Biopharmaceutical evaluation of oral controlled indomethacin delivery systems based on drug-polymer and drug-interpolyelectrolyte complexes

Introduction. Interpolyelectrolyte complexes (IPEC) are promising carriers for controlled drug delivery systems. The introduction of ionic API into delivery systems can lead to the formation of bonds with polyelectrolytes, which affects the release of the drug from the dosage form. Previously, a drug-polymer complex (DPC) based on Eudragit® EPO with indomethacin, as well as an drug-interpolyelectrolyte complex (DIPEC) with the participation of copolymers of Eudragit® EPO, Eudragit® S100 and indomethacin were obtained. The physicochemical properties of the optimal samples were assessed and the prospects for their use in controlled delivery systems of indomethacin were shown.

Aim. Comparative biopharmaceutical evaluation of drug-polymer and drug-interpolyelectrolyte complexes as oral controlled delivery systems for indomethacin.

Materials and methods. Drug-polymer complex based on Eudragit® EPO and indomethacin (DPC EPO/IND) and druginterpolyelectrolyte complex based on Eudragit® EPO, Eudragit® S100 and indomethacin (DIPEC EPO/S100/IND) were obtained at the molar ratio of components of 3 : 1 and 4.5 : 1 : 1, respectively. The release of indomethacin from DPC and DIPEC powders and tablets was assessed by apparatus II "Rotating Paddle" using a DT 828 dissolution tester (ERWEKA GmbH, Germany). The concentration of indomethacin was determined by UV spectrophotometry on a Lambda 25 spectrophotometer (PerkinElmer, USA) at a wavelength of 270 nm. Mathematical modeling of indomethacin release was performed using Microsoft Excel Office. Pharmacokinetic studies were performed on Soviet Chinchilla rabbits. The studied samples were administered orally, blood samples were taken from the ear at certain intervals of time after administration. The concentration of indomethacin in blood plasma was determined by HPLC on an LC-20 Prominence chromatograph (Shimadzu, Japan) with UV-detection. The main pharmacokinetic parameters were calculated using the Thermo Kinetica® program (Version 5.0, Build 5.00.11; Thermo Fisher Scientific, USA).

Results and discussion. The release profiles of indomethacin from DPC and DIPEC powders are characterized as "intestinal type", where the predominant mechanism is the process of relaxation of polymer chains during the release of the substance. The release of indomethacin from the tablet matrix based on DIPEC differs from the release profile from DIPEC powder and reaches 19 %. The release profile of indomethacin from DPC EPO/IND tablets is similar to the release profile from the powder and reaches 58 %. A hydrogel layer is formed on the surface of DIPEC tablets, which prevents the penetration of the dissolution medium into the matrix. The release of indomethacin from DIPEC EPO/S100/IND samples occurs due to the diffusion of the drug from the matrix. DPC and DIPEC in powder form have a longer mean retention time (MRT) compared to DPC and DIPEC tablets. MRT of DIPEC and DPC in powder form exceeds MRT of indomethacin substance by three and four times, respectively. Maximum concentration of indomethacin in blood plasma of rabbits after oral administration of DIPEC tablets is observed after 8 hours of the experiment.

Conclusion. Indomethacin release from DPC EPO/IND occurs due to the presence of "defective" regions and relaxation of polymer chains, this ensures a slow release of the API and low relative bioavailability, which allows using DPC in indomethacin delivery systems for the treatment of inflammatory diseases of the colon. Tablet systems DIPEC EPO/S100/IND allow changing the release profile of indomethacin due to the diffusion processes of the substance through the formed hydrogel layer on the surface of the matrix, ensuring high bioavailability, can be used as matrix systems for delivering the API to the optimal absorption zone.

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