Development of a New Dosage Form of Pentoxifylline Using 3D Printing

Background
Pentoxifylline is used in the treatment of mandibular osteoradionecrosis, a serious complication of head and neck radiation therapy. Since the drug was withdrawn from the market in August 2022, continued treatment with the 400 mg extended-release (ER) tablet formulation has relied on hospital-prepared 250 mg capsules, administered at a dose of 3 capsules per dose, due to the inability to replicate the extended-release profile. Conventional hospital compounding techniques do not allow for the production of precise modified-release formulations; therefore, 3D printing was investigated as a solution to this challenge. The hot extrusion technique has enabled the production of extended-release formulations, but it is difficult to implement in a hospital setting due to the time required and the need to formulate a filament containing the active ingredient. The objective is to develop a pentoxifylline-based “pharmaceutical ink” that meets the requirements for sustained release using semi-solid extrusion technology for the automatic filling of capsules.

Materials and Methods
Ten formulations were developed by varying the type and proportions of excipients, combining modified-release agents, plasticizers, and enteric-coated polymers. A dissolution test was performed on each formulation after filling the capsules to determine which ones met the USP (United States Pharmacopeia) monograph for the pentoxifylline finished product, which was used as a reference. The dissolution test was performed in accordance with monograph 2.9.3 of the European Pharmacopoeia. Once the dissolution criteria were met, dose accuracy testing and a stability study were conducted.

Results
The formulation selected was one combining pentoxifylline (30%), propylene glycol (47%), high-viscosity hydroxypropyl methylcellulose (15%), and Eudragit L100 (8%). Dissolution tests conducted at 75 revolutions per minute in 900 mL of water showed a sustained-release profile, with 12% of the active ingredient released at 1 hour, 25% at 2 hours, 43% at 4 hours, 54% at 6 hours, 73% at 10 hours, 77% at 12 hours, 86% at 16 hours, and 97% at 24 hours, with results reproducible across the tested capsules. The resulting profile is consistent with the specifications of the reference USP monograph. Accelerated degradation tests show stability starting at 3 months, and dose accuracy is within ±7%, which is better than that of capsules filled manually.

Conclusion
The selected formulation exhibits a sustained-release profile that complies with the specifications of the reference USP monograph, thereby validating the feasibility of a pentoxifylline-based semi-solid ink for capsule filling that is compatible with the treatment volume. Future work will focus on the rheological characterization of the ink to evaluate its printability over time.