Date Published: January 7, 2019
Publisher: Springer International Publishing
Author(s): Heidi Öblom, Jiaxiang Zhang, Manjeet Pimparade, Isabell Speer, Maren Preis, Michael Repka, Niklas Sandler.
The aim of the present work was to produce 3D-printed oral dosage forms with a sufficient drug dose displaying various release profiles. Hot-melt extrusion was utilized to produce drug-loaded feedstock material that was subsequently 3D-printed into 6, 8, and 10 × 2.5 mm tablets with 15% and 90% infill levels. The prepared formulations contained 30% (w/w) isoniazid in combination with one or multiple pharmaceutical polymers possessing suitable properties for oral drug delivery. Thirteen formulations were successfully hot-melt extruded of which eight had properties suitable for fused deposition modeling 3D printing. Formulations containing HPC were found to be superior regarding printability in this study. Filaments with a breaking distance below 1.5 mm were observed to be too brittle to be fed into the printer. In addition, filaments with high moisture uptake at high relative humidity generally failed to be printable. Different release profiles for the 3D-printed tablets were obtained as a result of using different polymers in the printed formulations. For 8 mm tablets printed with 90% infill, 80% isoniazid release was observed between 40 and 852 min. Drug release characteristics could further be altered by changing the infill or the size of the printed tablets allowing personalization of the tablets. This study presents novel formulations containing isoniazid for prevention of latent tuberculosis and investigates 3D printing technology for personalized production of oral solid dosage forms enabling adjustable dose and drug release properties.
Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis typically affecting the lungs, is the ninth most common cause of death worldwide (1). According to estimations by the World Health Organization (WHO), 10.4 million people fell ill with tuberculosis in 2016 and almost two million deaths were estimated among the people infected with the disease. Most deaths caused by tuberculosis could successfully be prevented with early diagnosis, suitable treatment, and prevention of latent tuberculosis in identified risk groups. Therefore, preventive treatment for tuberculosis and latent tuberculosis is needed (1). Treatment of latent tuberculosis with isoniazid monotherapy daily for 6 months is recommended for both adults and children in countries with both high and low disease prevalence. Currently, the recommended isoniazid dose for latent tuberculosis is 5 mg/kg for adults and 7–15 mg/kg for children with a maximum dose of 300 mg/day (2).
Isoniazid > 98% was purchased from TCI America (Portland, OR, USA). Hydroxypropylmethylcellulose (HPMC, Benecel™ grade E5 Pharm and K100M Pharm) and hydroxypropylcellulose (HPC, Klucel™ grade EF Pharm, MW 80,000 and HF Pharm, MW 1,150,000) were donated by Ashland (Covington, KY, USA). Polyethylene oxide (PEO, Sentry™ Polyox™ WSR N-80 NF, MW approx. 200,000, and Sentry™ Polyox™ WSR N-750 NF, MW approx. 300,000) was supplied by Dow Chemical Company (Midland, MI, USA). Eudragit® RS PO, RL PO and L 100 were kindly provided by Evonik Industries AG (Essen, Germany). Triethyl citrate ≥ 99% (TEC) was purchased from Sigma-Aldrich (Darmstadt, Germany), and Kolliphor® TPGS (vitamin E polyethylene glycol succinate, d-alpha tocopherol content min 250 mg/g) was acquired from BASF (Ludwigshafen, Germany). Buffering agents, potassium dihydrogen phosphate and sodium hydroxide pellets were of analytical grade and purchased from Merck (Darmstadt, Germany) and Sigma-Aldrich (Darmstadt Germany), respectively. Polylactic acid (PLA) 3D printable filament (PLA natural) with a diameter of 1.75 mm obtained from MakerBot (MakerBot Industries, NY, USA) was used as received.
In this study, drug-loaded feedstock material for FDM 3D printing was prepared utilizing hot-melt extrusion. Studying the prepared filaments revealed that breaking distance was a good initial predictor regarding printability and that the moisture uptake of the filaments revealed a trend, where unprintable filaments typically showed a greater total moisture uptake as compared to the printable formulations. Thirteen different formulations with suitable properties for oral drug delivery were produced and eight out of these were subsequently successfully processed into tablets of different sizes and infill levels using a Makerbot 3D printer. All printable formulations showed good correlation between the printed tablet size and mass of the tablet, highlighting the potential to utilize 3D printing for production of personalized doses for prevention of latent tuberculosis. The possibility to easily adjust the dose according to the weight and metabolic rate of the patient is expected to improve the efficacy and adherence to the therapy. In addition, in vitro drug release of the printed dosage forms revealed versatile properties, making it possible to administer the dosage form once or multiple times a day depending on the need and requirements of the patient. Due to the sustained isoniazid release, formulations 12 and 13 could be taken once daily, where formulations 1, 2, 3, 5, 10, and 11, that released the drug faster, would be suitable for a multiple times a day administering approach. This study further highlights that by combining formulation development of the feedstock material with the endless geometrical potentials associated with 3D printing, personalized oral dosage forms with nearly limitless properties can be produced.