Development of Composite, Reinforced, Highly Drug-Loaded Pharmaceutical Printlets Manufactured by Selective Laser Sintering—In Search of Relevant Excipients for Pharmaceutical 3D Printing

Abstract

3D printing by selective laser sintering (SLS) of high-dose drug delivery systems using pure brittle crystalline active pharmaceutical ingredients (API) is possible but impractical. Currently used pharmaceutical grade excipients, including polymers, are primarily designed for powder compression, ensuring good mechanical properties. Using these excipients for SLS usually leads to poor mechanical properties of printed tablets (printlets). Composite printlets consisting of sintered carbon-stained polyamide (PA12) and metronidazole (Met) were manufactured by SLS to overcome the issue. The printlets were characterized using DSC and IR spectroscopy together with an assessment of mechanical properties. Functional properties of the printlets, i.e., drug release in USP3 and USP4 apparatus together with flotation assessment, were evaluated. The printlets contained 80 to 90% of Met (therapeutic dose ca. 600 mg), had hardness above 40 N (comparable with compressed tablets) and were of good quality with internal porous structure, which assured flotation. The thermal stability of the composite material and the identity of its constituents were confirmed. Elastic PA12 mesh maintained the shape and structure of the printlets during drug dissolution and flotation. Laser speed and the addition of an osmotic agent in low content influenced drug release virtually not changing composition of the printlet; time to release 80% of Met varied from 0.5 to 5 h. Composite printlets consisting of elastic insoluble PA12 mesh filled with high content of crystalline Met were manufactured by 3D SLS printing. Dissolution modification by the addition of an osmotic agent was demonstrated. The study shows the need to define the requirements for excipients dedicated to 3D printing and to search for appropriate materials for this purpose.

3D Printing Technology as a Promising Tool to Design Nanomedicine-Based Solid Dosage Forms: Contemporary Research and Future Scope

“…The concept of building up an object from digital blueprints layer-by-layer is the basic concept of the 3D printing process. A diverse array of pharmaceutical excipients was successfully processed by the technique [ 59 , 60 , 61 ]. Smart materials utilized in the 4D printing technique for pharmaceutical product development can undergo programmable transformations within the formulated 3D objects [ 62 , 63 , 64 ].…”

Polymeric Excipients in the Technology of Floating Drug Delivery Systems

“…The porous insoluble matrix formed by nylon was a network structure with incorporated API. The resulting DF had a zero rise time delay, a flotation time of 30 to 600 min, and released metronidazole in a delayed manner over 0.5 to 5 h [82]. The removal method of Kumaraswamy et al, obtained porous floating microspheres, the matrix of which consisted of water-insoluble polycarbonates and polypropylene glycol, which provided an increase in the release of repaglinide into the aquatic environment.…”

“…Hollow granules (ionotropic gelation) Chitosan [25] Granules (ionotropic gelation) NA, Carrageenan [28] NA, Eudragit RL100 [85] Chitosan [26] Pectin [30] NA conjugate with bovine serum albumin [37] Hollow microspheres (solvent removal) EC [47] EC, HPMC E5 [50] EC, HPMC E50 [86] Eudragit S-100 [71] Eudragit S-100 [72] Acrycoat S 100 [74] Combination of Eudragit L100 and Eudragit RS100 [73] Polycarbonate, Polypropylene Glycol PFA [83] HPMC 3K, Eudragit RS PO [87] EC (10 cP), PVP [88] Microspheres (solvent removal) EC [89] EC, HPMC K4M [90] CA [62] Microspheres ("multiple emulsion method", solvent removal) EC, PVP [91] Tablets (direct compression) HPMC K4M, Camphor SA [55] Tablets (wet granulation) Locust bean gum, Camphor SA [41] HPC (Klucel LF), PEO (Polyox WSR N 60 K), Menthol SA [92] Tablets (shaping and freeze drying) EC, HPMC (100 cP) [49] Tablets (FDM 3D printing) HPC [60] HPMC acetate succinate, PEG 400 [93] HPC, PVP [94] Tablets (Tablet-core-direct compression; body-FDM 3D printing) HPC, EC [59] PLA [81] EVOH, HPMC K15M [65] Tablets (SLS 3D printing) Nylon [82] Cylindrical extrudate (3D printing with simultaneous ionotropic gelation) NA [23] Hydrogel (ionotropic gelation) Graft copolymer of chitosan and PVP [27] Nanofiber (electrospinning) PLA [64] Pellets or cylindrical extrudates (extrusion) Eudragit RSPO, HPMC K15 M, Ethanol PFA [95] Modular gastro-renal delivery system (wet granulation and compression) HPMC K15 M, PEG 6000, PVP K30…”

Releasing fast and slow: Non-destructive prediction of density and drug release from SLS 3D printed tablets using NIR spectroscopy

“…Following each layer sintering, a roller distributes a fresh layer of powder on top of the sintered object, which is repeated to produce 3D-printed tablets (Printlets™). This 3D printing process has been widely researched to have numerous benefits within pharmaceuticals, enabling the production of drug products with personalised dosages ( Gueche et al, 2021c ; Kulinowski et al, 2022 ; Trenfield et al, 2018 ), shapes ( Awad et al, 2020 ), sizes ( Awad et al, 2019 ), solid state properties ( Davis Jr. et al, 2021 ; Madžarević et al, 2021 ; Santitewagun et al, 2022 ; Thakkar et al, 2021 ; Trenfield et al, 2022 ), and multi-drug combinations ( Trenfield et al, 2020 ).…”