Advancements in Colon-Targeted Drug Delivery: A Comprehensive Review on Recent Techniques with Emphasis on Hot-Melt Extrusion and 3D Printing Technologies.

This review investigates the progression and effectiveness of colon-targeted drug delivery systems, offering a comprehensive understanding of the colon's anatomy and physiological environment. Recognizing the distinctive features of the colon is crucial for successfully formulating oral dosage forms that precisely target specific areas in the gastrointestinal tract (GIT) while minimizing side effects through mitigating off-target sites. This understanding forms the basis for designing effective targeted drug delivery systems. The article extensively examines diverse approaches to formulating drugs for colonic targeting, highlighting key polymers and excipients in their production. Special emphasis is given to innovative approaches such as hot-melt extrusion (HME) and three-dimensional printing (3D-P), renowned for their accuracy in drug release kinetics and intricate dosage form geometry. However, challenges arise regarding material standardization and the complex network of regulatory clearances required to confirm safety and effectiveness. The review provides insights into each application's advantages and potential challenges. Furthermore, it sheds light on the local diseases that necessitate colon targeting and the available marketed products, providing an overview of the current state of colon-targeted drug delivery systems. Additionally, the review emphasizes the importance of testing drugs in a controlled in vitro environment during the development phase. It also discusses the future directions for successful development in this field. By integrating knowledge across anatomy, formulation techniques, and assessment methodologies, this review is a valuable resource for researchers navigating the dynamic field of colonic drug delivery.

Accuracy of a chairside, fused deposition modeling three-dimensional-printed, single tooth surgical guide for implant placement: A randomized controlled clinical trial.

PURPOSE: To compare the accuracy of chairside, fused deposition modeling (FDM) three-dimensional (3D)-printed surgical guides with that of stereolithographic guides for implant placement in single edentulous sites within a clinical setting. MATERIALS AND METHODS: A total of 28 participants with 30 single posterior edentulous sites were included. The sites were randomized into a FDM 3D-printed surgical guide group (test) or stereolithographic guide group (control) of equal size (n = 15). In both groups, digital implant planning was performed using data from cone beam-computed tomography and intraoral scans. The test group's surgical guides were fabricated using a chairside, FDM 3D-printer; those in the control group were fabricated using a light-curing 3D-printer. Postoperative intraoral scans were used to obtain the 3D position of the implants. Compared to preoperative design, the angular, 3D, mesiodistal, buccolingual and apicocoronal deviations at the implant shoulder and apex were recorded. RESULTS: The workflow for the design and chairside fabrication of implant guides was established. The mean angular deviations of the test and control group were (4.23 ± 2.38) ° and (4.13 ± 2.42) ° (p > .05), respectively. The respective 3D deviations at the implant shoulder were (0.70 ± 0.44) mm and (0.55 ± 0.27) mm (p > .05); those at the implant apex were (1.25 ± 0.61) mm and (1.11 ± 0.54) mm (p > .05). The mesiodistal, buccolingual, and apicocoronal deviations at the implant shoulder and apex did not significantly differ between the groups (p > .05). CONCLUSIONS: Implants for single posterior edentulous spaces were placed as accurately with the test guide as with the control. Further research under more complex situations involving multiple missing teeth is needed.

Fabrication of bilayer tablets using hot melt extrusion-based dual-nozzle fused deposition modeling 3D printing.

The objective of this study was to fabricate bilayer tablets using hot-melt extrusion (HME)-based dual-nozzle fused deposition modeling (FDM) three-dimensional (3D) printing techniques. Acetaminophen (APAP) and caffeine citrate (CC) were used as the model drugs. Five bilayer tablets with different formulations were developed and two different structures were printed for each formulation. Three-point bending, Hooke's law, and resistance and stiffness tests were conducted to determine the mechanical properties of the filaments. A novel method, 3D printed tablet retention rate, was developed and used for the first time to compare the printing quality of different filaments. The 3D printed tablets were evaluated to derive the drug release rates using a USP-II dissolution apparatus. HPMC HME 15LV and HPMCAS-LG were identified as good printing materials; however, HPMC HME 100LV was not suitable for printing under frequent nozzle switching conditions. Although mechanical characterization tests can be used to determine whether filaments can be printed, they cannot specifically distinguish the quality of printing between the filaments. Overall, this study revealed the successful fabrication of bilayer tablets via HME paired with dual-nozzle FDM 3D printing.

