Controlled drug release systems have been a focus on providing predictable drug delivery. The systems involve various mechanisms including diffusion of water and drugs, matrix erosion, polymer swelling, osmotic effects, and ion exchange. Among these mechanisms, diffusion is the fundamental mechanism for most dosage forms. 

Multi-unit pellet systems represent a novel type of controlled release system, offering advantages like avoiding excessive local drug concentrations, improving high patient compliance, and reducing side effects. Exploring drug release process and mechanism from the perspective of three-dimensional (3D) formulation structures is essential for understanding dosage forms, particularly the in vitro and in vivo behavior of advanced formulations like multiple unit tablets made of pellets.

In a study published in Journal of Controlled Release, a research team led by ZHANG Jiwen and WU Li from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, along with collaborators, using synchrotron radiation X-ray micro-computed tomography (SR-μCT), revealed “3D channel maze” mechanism to control drug release from multiple unit tablets.

Researchers applied SR-μCT to obtain 3D images of theophylline multiple unit tablets made of pellets. They investigated the overall structure of tablets and internal structural changes of individual pellets during the drug release process. By combining release kinetics of the entire tablet and individual pellets, they proposed a “3D channel maze” mechanism for controlled release.

Analysis of the internal structure of theophylline multiple unit tablets revealed that the pellets were randomly distributed radially with a higher number of pellets located on the back side of the tablet compared to the front. Both radial and axial slices indicated that the tablets were primarily composed of three regions: the theophylline pellets, the protective cushion layer, and the matrix layer. 

Using reconstructed 3D images, the structure of individual pellets within the tablet were extracted. Each pellet consisted of a core and a coating layer with diameters ranging from 0.5 to 1.2 mm. The coating layer was relatively uniform and compact, with an average thickness of approximately 100 μm.

Besides, researchers found that the matrix layer and dominant region including the protective cushion layer and theophylline pellets played key roles in the release profiles. 

During the rapid release stage, the outer matrix layer of the tablet, comprised of drugs and soluble excipients, dissolved rapidly, while the dominant region remained largely intact. Pellets located at the tablet edges, unprotected by the buffer layer, began to dissolve. During the controlled release stage, as pellets dissolved, small outlets and channels emerged to release dissolved drug molecules. The partially soluble protective cushion layer acted as a barrier, slowing drug release through tortuous pore channels. 

Over time, these pores and channels between the pellets became interconnected, forming a complex and labyrinthine “3D channel maze” structure. Drug molecules dissolved in the liquid medium had to navigate their way out of this maze. While some molecules exited quickly, others required more time to traverse the maze. 

The release of drug within the “3D channel maze” was governed by multiple processes, including diffusion of water, dissolution of drug, diffusion within the 3D channel network, and the eventual escape from the maze. The gating effect of the maze played a critical role in achieving controlled release.

The “3D channel maze” mechanism offers a new perspective on controlled release process of theophylline multiple unit tablets. Unlike diffusion-based mechanisms of conventional theories, it emphasizes the gating effect of the internal pore network within the tablet. While the drug dissolves and diffuses freely within the pore network, its movement is restricted by intricate and tortuous channel structure to elongate the drug release profiles.