Surface Engineering Methods for Powder Bed Printed Tablets to Optimize External Smoothness and Facilitate the Application of Different Coatings.

In a previous attempt to achieve ileo-colonic targeting of bovine intestinal alkaline phosphatase (BIAP), we applied a pH-dependent coating, the ColoPulse coating, directly on powder bed printed (PBP) tablets. However, the high surface roughness necessitated an additional sub-coating layer [Nguyen, K. T. T., Pharmaceutics 2022]. In this study, we aimed to find a production method for PBP tablets containing BIAP that allows the direct application of coating systems. Alterations of the printing parameters, binder content, and printing layer height, when combined, were demonstrated to create visually less rough PBP tablets. The addition of ethanol vapor treatment further improved the surface's smoothness significantly. These changes enabled the direct application of the ColoPulse, or enteric coating, without a sub-coating. In vitro release testing showed the desired ileo-colonic release or upper-intestinal release for ColoPulse or enteric-coated tablets, respectively. Tablets containing BIAP, encapsulated within an inulin glass, maintained a high enzymatic activity (over 95%) even after 2 months of storage at 2-8 °C. Importantly, the coating process did not affect the activity of BIAP. In this study, we demonstrate, for the first time, the successful production of PBP tablets with surfaces that are directly coatable with the ColoPulse coating while preserving the stability of the encapsulated biopharmaceutical, BIAP.

Formulation of a 3D Printed Biopharmaceutical: The Development of an Alkaline Phosphatase Containing Tablet with Ileo-Colonic Release Profile to Treat Ulcerative Colitis.

Powder bed printing is a 3D-printing process that creates freeform geometries from powders, with increasing traction for personalized medicine potential. Little is known about its applications for biopharmaceuticals. In this study, the production of tablets containing alkaline phosphatase using powder bed printing for the potential treatment of ulcerative colitis (UC) was investigated, as was the coating of these tablets to obtain ileo-colonic targeting. The printing process was studied, revealing line spacing as a critical factor affecting tablet physical properties when using hydroxypropyl cellulose as the binder. Increasing line spacing yielded tablets with higher porosity. The enzymatic activity of alkaline phosphatase (formulated in inulin glass) remained over 95% after 2 weeks of storage at 45 °C. The subsequent application of a colonic targeting coating required a PEG 1500 sub-coating. In vitro release experiments, using a gastrointestinal simulated system, indicated that the desired ileo-colonic release was achieved. Less than 8% of the methylene blue, a release marker, was released in the terminal ileum phase, followed by a fast release in the colon phase. No significant impact from the coating process on the enzymatic activity was found. These tablets are the first to achieve both biopharmaceutical incorporation in powder bed printed tablets and ileo-colonic targeting, thus might be suitable for on-demand patient-centric treatment of UC.

Formulation and In Vitro Evaluation of Pellets Containing Sulfasalazine and Caffeine to Verify Ileo-Colonic Drug Delivery.

The ColoPulse coating is a pH-dependent coating that can be used to target drug release to the ileo-colonic region. ColoPulse coated tablets and capsules have demonstrated their targeting capabilities in vivo in more than 100 volunteers and patients. However, so far the ColoPulse coating has not been used for multi-particulate pellet formulations. The sulfasalazine-caffeine method can be used to confirm ileo-colonic drug delivery in vivo. Caffeine serves as a release marker in this method, while sulfasalazine serves as a marker for colonic arrival. In this study, extrusion-spheronization was used to produce microcrystalline cellulose based pellets containing both caffeine and sulfasalazine. Dissolution tests revealed that a superdisintegrant, i.e., croscarmellose sodium or sodium starch glycolate, should be incorporated in the formulation to achieve acceptable release profiles for both sulfasalazine and caffeine. However, acceptable release profiles were only obtained when the pelletizing liquid consisted of ethanol/water 1/1 (v/v) but not with pure water. This phenomenon was ascribed to the differences in the degree of swelling of the superdisintegrant in the pelletizing liquid during the granulation process. The pellets were coated with the ColoPulse coating and showed the desired pH-dependent pulsatile release profile in vitro. In future clinical studies, ileo-colonic targeting should be verified.