Development of a 3D-Printed Dosing Platform to Aid in Zolpidem Withdrawal Therapy

Abstract

The long-term use of benzodiazepine receptor agonists (BZRAs) is associated with multiple side effects, such as increased sedation, hangover or an elevated risk of dependency and abuse. Unfortunately, the long-term use of BZRAs is reaching worrying intake rates, and therefore, the need for action is high. It was demonstrated already that the overall willingness of patients for deprescription increased when a slow dose reduction scheme with the possibility for dose increase, if needed, is employed. The current study aims to develop a flexible dosing platform of zolpidem hemitartrate (ZHT) to facilitate such withdrawal therapy. As this is the first report on the extrusion and 3D printing of ZHT, its thermal behaviour and sensitivity towards photolytic degradation was characterised. It was shown that ZHT possesses multiple polymorphs and was especially prone to oxidative photolysis. Next, a variety of immediate release polymers (Eudragit EPO, Kollidon VA64, Kollidon 12PF and Soluplus) were blended and extruded with Polyox WSR N10 to investigate their feedability and printability by mechanical and rheological analysis. The addition of PEO was shown to enable printing of these brittle pharmaceutical polymers, although the processing temperature was deemed critical to avoid surface defects on the resulting filaments. An EPO(70)PEO(30) system was selected based on its suitable mechanical properties and low hygroscopicity favoring ZHT stability. The matrix was blended with 1% or 10% API. The effect of certain printing parameters (caplet size, nozzle diameter, % overlap) on dissolution behaviour and caplet weight/dimensions/quality was assessed. A flexible dosing platform capable of delivering <1 mg and up to 10 mg of ZHT was created. Either caplet modification (incorporation of channels) or disintegrant addition (Primojel, Explotab, Ac-Di-Sol, Primellose and Polyplasdone-XL) failed to achieve an immediate release profile. This study provides the first report of a 3D-printed flexible dosing platform containing ZHT to aid in withdrawal therapy.

Influence of Print Settings on the Critical Quality Attributes of Extrusion-Based 3D-Printed Caplets: A Quality-by-Design Approach

“…Certain factors influence the visual quality of the resulting dosage form as discussed previously [18,24]. A smaller layer height results in a finer resolution as can be seen in Figure 11, and it is anticipated that a patient would prefer such detail.…”

“…Polymer systems consisting of Eudragit EPO (EPO) and Polyox WSR N10 (PEO) were blended with ZHT and extruded to generate feedstock filament for FDM 3D-printing. EPO was chosen as main polymer component as it displayed favourable thermal and rheological properties for 3D printing in combination with excellent stability due to its low hygroscopicity as discussed in a previous paper [24]. PEO was added to the formulation to enhance the mechanical properties of the filament and to enable feeding [24].…”

“…These settings were previously optimized and generated a stable extrusion process with a torque of approximately 35% of the maximal achievable torque [24]. A screw configuration consisting of transporting elements, two kneading blocks and a discharge element were used [39].…”

“…Resulting filaments were collected on a self-winding roller with adapted speed to obtain filaments with a diameter of 1.75 ± 0.05 mm as measured with a digital caliper. Filaments with a diameter out of this range were discarded [24].…”

“…A tablet with 100% infill is completely filled and possesses a theoretical porosity of 0%. Such a high infill was found to be detrimental for the quality of the resulting caplet, especially on the rounded edges [24]. Infill was previously varied to create dosage forms with a range of drug release profiles [25,26].…”