RESOURCES

Abstract
Oromucosal patches for drug delivery allow fast onset of action and ability to circumvent hepatic first pass metabolism of drugs. While conventional fabrication methods such as solvent casting or hot melt extrusion are ideal for scalable production of low-cost delivery patches, these methods chiefly allow for simple, homogenous patch designs. As alternative, a multi-material direct-ink-write 3D printing for rapid fabrication of complex oromucosal patches with unique design features was demonstrated in the present study. Specifically, three print-materials: an acidic saquinavir-loaded hydroxypropyl methylcellulose ink, an alkaline effervescent sodium carbonate-loaded ink, and a methyl cellulose backing material were combined in various designs. The CO2 content and pH of the microenvironment were controlled by adjusting the number of alkaline layers in the patch. Additionally, the rigid and brittle patches were converted to compliant and stretchable patches by implementing mesh-like designs. Our results illustrate how 3D printing can be used for rapid design and fabrication of multifunctional or customized oromucosal patches with tailored dosages and changed drug permeation.

Abstract
Direct powder three-dimensional (3D)-printing (DPP) of tablets to simplify fused deposition modelling (FDM) was explored. The FDM paradigm involving hot-melt extrusion for making 3D-printable drug-loaded filaments as intermediate products for tablet manufacturing has been gaining attention for the decentralized on-site production of personalized dosage forms. For direct 3D-printing, powder blends were loaded into a cartridge-like head and were successfully printed with honeycomb design following heating of the extrusion cartridge. This 1-step DPP with incorporation of in-built porosity providing higher surface area served as proof of concept for manufacture of rapid release dosage forms. Water soluble hydroxypropylcellulose SSL was chosen as matrix former and caffeine as model drug. The effect of PEG4000 as plasticizer/pore former and Kollidon VA64 as rapidly dissolving polymer on DPP processability and dissolution rate was investigated. Directly 3D-printed tablets with low (30%) infill density showed rapid dissolution independently of the formulation, whereas for high (80%) infill density a combination of PEG4000 and Kollidon VA64 was required to achieve rapid release. The obtained tablets demonstrated good uniformity of percent drug content but had variable weight. Caffeine was present in crystalline state and in the stable polymorph in the tablets. Hence, DPP feasibility for immediate release dosage form manufacture was demonstrated. This technique might create an opportunity to avoid hot-melt extrusion allowing 3D-printing independently of mechanical properties of a filament and potentially prolonging product shelf life by reducing thermal stress.

Abstract
An extrusion-based 3D printer was used to fabricate paracetamol tablets with different geometries (mesh, ring and solid) from a single paste-based formulation formed from standard pharmaceutical ingredients. The tablets demonstrate that tunable drug release profiles can be achieved from this single formulation even with high drug loading (>{thinspace}80{%} w/w). The tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed well-defined release profiles (from immediate to sustained release) controlled by their different geometries. The dissolution results showed dependency of drug release on the surface area/volume (SA/V) ratio and the SA of the different tablets. The tablets with larger SA/V ratios and SA had faster drug release. The 3D printed tablets were also evaluated for physical and mechanical properties including tablet dimension, drug content, weight variation and breaking force and were within acceptable range as defined by the international standards stated in the US Pharmacopoeia. X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy were used to identify the physical form of the active and to assess possible drug-excipient interactions. These data again showed that the tablets meet USP requirement. These results clearly demonstrate the potential of 3D printing to create unique pharmaceutical manufacturing, and potentially clinical, opportunities. The ability to use a single unmodified formulation to achieve defined release profiles could allow, for example, relatively straightforward personalization of medicines for individuals with different metabolism rates for certain drugs and hence could offer significant development and clinical opportunities.

Abstract
Abstract We have used three dimensional (3D) extrusion printing to manufacture a multi-active solid dosage form or so called polypill. This contains five compartmentalised drugs with two independently controlled and well-defined release profiles. This polypill demonstrates that complex medication regimes can be combined in a single personalised tablet. This could potentially improve adherence for those patients currently taking many separate tablets and also allow ready tailoring of a particular drug combination/drug release for the needs of an individual. The polypill here represents a cardiovascular treatment regime with the incorporation of an immediate release compartment with aspirin and hydrochlorothiazide and three sustained release compartments containing pravastatin, atenolol, and ramipril. X-ray powder diffraction (XRPD) and Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) were used to assess drug-excipient interaction. The printed polypills were evaluated for drug release using {USP} dissolution testing. We found that the polypill showed the intended immediate and sustained release profiles based upon the active/excipient ratio used.