3D Printed Intragastric Floating and Sustained-Release Tablets with Air Chambers.

This work aimed to use hot-melt extrusion (HME) and dual fused deposition modeling (FDM) 3D printing technology to develop a novel intragastric floating and sustained-release drug delivery system. The intragastric floating and sustained-release tablet was engineered by employing hydroxypropyl methylcellulose (AffinisolTM HPMC HME 15LV) for a drug-loaded core and polylactic acid (PLA) for an insoluble shell with an air chamber. Filaments for the drug-loaded core were compounded using a single-screw hot melt extruder. 3DMAX software was utilized to design a core with a complementary shell which consisted of a hollow chamber at the top and a drug-release window with different sizes (radius in 1.5, 2.5, 3, 3.5, 4.5 mm) at the bottom. Pharmaceutical characterization, solid dispersion evaluation, and drug release behavior were studied. The model drug in all formulations kept stable, and part of the drug in the extruded filaments and 3D printed tablets became amorphous. The introduction of an air chamber reduced the tablet density to below 0.9 g/cm3 and the 3D printed tablets floated immediately and continuously during the drug release process. The presence of the insoluble shell greatly prolonged the drug release time, and the drug release rate was positively correlated with the area of the release window. In addition, compared with shellless tablets, the 3D printed tablets with air chambers (radius in 4.5 mm) showed closer zero-order drug release for 24 h and released drug by diffusion-erosion combined mechanism. The developed intragastric floating and sustained-release tablets with air chambers could be applied to various drugs and provided a new way for the development of personalized drug delivery systems.

Fabrication of Intragastric Floating, Controlled Release 3D Printed Theophylline Tablets Using Hot-Melt Extrusion and Fused Deposition Modeling.

This work presents a novel approach for producing gastro-retentive floating tablets (GRFT) by coupling hot-melt extrusion (HME) and fused deposition three-dimensional printing (3DP). Filaments containing theophylline (THEO) within a hydroxypropyl cellulose (HPC) matrix were prepared using HME. 3DP tablets with different infill percentages and shell thickness were developed and evaluated to determine their drug content, floating behavior, dissolution, and physicochemical properties. The dissolution studies revealed a relationship between the infill percentage/shell thickness and the drug release behavior of the 3DP tablets. All the developed GRFTs possessed the ability to float for 10 h and exhibited zero-order release kinetics. The drug release could be described by the Peppas-Sahlin model, as a combination of Fickian diffusion and swelling mechanism. Drug crystallinity was found unaltered throughout the process. 3DP coupled with HME, could be an effective blueprint to produce controlled-release GRFTs, providing the advantage of simplicity and versatility compared to the conventional methods.

Impact of Processing Parameters on the Quality of Pharmaceutical Solid Dosage Forms Produced by Fused Deposition Modeling (FDM).

