Towards Printed Pediatric Medicines in Hospital Pharmacies: Comparison of 2D and 3D-Printed Orodispersible Warfarin Films with Conventional Oral Powders in Unit Dose Sachets

Abstract

To date, the lack of age-appropriate medicines for many indications results in dose manipulation of commercially available dosage forms, commonly resulting in inaccurate doses. Various printing technologies have recently been explored in the pharmaceutical field due to the flexible and precise nature of the techniques. The aim of this study was, therefore, to compare the currently used method to produce patient-tailored warfarin doses at HUS Pharmacy in Finland with two innovative printing techniques. Dosage forms of various strengths (0.1, 0.5, 1, and 2 mg) were prepared utilizing semisolid extrusion 3D printing, inkjet printing and the established compounding procedure for oral powders in unit dose sachets (OPSs). Orodispersible films (ODFs) drug-loaded with warfarin were prepared by means of printing using hydroxypropylcellulose as a film-forming agent. The OPSs consisted of commercially available warfarin tablets and lactose monohydrate as a filler. The ODFs resulted in thin and flexible films showing acceptable ODF properties. Moreover, the printed ODFs displayed improved drug content compared to the established OPSs. All dosage forms were found to be stable over the one-month stability study and suitable for administration through a naso-gastric tube, thus, enabling administration to all possible patient groups in a hospital ward. This work demonstrates the potential of utilizing printing technologies for the production of on-demand patient-specific doses and further discusses the advantages and limitations of each method.

Keywords: 3D printing; hospital pharmacy; inkjet printing; on-demand manufacturing; oral powder; orodispersible film; pediatric; personalized medicine; semisolid extrusion 3D printing; warfarin.

Figure 1

(A) EXT drug-loaded ODF imprinted with a QR code containing information about the dosage form and (B) the same EXT ODF rolled up to visualize the flexibility of the film. (C) IJP drug-loaded ODF with a printed QR code and (D) the flexible ODF is subsequently coiled up for illustrative purposes.

Figure 2

Example of the information that could be included in the QR code.

Figure 3

Pictures of the prepared dosage forms: (A) EXT ODFs; (B) IJP ODFs; (C) oral powder; and (D) OPS.

Figure 4

(A) Burst strength representing the maximum force (N) and (B) burst distance representing the elongation (mm) of the ODF before rupturing. Drug-loaded ODFs are shown as colored columns and placebo ODFs are presented as colored columns with a pattern. Data is shown as average ± SD, n = 5 for each time point.

Figure 5

The moisture content reported as mass % weight loss of the sample, for the prepared dosage forms. Results presented as average ± SD, n = 3. Drug-loaded ODFs are shown as colored columns and placebo ODFs are presented as colored columns with a pattern.

Figure 6

Drug content of the aimed doses of 0.1, 0.5, 1, and 2 mg for the prepared batches and various manufacturing techniques. Gray columns represent the target dose and the following columns represents batch 1, 2, and 3, respectively, for each manufacturing method. Data are presented as the average ± SD, n = 10.

Figure 7

Stability of the manufactured dosage forms with a target dose of 2 mg at time points 1, 7, 14, 21, and 28 days. The gray columns represent the target dose of 2 mg. Data shown as average ± SD, n = 10.

Figure 8

In vitro drug release of the prepared dosage forms in 100 mL of purified water, average ± SD (n = 3); (A) EXT ODFs, (B) IJP ODFs, (C) OPSs, and (D) an overview of all manufacturing methods and pure drug for the 2 mg dose.

Figure 9

On-line in vitro drug release (%) of the different dosage forms conducted in 500 mL of purified water at 50 rpm, average ± SD, n = 3.

Figure 10

FT-IR spectra for (A) raw materials and/or starting materials; (B) OPS; (C) drug-loaded EXT; (D) placebo EXT ODF; (E) drug-loaded IJP ODF; and (F) placebo IJP ODF. The graphs present the spectra for the prepared drug-loaded and placebo dosage forms for day 1, 7, 14, 21, and 28.

Figure 11

Thermograms (exo up) for (A) raw materials and the physical mixture of HPC and warfarin sodium; (B) OPS; (C) drug-loaded EXT ODF; (D) placebo EXT ODF; (E) drug-loaded IJP ODF; and (F) placebo IJP ODF over a one-month period.