Abstract
The manufacture of immediate release high drug loading paracetamol oral tablets was achieved using an extrusion based 3D printer from a premixed water based paste formulation. The 3D printed tablets demonstrate that a very high drug (paracetamol) loading formulation (80% w/w) can be printed as an acceptable tablet using a method suitable for personalisation and distributed manufacture. Paracetamol is an example of a drug whose physical form can present challenges to traditional powder compression tableting. Printing avoids these issues and facilitates the relatively high drug loading. The 3D printed tablets were evaluated for physical and mechanical properties including weight variation, friability, breaking force, disintegration time, and dimensions and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). X-ray Powder Diffraction (XRPD) was used to identify the physical form of the active. Additionally, XRPD, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to assess possible drug-excipient interactions. The 3D printed tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed a profile characteristic of the immediate release profile as intended based upon the active/excipient ratio used with disintegration in less than 60 s and release of most of the drug within 5 min. The results demonstrate the capability of 3D extrusion based printing to produce acceptable high-drug loading tablets from approved materials that comply with current USP standards.

Abstract
Abstract We have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well-defined and separate controlled release profiles for three different drugs. This ‘polypill’ made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and ‘dial up’ this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug–excipient interaction. The printed formulations were evaluated for drug release using {USP} dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer–Peppas release kinetics dependent upon the active/excipient ratio used.

Abstract
The current healthcare system is widely based on the concept of “one size fit for all”, which emphasizes treating a disease by prescribing the same drug to all patients with equivalent doses and dosing frequency. This medical treatment scenario has shown varied responses with either no or weak pharmacological effects and exaggerated adverse reactions preceded by more patient complications. The hitches to the concept of “one size fits all” have devoted the attention of many researchers to unlocking the concept of personalized medicine (PM). PM delivers customized therapy with the highest safety margin for an individual patient’s needs. PM has the potential to revolutionize the current healthcare system and pave the way to alter drug choices and doses according to a patient’s clinical responses, providing physicians with the best treatment outcomes. The 3D printing techniques is a solid-form fabrication method whereby successive layers of materials based on computer-aided designs were deposited to form 3D structures. The 3D printed formulation achieves PM goals by delivering the desired dose according to patient needs and drug release profile to achieve a patient’s personal therapeutic and nutritional needs. This pre-designed drug release profile attains optimum absorption and distribution, exhibiting maximum efficacy and safety profiles. This review aims to focus on the role of the 3D printing technique as a promising tool to design PM in metabolic syndrome (MS).

Abstract
Summary
Acinetobacter baumannii causes a wide range of infections, including wound infections. Multidrug-resistant A. baumannii is a major healthcare concern and the development of novel treatments against these infections is needed. Fosmidomycin is a repurposed antimalarial drug targeting the non-mevalonate pathway, and several derivatives show activity towards A. baumannii. We evaluated the antimicrobial activity of CC366, a fosmidomycin prodrug, against a collection of A. baumannii strains, using various in vitro and in vivo models; emphasis was placed on the evaluation of its anti-biofilm activity. We also developed a 3D-printed wound dressing containing CC366, using melt electrowriting technology. Minimal inhibitory concentrations of CC366 ranged from 1 to 64 μg/mL, and CC366 showed good biofilm inhibitory and moderate biofilm eradicating activity in vitro. CC366 successfully eluted from a 3D-printed dressing, the dressings prevented the formation of A. baumannnii wound biofilms in vitro and reduced A. baumannii infection in an in vivo mouse model.

Abstract
This work reports the construction of a bicomponent scaffold co-loaded with both a prodrug and a drug (BiFp@Ht) as an efficient platform for wound dressing, by combining the electrospinning and 3D-printing technologies. The outer component consisted of a chitosan/polyethylene oxide-electrospun membrane loaded with the indomethacin–polyethylene glycol–indomethacin prodrug (Fp) and served as a support for printing the inner component, a gelatin methacryloyl/sodium alginate hydrogel loaded with tetracycline hydrochloride (Ht). The different architectural characteristics of the electrospun and 3D-printed layers were very well highlighted in a morphological analysis performed by Scanning Electron Microscopy (SEM). In vitro release profile studies demonstrated that both Fp and Ht layers were capable to release the loaded therapeutics in a controlled and sustained manner. According to a quantitative in vitro biological assessment, the bicomponent BiFp@Ht scaffold showed a good biocompatibility and no cytotoxic effect on HeLa cell cultures, while the highest proliferation level was noted in the case of HeLa cells seeded onto an Fp nanofibrous membrane. Furthermore, the BiFp@Ht scaffold presented an excellent antimicrobial activity against the E. coli and S. aureus bacterial strains, along with promising anti-inflammatory and proangiogenic activities, proving its potential to be used for wound dressing.

