3D-printed solid oral dosage forms for mental and neurological disorders: recent advances and future perspectives

Figures & data

Figure 1. Main limitations of conventional solid oral dosage forms. Created with BioRender.com.

Figure 2. 3D printing methods, divided by inkjet, extrusion, and laser based: drop on demand (DoD); semi-solid extrusion (SSE); fused deposition modelling (FDM); stereolithography (SLA); digital light processing (DLP); liquid-crystal display (LCD); selective laser sintering (SLS). Created with BioRender.com.

Figure 3. Step by step assembly process of the LEGO® like solid dosage forms in (a) CAD and (b) 3D printed format, (c) in silico assembly of the individual compartment in the X-ray CT space-ray CT space; reprinted from Tabriz et al. [70].

Figure 4. Model image of an intragastric floating and sustained-release tablet with an air chamber; reprinted with permission from Zhao et al. [71].

Figure 5. Printed polypills in various designs; reprinted from Windolf et al. [70].

Table 1. Summary of the attempts to obtain 3DP solid oral dosage forms in the field of mental and neurological diseases.

Disorder	3DP method	Matrix base (Polymer/photopolymerizable monomer)	API	Dosage form	Aim of the study	Reference
Epilepsy	SSE	Croscarmellose sodium, hydroxypropyl cellulose	Levetiracetam	Tablet	Using SSE method for fabrication of high drug loading (96%) levetiracetam tablets.	[41]
	SSE	Croscarmellose Sodium, carboxymethylcellulose sodium, polyvinylpyrrolidone (PVP K30)	Levetiracetam	Rapid-release tablet	Obtaining a dose-flexible control system for rapid release tablets equipped with high drug loading and a cylindrical model design.	[42]
	PAM	Polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG, Kollicoat® IR)	Levetiracetam	Tablet	Developing a novel drug-printing model using PAM technology, for precise dispensing of drug substances.	[43]
	PAM	Polyvinyl alcoholpolyethylene glycol graft copolymer (PVA-PEG, Kollicoat® IR), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-PVAc, Kollidon VA 64)	Levetiracetam	Immediate-release tablet	Investigate producing immediate release levetiracetam tablets using PAM method and only water as solvent, examining the drying process.	[44]
	SSE	Hydroxypropyl methylcellulose (HPMC), Methocel K3 Premium, Kollidon CL	Gabapentin	Printlets	Obtaining and assessing pet-friendly tailored gabapentin dosage forms.	[45]
	Binder jetting	Polyvinylpyrrolidone, microcrystalline cellulose	Levetiracetam, pyridoxine	Dispersible tablets	Obtaining dispersible tablets using a self-developed binder jet 3D printer, manufacturing of the dosage form with one drug in the powder and another in the ink.	[46]
	Binder jetting	No specific information	Levetiracetam	Instant-dissolving tablets	Using physiological pharmacokinetic modeling to estimate the dose of levetiracetam in children, bioequivalence study with comparison to Spritam®.	[47]
	SSE	Hydroxypropyl methylcellulose E15	Phenytoin	‘Tablet-in-Syringe’ system containing Fast-Disintegrating Tablet	Evaluating the feasibility of SSE to produce fast-disintegrating tablets with high drug loading of water-soluble drugs. Producing the system suitable for patients with dysphagia.	[48]
	SSE	Hydroxypropyl methylcellulose (HPMC) as Methocel™ E4M Premium, Methocel™ F4M Premium, Polyvinylpyrrolidone (PVP) Plasdone® K-25, Sodium carboxymethylcellulose Blanose™ CMC 9M31 F PH, Croscarmellose sodium (Ac-Di-Sol®)	Carbamazepine	Fast-dissolving printlets	Investigating the use of cyclodextrins to prepare printlets of poorly soluble drugs.	[49]
	SSE	Ac-Di-Sol®^, Kollidon 30	Carbamazepine	Orodispersible Mini-Tablets	Developing a child-appropriate dosage form, to address swallowing problems, and facilitate therapy in pediatric patients.	[50]
	FDM	Hypromellose (HPMC E4), (HPMC HME 15LV), hypromellose acetate succinate (HPMCAS, AQUOT AS-HG)	Pregabalin	Floating tablet	Manufacturing a floating tablet with a controlled drug delivery profile.	[51]
	FDM	Ethylcellulose (ETHOCEL^TM Standard 10 Premium), Medium viscosity hydroxypropyl cellulose	Carbamazepine	Tablet	Using hot-melt extrusion (HME) and FDM in order to produce tablets with zero order release profile.	[54]
	DLP	Poly(ethylene glycol) diacrylate	Acetaminophen, theophylline, carbamazepine	Tablet	Preparing tablets based on poly(ethylene glycol) diacrylate using DLP method, and investigating how the composition of the printer ink affects the drug release.	[55]
	FDM	Vinylpyrrolidone-vinyl acetate copolymer (Kollidon® VA 64), PEG 6000/vinylcaprolactam/vinyl acetate copolymer (Soluplus®), Hydroxypropyl methylcellulose (Affinisol® HME 15 cP)	Rufinamide	Tablet	Improving the dissolution of an orphan antiepileptic drug – rufinamide, through the use of 3DP technology.	[56]
