Pharmaceutical excipients: Metamorphosis from conventional formulation to 3D printing

Pharmaceutical excipients such as P-glycoprotein inhibitors can also increase the solubility and affinity of drugs to the intestinal membrane, enhance paracellular pathways and endocyte uptake, and activate lymph transport pathways, thereby increasing the bioavailability of oral drugs. This review aims to review and assess the performance of pharmaceutical excipients as P-glycoprotein permeability inhibitors in improving oral drug bioavailability in drug formulations by evaluating meta data from P-glycoprotein efflux in permeability and pharmacokinetics studies. The review results are pharmaceutical excipients that have proven effective as P-glycoprotein inhibitors from the surfactant and polymer groups, namely TPGS and Poloxamer 188, respectively. All nanosystems incorporating pharmaceutical excipients as P-gp inhibitors show potential in enhancing the permeability and bioavailability of oral drugs when compared to conventional formulations. The effectiveness of these systems has been evaluated through in vitro (Caco-2 cells), ex vivo (everted gut sac), in situ (SPIP), and in vivo (AUC) methods.

Melt extrusion deposition (MED™) 3D printing technology – A paradigm shift in design and development of modified release drug products

Three-dimensional printing, also known as additive manufacturing, is a fabrication process whereby a 3D object is created layer-by-layer by depositing a feedstock material such as thermoplastic polymer. The 3D printing technology has been widely used for rapid prototyping and its interest as a fabrication method has grown significantly across many disciplines. The most common 3D printing technology is called the Fused Deposition Modelling (FDM) which utilises thermoplastic filaments as a starting material, then extrudes the material in sequential layers above its melting temperature to create a 3D object. These filaments can be fabricated using the Hot-Melt Extrusion (HME) technology. The advantage of using HME to manufacture polymer filaments for FDM printing is that a homogenous solid dispersion of two or more pharmaceutical excipients i.e., polymers can be made and a thermostable drug can even be introduced in the filament composition, which is otherwise impractical with any other techniques. By introducing HME techniques for 3D printing filament development can improve the bioavailability and solubility of drugs as well as sustain the drug release for a prolonged period of time. The latter is of particular interest when medical implants are considered via 3D printing. In recent years, there has been increasing interest in implementing a continuous manufacturing method on pharmaceutical products development and manufacture, in order to ensure high quality and efficacy with less batch-to-batch variations of the pharmaceutical products. The HME and FDM technology can be combined into one integrated continuous processing platform. This article reviews the working principle of Hot Melt Extrusion and Fused Deposition Modelling, and how these two technologies can be combined for the use of advanced pharmaceutical applications.

3D Printing is an innovative technology within the pharma and food industries that allows the design and manufacturing of novel delivery systems. Orally safe delivery of probiotics to the gastrointestinal tract faces several challenges regarding bacterial viability, in addition to comply with commercial and regulatory standpoints. Lactobacillus rhamnosus CNCM I-4036 (Lr) was microencapsulated in generally recognised as safe (GRAS) proteins, and then assessed for robocasting 3D printing. Microparticles (MP-Lr) were developed and characterised, prior to being 3D printed with pharmaceutical excipients. MP-Lr showed a size of 12.3 ± 4.1 µm and a non-uniform wrinkled surface determined by Scanning Electron Microscopy (SEM). Bacterial quantification by plate counting accounted for 8.68 ± 0.6 CFU/g of live bacteria encapsulated within. Formulations were able to keep the bacterial dose constant upon contact with gastric and intestinal pH. Printlets consisted in oval-shape formulations (15 mm × 8 mm × 3.2 mm) of ca. 370 mg of total weight, with a uniform surface. After the 3D printing process, bacterial viability remained even as MP-Lr protected bacteria alongside the process (log reduction of 0.52, p > 0.05) in comparison with non-encapsulated probiotic (log reduction of 3.05). Moreover, microparticle size was not altered during the 3D printing process. We confirmed the success of this technology for developing an orally safe formulation, GRAS category, of microencapsulated Lr for gastrointestinal vehiculation.

In the last few years, the employment of 3D printing technologies in the manufacture of drug delivery systems has increased, due to the advantages that they offer for personalized medicine. Thus, the possibility of producing sophisticated and tailor-made structures loaded with drugs intended for tissue engineering and optimizing the drug dose is particularly interesting in the case of pediatric and geriatric population. Natural products provide a wide range of advantages for their application as pharmaceutical excipients, as well as in scaffolds purposed for tissue engineering prepared by 3D printing technologies. The ability of biopolymers to form hydrogels is exploited in pressure assisted microsyringe and inkjet techniques, resulting in suitable porous matrices for the printing of living cells, as well as thermolabile drugs. In this review, we analyze the 3D printing technologies employed for the preparation of drug delivery systems based on natural products. Moreover, the 3D printed drug delivery systems containing natural products are described, highlighting the advantages offered by these types of excipients.

Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing

Pharmaceutical products continue to be developed for improved patient compliance, but the issue of hydrophobicity, low permeability, short half-life, and stability of various drugs always has been a challenging task for formulation development. Conventional formulations lack the features of prolong release of drug over an extended period of time and site-specific action. To resolve these issues, cyclodextrin has emerged as an exceptional pharmaceutical excipient with the features of bioavailability, nontoxicity, inclusion ability, and water solubility. Additionally, nanoparticles overcome the drawbacks associated with conventional formulations such as prolong release and site-specific action of active molecules. Cyclodextrins and chemically altered cyclodextrins in combination with certain polymers have sparked various researchers for exceptional advancements in the field of novel drug delivery. More recently, these substances have been incorporated in polymer systems to develop nanoparticles. Cyclodextrin conjugated nanoparticles offer synergistic advantages such as enhanced drug solubility, served as drug carriers to a specific target site such as cancer cells with minimum toxicity to normal cells, greater surface area over microparticles, and higher stability over liposomes. Accordingly, nanoparticles based on cyclodextrins have gained notable interest, and a variety of nanoparticles have been developed since the last two decades.This chapter review major critical research on cyclodextrin-based nanoparticles to explain their versatility and high potential for advanced drug delivery, protein and peptide drug delivery, and gene delivery. This chapter also highlights the role of cyclodextrins in specific types of nanoparticles such as gold, silver, and magnetic, polymeric, and lipid-based nanoparticles. Finally, pharmaceutical applications of amphiphilic cyclodextrin nanoparticles and miscellaneous administration routes of cyclodextrin-based nanoparticles are also discussed.

Unraveling the pharmaceutical excipient-drug interactions: The effects of polyethylene glycol copolymers on drug metabolism and transport systems.

Chapter 11 - Applicability of machine learning in three-dimensionally (3D) printed dosage forms

3D printing technology has been applied to various fields and its medical applications are expanding. Here, we fabricated implantable 3D bio-printed hydrogel patches containing a nanomedicine as a future tailored cancer treatment. The patches were prepared using a semi-solid extrusion-type 3D bioprinter, a hydrogel-based printer ink, and UV-LED exposure. We focused on the composition of the printer ink and semi-synthesized fish gelatin methacryloyl (F-GelMA), derived from cold fish gelatin, as the main component. The low viscosity of F-GelMA due to its low melting point was remarkably improved by the addition of carboxymethyl cellulose sodium (CMC), a pharmaceutical excipient. PEGylated liposomal doxorubicin (DOX), as a model nanomedicine, was incorporated into the hydrogel and liposome stability after photo-polymerization was evaluated. The addition of CMC inhibited particle size increase. Three types of 3D-designed patches (cylinder, torus, gridlines) were produced using a 3D bioprinter. Drug release was dependent on the shape of the 3D-printed patches and UV-LED exposure time. The current study provides useful information for the preparation of 3D printed nanomedicine-based objects.

M3DISEEN: A novel machine learning approach for predicting the 3D printability of medicines.

Multi-material 3D printing has revolutionized pharmaceutical tablet manufacturing by enabling unprecedented control over the spatial arrangement of active pharmaceutical ingredients (APIs) and excipients. This systematic review analyzes the significant advances in computational methods and 3D printing technologies for pharmaceutical applications from 2005 to 2024. The review explores the integration of artificial intelligence and evolutionary algorithms in solving complex inverse problems of tablet design, where computational methods achieve better accuracy in predicting drug release profiles. Recent developments in material science, including novel thermoresponsive polymers and stimuli-responsive materials, have enhanced manufacturing capabilities while maintaining drug stability. Clinical trials and real-world implementations demonstrate improvements in therapeutic outcomes, with personalized 3D printed medications showing enhanced treatment efficacy and better safety profiles compared to conventional formulations. The review also addresses critical challenges in regulatory compliance, quality control, and scale-up processes, providing a framework for future developments in personalized medicine manufacturing. This work synthesizes current knowledge and identifies emerging trends, offering insights into the future direction of pharmaceutical 3D printing technology and its implications for personalized medicine.

The recent advancement of 3D-printed drugs is an emerging technology that has the potential for effective and safe oral delivery of personalized treatment regimens to patients, replacing the current “one size fits all” philosophy. The objective of this literature review is to highlight the importance of 3D-printing technology in the development of personalized treatments, focusing on Levetiracetam, the first FDA-approved 3D-printed drug, for the treatment of epilepsy. Levetiracetam serves as an ideal paradigm for exploring how precision medicine and 3D printing can be applied to improve treatment outcomes for other complex diseases such as diabetes, cardiovascular diseases, and cancer. 3D printing enables precise dosage and time-release profiles by modifying factors such as shape and size, and the combination of active pharmaceutical ingredients (APIs) and excipients, ensuring consistent therapeutic levels over the treatment period. Design of oral tablets with multiple compartments allows for simultaneous treatment with multiple APIs, each one with a different release profile, minimizing drug–drug interactions and side effects. This technology also supports on-demand production, making it particularly beneficial in resource-limited or urgent situations, and offers the flexibility to customize dosage forms. Additive manufacturing could be an important tool for developing personalized treatments to address the diverse medical needs of patients with complex diseases. Therefore, there is a need for more 3D-printed FDA-approved drugs in the biopharmaceutical industry to enable personalized treatment, improved patient compliance, and precise drug release control.

In-use and long-term physicochemical, rheological and biopharmaceutical stability of 3D-printed inks and/or their respective pimobendan printlets for veterinary use: A pilot study.

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.