Abstract
Abstract The overall success in launching discovered drugs is tightly restricted to the high rate of late-stage failures, which ultimately inhibits the distribution of medicines in markets. As a result, it is imperative that methods reliably predict the effectiveness and, more critically, the toxicity of medicine early in the drug development process before clinical trials be continuously innovated. We must stay up to date with the fast appearance of new infections and diseases by rapidly developing the requisite vaccinations and medicines. Modern in vitro models of disease may be used as an alternative to traditional disease models, and advanced technology can be used for the creation of pharmaceuticals as well as cells, drugs, and gene delivery systems to expedite the drug discovery procedure. Furthermore, in vitro models that mimic the spatial and chemical characteristics of native tissues, such as a 3D bioprinting system or other technologies, have proven to be more effective for drug screening than traditional 2D models. Viral and non-viral gene delivery vectors are a hopeful tool for combinatorial gene therapy, suggesting a quick way of simultaneously deliver multiple genes. A 3D bioprinting system embraces an excellent potential for gene delivery into the different cells or tissues for different diseases, in tissue engineering and regeneration medicine, in which the precise nucleic acid is located in the 3D printed tissues and scaffolds. Non-viral nanocarriers, in combination with 3D printed scaffolds, are applied to their delivery of genes and controlled release properties. There remains, however, a big obstacle in reaching the full potential of 3D models because of a lack of in vitro manufacturing of live tissues. Bioprinting advancements have made it possible to create biomimetic constructions that may be used in various drug discovery research applications. 3D bioprinting also benefits vaccinations, medicines, and relevant delivery methods because of its flexibility and adaptability. This review discusses the potential of 3D bioprinting technologies for pharmaceutical studies.

Abstract
Three-dimensional (3D) printing is an innovative additive manufacturing technology, capable of fabricating unique structures in a layer-by-layer manner. Semi-solid extrusion (SSE) is a subset of material extrusion 3D printing, and through the sequential deposition of layers of gel or paste creates objects of any desired size and shape. In comparison to other extrusion-based technologies, SSE 3D printing employs low printing temperatures which makes it suitable for drug delivery and biomedical applications, and the use of disposable syringes provides benefits in meeting critical quality requirements for pharmaceutical use. Besides pharmaceutical manufacturing, SSE 3D printing has attracted increasing attention in the field of bioelectronics, particularly in the manufacture of biosensors capable of measuring physiological parameters or as a means to trigger drug release from medical devices. This review begins by highlighting the major printing process parameters and material properties that influence the feasibility of transforming a 3D design into a 3D object, and follows with a discussion on the current SSE 3D printing developments and their applications in the fields of pharmaceutics, bioprinting and bioelectronics. Finally, the advantages and limitations of this technology are explored, before focusing on its potential clinical applications and suitability for preparing personalised medicines.

Abstract
Three-dimensional (3D) printing is a revolutionary technology that is disrupting pharmaceutical development by enabling the production of personalised printlets (3D printed drug products) on demand. By creating small batches of dose flexible medicines, this versatile technology offers significant advantages for clinical practice and drug development, namely the ability to personalise medicines to individual patient needs, as well as expedite drug development timelines within preclinical studies through to first-in-human (FIH) and Phase I/II clinical trials. Despite the widely demonstrated benefits of 3D printing pharmaceuticals, the clinical potential of the technology is yet to be realised. In this timely review, we provide an overview of the latest cutting-edge investigations in 3D printing pharmaceuticals in the pre-clinical and clinical arena and offer a forward-looking approach towards strategies to further aid the translation of 3D printing into the clinic.

Abstract
Since additive manufacturing of pharmaceuticals has been introduced as viable method to produce individualized drug delivery systems with complex geometries and release profiles, semi-solid micro-extrusion has shown to be uniquely beneficial. Easy incorporation of actives, room-temperature processability and avoidance of cross-contamination by using disposables are some of the advantages that led many researchers to focus their work on this technology in the last few years. First acceptability and in-vivo studies have brought it closer towards implementation in decentralized settings. This review covers recently established process models in light of viscosity and printability discussions to help develop high quality printed medicines. Quality defining formulation and process parameters to characterize the various developed dosage forms are presented before critically discussing the role of semi-solid micro-extrusion in the future of personalized drug delivery systems. Remaining challenges regarding regulatory guidance and quality assurance that pose the last hurdle for large scale and commercial manufacturing are addressed.

Abstract
3D printing, as one of the most rapidly-evolving fabrication technologies, has released a cascade of innovation in the last two decades. In the pharmaceutical field, the integration of 3D printing technology has offered unique advantages, especially at the micro-scale. When printed at a micro-scale, materials and devices can provide nuanced solutions to controlled release, minimally invasive delivery, high-precision targeting, biomimetic models for drug discovery and development, and future opportunities for personalized medicine. This review aims to cover the recent advances in this area. First, the 3D printing techniques are introduced with respect to the technical parameters and features that are uniquely related to each stage of pharmaceutical development. Then specific micro-sized pharmaceutical applications of 3D printing are summarized and grouped according to the provided benefits. Both advantages and challenges are discussed for each application. We believe that these technologies provide compelling future solutions for modern medicine, while challenges remain for scale-up and regulatory approval.