A floating 3D printed polypill formulation for the coadministration and sustained release of antihypertensive drugs.

Polypharmacy is a common issue, especially among elderly patients resulting in administration errors and patient inconvenience. Hypertension is a prevalent health condition that frequently leads to polypharmacy, as its treatment typically requires the co-administration of more than one different Active Pharmaceutical Ingredients (API's). To address these issues, floating hollow torus-shaped dosage forms were developed, aiming at providing prolonged gastric retention and sustained drug release. The dosage forms (polypills) containing three anti-hypertensive API's (diltiazem (DIL), propranolol (PRP) and hydrochlorothiazide (HCTZ)) were created via Fused Deposition Modelling 3D printing. A multitude of the dosage forms were loaded into a capsule and the resulting formulation achieved prolonged retention times over a 12-hour period in vitro, by leveraging both the buoyancy of the dosage forms, and the "cheerios effect" that facilitates the aggregation and retention of the dosage forms via a combination of surface tension and shape of the objects. Physicochemical characterization methods and imaging techniques were employed to investigate the properties and the internal and external structure of the dosage forms. Furthermore, an ex vivo porcine stomach model revealed substantial aggregation, adhesion and retention of the 3D printed dosage forms in porcine stomach. In vitro dissolution testing demonstrated almost complete first-order release of PRP and DIL (93.52 % and 99.9 %, respectively) and partial release of HCTZ (65.22 %) in the 12 h timeframe. Finally, a convolution-based single-stage approach was employed in order to predict the pharmacokinetic (PK) parameters of the API's of the formulation and the resemblance of their PK behavior with previously reported data.

Correction: Andreadis et al. The Advent of a New Era in Digital Healthcare: A Role for 3D Printing Technologies in Drug Manufacturing? Pharmaceutics2022, 14, 609.

In the original publication [...].

Quality control evaluation of paediatric chocolate-based dosage forms: 3D printing vs mold-casting method.

Pharmaceutical compounding is a core activity in the preparation of patient-specific dosage forms. In the current study we aimed to investigate whether 3D printing could be employed for the preparation of pediatric-friendly personalized dosage forms that fulfil the acceptance criteria specified in the pharmacopoeias for conventional dosage forms. We then compared the 3D printed dosage forms with the same formulations prepared with mold-casting, a method frequently applied during pharmaceutical compounding. The molded dosage forms failed to pass most of the quality control tests, including the mass uniformity and content uniformity tests, as well as dose accuracy, contrary to the 3D printed, which not only passed all tests but also enabled precision overdose adjustment. Hence, 3D printing of chocolate-based dosage forms may effectively serve as an acceptable alternative method to mold casting in compounding patient-specific medication at the point-of-care.

The Advent of a New Era in Digital Healthcare: A Role for 3D Printing Technologies in Drug Manufacturing?

The technological revolution has physically affected all manufacturing domains, at the gateway of the fourth industrial revolution. Three-dimensional (3D) printing has already shown its potential in this new reality, exhibiting remarkable applications in the production of drug delivery systems. As part of this concept, personalization of the dosage form by means of individualized drug dose or improved formulation functionalities has concentrated global research efforts. Beyond the manufacturing level, significant parameters must be considered to promote the real-time manufacturing of pharmaceutical products in distributed areas. The majority of current research activities is focused on formulating 3D-printed drug delivery systems while showcasing different scenarios of installing 3D printers in patients' houses, hospitals, and community pharmacies, as well as in pharmaceutical industries. Such research presents an array of parameters that must be considered to integrate 3D printing in a future healthcare system, with special focus on regulatory issues, drug shortages, quality assurance of the product, and acceptability of these scenarios by healthcare professionals and public parties. The objective of this review is to critically present the spectrum of possible scenarios of 3D printing implementation in future healthcare and to discuss the inevitable issues that must be addressed.

Fabrication of an osmotic 3D printed solid dosage form for controlled release of active pharmaceutical ingredients.

In pharmaceutical formulations, pharmacokinetic behavior of the Active Pharmaceutical Ingredients (API's) is significantly affected by their dissolution profiles. In this project, we attempted to create personalized dosage forms with osmotic properties that exhibit different API release patterns via Fused Deposition Modelling (FDM) 3D printing. Specifically, cellulose acetate was employed to create an external shell of an osmotically active core containing Diltiazem (DIL) as model drug. By removing parts of the shell (upper surface, linear lateral segments) were created dosage forms that modify their shape at specific time frames under the effect of the gradually induced osmotic pressure. Hot-Melt Extrusion (HME) was employed to fabricate two different 3DP feeding filaments, for the creation of either the shell or the osmotic core (dual-extrusion printing). Printed formulations and filaments were characterized by means of (TGA, XRD, DSC) and inspected using microscopy (optical and electron). The mechanical properties of the filaments were assessed by means of micro- and macro mechanical testing, whereas micro-Computed Tomography (µCT) was employed to investigate the volumetric changes occurring during the hydration process. XRD indicated the amorphization of DIL inside HME filaments and printed dosage forms, whereas the incorporated NaCl (osmogen) retained its crystallinity. Mechanical properties' testing confirmed the printability of produced filaments. Dissolution tests revealed that all formulations exhibited sustained release differing at the initiation time of the API dissolution (0, 120 and 360 min for the three different formulations). Finally, µCT uncovered the key structural changes associated with distinct phases of the release profile. The above results demonstrate the successful utilization of an FDM 3D printer in order to create osmotic 3D printed formulations exhibiting sustained and/or delayed release, that can be easily personalized containing API doses corresponding to each patient's specific needs.