Fused deposition modeling (FDM) three-dimensional (3D) printing is being increasingly explored as a direct manufacturing method to product pharmaceutical solid dosage forms. Despite its many advantages as a pharmaceutical formulation tool, it remains restricted to proof-of-concept formulations. The optimization of the printing process in order to achieve adequate precision and printing quality remains to be investigated. Demonstrating a thorough understanding of the process parameters of FDM and their impact on the quality of printed dosage forms is undoubtedly necessary should FDM advance from a proof-of-concept stage to an adapted pharmaceutical manufacturing tool. This article describes the findings of an investigation into a number of critical process parameters of FDM and their impact on quantifiable, pharmaceutically-relevant measures of quality. Polycaprolactone, one of the few polymers which is both suitable for FDM and is a GRAS (generally regarded as safe) material, was used to print internally-exposed grids, allowing examination of both their macroscopic and microstructural reproducibility of FDM. Of the measured quality parameters, dimensional authenticity of the grids was found to poorly match the target dimensions. Weights of the grids were found to significantly vary upon altering printing speed. Printing temperature showed little effect on weight. Weight uniformity per batch was found to lie within acceptable pharmaceutical quality limits. Furthermore, we report observing a microstructural distortion relating to printing temperature which we dub The First Layer Effect (FLE). Principal Component Analysis (PCA) was used to study factor interactions and revealed, among others, the existence of an interaction between weight/dosing accuracy and dimensional authenticity dictating a compromise between the two quality parameters. The Summed Standard Deviation (SSD) is proposed as a method to extract the optimum printing parameters given all the perceived quality parameters and the necessary compromises among them.

Accuracy of a chairside fused deposition modeling 3D-printed single-tooth surgical template for implant placement: An in vitro comparison with a light cured template.

PURPOSE: To compare the accuracy of a chairside fused deposition modeling (FDM) 3D-printed surgical template with that of a light-cured template for implant placement. MATERIALS AND METHODS: Twenty standard mandibular resin models with missing teeth 36 and 46 were selected. Surgical templates were fabricated using a chairside FDM 3D-printer (test group) or a light-curing 3D printer (control group) (n = 20/group). Forty implants were placed by a clinician blinded to group allocation. The angular, 3D, mesiodistal, buccolingual, and apicocoronal deviations at the implant base and tip between preoperative design and postoperative implant position were recorded. RESULTS: The mean angular (test vs control groups: 3.22° ± 1.55° vs 2.74° ± 1.24°, p = 0.343) and 3D deviations at the implant base (test vs control groups: 0.41 ± 0.13 mm vs 0.35 ± 0.11 mm, p = 0.127) and tip (test vs control groups: 0.91 ± 0.34 mm vs 0.75 ± 0.28 mm, p = 0.150) were similar. The mesiodistal, buccolingual, and apicocoronal deviations at the implant base and tip also did not differ significantly between groups (p > 0.05). CONCLUSIONS: For single tooth gap indications, implant placement with an FDM 3D-printed surgical template was as accurate as that with a light-cured template, and more efficient.

The Digital Pharmacies Era: How 3D Printing Technology Using Fused Deposition Modeling Can Become a Reality.

The pharmaceutical industry is set to join the fourth industrial revolution with the 3D printing of medicines. The application of 3D printers in compounding pharmacies will turn them into digital pharmacies, wrapping up the telemedicine care cycle and definitively modifying the pharmacotherapeutic treatment of patients. Fused deposition modeling 3D printing technology melts extruded drug-loaded filaments into any dosage form; and allows the obtainment of flexible dosages with different shapes, multiple active pharmaceutical ingredients and modulated drug release kinetics-in other words, offering customized medicine. This work aimed to present an update on this technology, discussing its challenges. The co-participation of the pharmaceutical industry and compounding pharmacies seems to be the best way to turn this technology into reality. The pharmaceutical industry can produce drug-loaded filaments on a large scale with the necessary quality and safety guarantees; while digital pharmacies can transform the filaments into personalized medicine according to specific prescriptions. For this to occur, adaptations in commercial 3D printers will need to meet health requirements for drug products preparation, and it will be necessary to make advances in regulatory gaps and discussions on patent protection. Thus, despite the conservatism of the sector, 3D drug printing has the potential to become the biggest technological leap ever seen in the pharmaceutical segment, and according to the most optimistic prognostics, it will soon be within reach.

Development of a Simple Mechanical Screening Method for Predicting the Feedability of a Pharmaceutical FDM 3D Printing Filament.