Schizophrenia	FDM	Hydroxypropyl cellulose, polyvinyl alcohol,	Aripiprazole	Orodispersible Films	Designing and evaluating an orodispersible film with aripiprazole in comparison with ODF made by solvent- casting method.	[59]
	Hot Melt Pneumatic 3DP	Poly (ethylene oxide), Poloxamer 188	Aripiprazole	QR (Quick Response)-coded orodispersible film	Preparing and evaluating QR-orodispersible films using 3D printer directly feeding nozzle under the hot melt pneumatic (HMP) conditions.	[60]
	FDM	Polyvinyl alcohol	Aripiprazole	Orodispersible Films	Comparing the FDM method of orodispersible films manufacturing with electrospun and casting methods.	[61]
	FDM	polyvinyl alcohol-polyethylene glycol graft-copolymer	Olanzapine	Immediate-release tablets	Preparing immediate-release tablets with olanzapine using FDM method, and enhancing the solubility using a fast disintegrating polymer.	[62]
	Hot Melt Pneumatic Extrusion	Polyethylene oxide (POLYOX WSR N10 LEO), Kollidon® VA 64, poloxamer 407, poloxamer 188	Olanzapine	Orodispersible films	Developing orodispersible films with amorphous solid dispersions of a poorly water-soluble drug in hydrophilic polymeric carriers.	[63]
	FDM	Polyvinylpyrrolidone-vinyl acetate copolymer (Kollidon® VA64), polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat® IR), Hydroxypropyl methylcellulose HME 15 cP, hydroxypropyl methylcellulose acetate succinate (HPMCAS MG; Aqoat® AS-MG)	Haloperidol	Immediate-release tablet	Identifying amorphous polymers suitable for manufacturing tablets with haloperidol for rapid release.	[65]
	FDM	Polyvinyl alcohol	Haloperidol	Tablet	Investigating of processability of polyvinyl alcohol as a water-soluble polymer for manufacturing filaments and 3DP tablets by FDM method.	[66]
Insomnia	FDM	Eudragit EPO, Kollidon VA64, Kollidon 12PF, Soluplus®, Polyox WSR N10	Zolpidem	Immediate-release caplets	Developing a flexible dosing platform of zolpidem to facilitate zolpidem withdrawal therapy.	[67]
	DLP	Poly(ethylene glycol) diacrylate, BenecelTM K35M Hypromellose	Zolpidem	Immediate-release cuboid tablets and mini-tablets	Investigating the influence of geometry on the drug dissolution rate, examining the feasibility of obtaining drug dosage form by DLP 3D printing technique with a viscosity-increasing agent.	[68]
	PAM	Microcrystalline cellulose, croscarmellose sodium, hypromellose	Zolpidem	Printlets	Providing a standardized protocol to the manufacturing of the dosage form from the mixture, and developing a decisional tree to perform a quality-control.	[69]
	FDM	Hydroxypropyl Cellulose, hypromellose acetate succinate	Caffeine, melatonin	LEGO® -like tablets	Co-administration of caffeine and melatonin for sleep regulation.	[70]
Depression	FDM	Affinisol^TM HPMC HME 15LV, polylactic acid	Venlafaxine	Intragastric floating and sustained-release tablet	Developing a novel intragastric floating and sustained-release drug delivery system.	[71]
	FDM	Hydroxypropyl cellulose	Paroxetine	Tablet	Developing a method for the preparation and characterization of paroxetine tablets, obtained by FDM 3DP technology.	[72]
	Syringe extrusion 3DP	Hydroxypropyl methylcellulose E15	Mirtazapine	Orodispersible Film	Manufacturing the orodispersible film with mirtazapine, comparing its properties with films obtained by solvent-casting method.	[73]
Parkinson’s disease	FDM	Polyvinyl alcohol, ethylene-vinyl acetate copolymer, vinylpyrrolidone-vinyl acetate copolymer	Levodopa, benserazide, pramipexole	Mini-Floating-Polypill	Creating polypill-dosage form containing three APIs with different release kinetics for the therapy of Parkinson’s disease.	[75]
	FDM	Polyvinyl alcohol, vinylpyrrolidone-vinyl acetate copolymer, ethylene-vinyl acetate	Pramipexole, levodopa, praziquantel	Hollow cylinder-based (HCb) geometry model	Developing the model where variable dosages can be used, but drug release profiles remain similar.	[76]
	FDM	POLYOX N80, Eudragit RLPO, Eudragit RSPO, Eudragit RL100, Eudragit RS100	Pramipexole	Extended- release tablet	Manufacturing extended release tablets for once daily use in Parkinson’s disease, comparison with marketed tablet.	[77]
	FDM	Eudragit EPO, POLYOX™ WSR N10, POLYOX™ WSR N80	Pramipexole	Immediate-release tablet	Obtaining low-dose immediate-release tablets without the use of disintegrant or filling agents, optimizing release profile by physical structure changes.	[78]
	FDM	POLYOX N10/N80, Soluplus®, Eudragit EPO, AFFINISOL, Plasdone S-630, Kollidon VA64	Pramipexole	Immediate-release tablet	Preparing immediate release 3D-printed tablets, process optimization using a design of experiment (DoE), investigation the suitability of different polymers for filament preparation.	[79]

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