new formulation with alternative excipients as well(2～16h, r=0.9956,F₁₆＞80%).Its drug release profile can hardly influenced and drug release mechanism based on swelling pressure and osmotic pressure.4.Colchicine hydrogel matrix tablet composed of PEO released drug completely with the rate of 7.27%·h^-1.Its release profile can be influenced and drug release mechanism was the result of matrix erosion and gel diffusion.5.Colchicine gastro retentive tablet showed markedly sustained-release characteristics with the mechanism of diffusion and erosion.Its floating property was based on the effervescent agents and PEO as "hydrodynamically balanced systems", and its gastric retention ability relied on size expanding and system floating properties.6.The drug concentration fluctuation in plasma and relative bioavailability of three dosage forms showed bellowed:osmotic-pump tablet＜matrix tablet＜gastro retentive tablet.The former two showed more steady plasma drug concentration but not bioequivalent with common tablet,and the latter showed prolonged gastric retention time and was more safe and effective. Conclusions:Taken together,the results suggest that gastro retentive sustained-release tablet is more acceptable dosage form for oral sustained/controlled delivery of colchicine than osmotic-pump tablet and hydrogel matrix tablet,in which its formulation and process being more convenient,drug release in vitro being more complete,drug concentration in plasma being more steady and keeping longer period in range of therapeutic index,higher relative bioavailability in vivo.In other words,gastro retentive delivery system of colchicine is expected to improve patient-compliance and to be more safe and effective clinically.Innovations:1.Swelling and erosion properties of common hydrophilic polymers in water were compared initially.2.Osmotically controlled-release tablets,hydrogel matrix tablets and gastro retentive sustained-release tablets of colchicines were prepared,their drug release mechanism in vitro were discussed,their relative bioavailability and pharmacokinetic parameters were studied.3.Gastro retentive drug delivery system was found to be the best dosage form for research and development of oral products for colchicine.