PURPOSE: The filament-based feeding mechanism employed by the majority of fused deposition modelling (FDM) 3D printers dictates that the materials must have very specific mechanical characteristics. Without a suitable mechanical profile, the filament can cause blockages in the printer. The purpose of this study was to develop a method to screen the mechanical properties of pharmaceutically-relevant, hot-melt extruded filaments to predetermine their suitability for FDM. METHODS: A texture analyzer was used to simulate the forces a filament is subjected to inside the printer. The texture analyzer produced a force-distance curve referred to as the flexibility profile. Principal Component Analysis and Correlation Analysis statistical methods were then used to compare the flexibility profiles of commercial filaments to in-house made filaments. RESULTS: Principal component analysis showed clearly separated clustering of filaments that suffer from mechanical defects versus filaments which are suitable for printing. Correlation scores likewise showed significantly greater values with feedable filaments than their mechanically deficient counterparts. CONCLUSION: The screening method developed in this study showed, with statistical significance and reproducibility, the ability to predetermine the feedability of extruded filaments into an FDM printer.

Novel biorenewable composite of wood polysaccharide and polylactic acid for three dimensional printing.

Hemicelluloses, the second most abundant polysaccharide right after cellulose, are in practice still treated as a side-stream in biomass processing industries. In the present study, we report an approach to use a wood-derived and side-stream biopolymer, spruce wood hemicellulose (galactoglucomannan, GGM) to partially replace the synthetic PLA as feedstock material in 3D printing. A solvent blending approach was developed to ensure the even distribution of the formed binary biocomposites. The blends of hemicellulose and PLA with varied ratio up to 25% of hemicellulose were extruded into filaments by hot melt extrusion. 3D scaffold prototypes were successfully printed from the composite filaments by fused deposition modeling 3D printing. Combining with 3D printing technique, the biocompatible and biodegradable feature of spruce wood hemicellulose into the composite scaffolds would potentially boost this new composite material in various biomedical applications such as tissue engineering and drug-eluting scaffolds.

Hydroxypropyl methylcellulose-based controlled release dosage by melt extrusion and 3D printing: Structure and drug release correlation.

The objective of this study was to develop a new approach for fabrication of zero order release of active pharmaceutical ingredients (APIs) using hot-melt extrusion (HME) and 3D printing technology to generate tablets with specific 3D structures. By correlating the geometry of the 3D printed tablets with their dissolution and drug release rates, mathematical models that have been developed to describe drug release mechanisms were also studied. Acetaminophen was used as a model drug, and Benecel™ hydroxypropyl methylcellulose (HPMC) E5 and Soluplus® were used to formulate nine fuse depositional 3D-printed tablets with different inner core fill densities and outside shell thicknesses. This work reports the successful fabrication of solid-dispersion filaments with an API dispersed in HPMC based matrix via HME technology, and the production of zero order controlled release tablets with different 3D structures (tablets #3, 5, 6, and 9) using a 3D printer.

Dry coating of solid dosage forms: an overview of processes and applications.

Dry coating techniques enable manufacturing of coated solid dosage forms with no, or very limited, use of solvents. As a result, major drawbacks associated with both organic solvents and aqueous coating systems can be overcome, such as toxicological, environmental, and safety-related issues on the one hand as well as costly drying phases and impaired product stability on the other. The considerable advantages related to solventless coating has been prompting a strong research interest in this field of pharmaceutics. In the article, processes and applications relevant to techniques intended for dry coating are analyzed and reviewed. Based on the physical state of the coat-forming agents, liquid- and solid-based techniques are distinguished. The former include hot-melt coating and coating by photocuring, while the latter encompass press coating and powder coating. Moreover, solventless techniques, such as injection molding and three-dimensional printing by fused deposition modeling, which are not purposely conceived for coating, are also discussed in that they would open new perspectives in the manufacturing of coated-like dosage forms.