Recent advances in pharmaceutical dosage forms and devices using additive manufacturing technologies.

The era of 'one-size-fits-all' treatment approaches is becoming history for pharmaceutical manufacturing with the future encountering a revolution in drug development through the introduction of additive manufacturing technologies. The innovative elements of this disruptive technology will affect all shareholders of the pharmaceutical chain from the industrial sector to the dispensing facilities and, ultimately, the patient end-user. In this review, we provide an overview of the most recent advances in dosage forms and devices using additive manufacturing technologies, along with the regulatory landscape framing the development and safety requirements for 3D-printed drug products before entering the pharmaceutical market.

Controlled Release of 5-Fluorouracil from Alginate Beads Encapsulated in 3D Printed pH-Responsive Solid Dosage Forms.

Three-dimensional printing is being steadily deployed as manufacturing technology for the development of personalized pharmaceutical dosage forms. In the present study, we developed a hollow pH-responsive 3D printed tablet encapsulating drug loaded non-coated and chitosan-coated alginate beads for the targeted colonic delivery of 5-fluorouracil (5-FU). A mixture of Eudragit® L100-55 and Eudragit® S100 was fabricated by means of hot-melt extrusion (HME) and the produced filaments were printed utilizing a fused deposition modeling (FDM) 3D printer to form the pH-responsive layer of the tablet with the rest comprising of a water-insoluble poly-lactic acid (PLA) layer. The filaments and alginate particles were characterized for their physicochemical properties (thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction), their surface topography was visualized by scanning electron microscopy and the filaments' mechanical properties were assessed by instrumented indentation testing and tensile testing. The optimized filament formulation was 3D printed and the structural integrity of the hollow tablet in increasing pH media (pH 1.2 to pH 7.4) was assessed by means of time-lapsed microfocus computed tomography (µCT). In vitro release studies demonstrated controlled release of 5-FU from the alginate beads encapsulated within the hollow pH-sensitive tablet matrix at pH values corresponding to the colonic environment (pH 7.4). The present study highlights the potential of additive manufacturing in fabricating controlled-release dosage forms rendering them pertinent formulations for further in vivo evaluation.

A 3D printed bilayer oral solid dosage form combining metformin for prolonged and glimepiride for immediate drug delivery.

Fused Deposition Modelling (a.k.a. FDM-3D printing) has been previously employed in the development of personalized medicines with unique properties and release behavior. In the present work, a bilayer dosage form containing two anti-diabetic drugs with different daily dosage regimens; i.e. metformin and glimepiride, was manufactured via FDM 3D printing, studied using a variety of techniques and characterized in vitro. Metformin and glimepiride were embedded in Eudragit® RL sustained release layer and polyvinyl alcohol (PVA) layer respectively. Incorporation of more than one API's into the formulation is desirable, as it increases patient compliance and reduces cost of treatment, especially when distinct dosages of API's can be adjusted individually in situ, in order to meet each patient's specific needs, a capability provided by 3D printing. A number of different preparation methods, which involved different plasticizers and extruders, were tested on manufacturing Eudragit® RL drug-loaded filaments for printing the sustained release layer. The properties of the produced filaments were assessed by means of mechanical and physicochemical characterization techniques and the filaments with the optimum properties were used for printing. Microfocus computed tomography (µCT) imaging-based actual/nominal comparison analysis showed a printing accuracy ranging between -100, +200 µm, while X-ray (XRD) diffractograms revealed the incorporation of the (initially crystalline) API's as amorphous dispersions into polymer matrices. Dissolution tests showed sufficient drug release for both drugs in desired time frames (75 min for glimepiride and 480 min for metformin). The results from the current study emphasize the potentiality of 3D printing technology for tailor-made solid dosage forms for combined pharmacotherapy, even at the cases when API's with different desirable release profiles are employed.

Negative electrospray ionization mode in mass spectrometry: A new perspective via modeling.

Electrospray ionization technique is used for production of gas phase ions without fragmentation and is considered as one of the most sensitive analytical methods for structural characterization of molecules. Nonetheless, the determination of some parameters (physicochemical properties or structural features) that may enhance the signal response especially in the negative ion mode has not yet been clarified. The present work is an attempt to correlate the signal response behavior of 110 compounds used as probes, with their characteristics (molecular descriptors, X variables). In order to quantify this phenomenon, Partial Least Squares which is a software capable of performing linear multivariate analysis was applied. The models derived explore the positive or negative effect of 49 X variables on the signal response of each analyte, expressed as Y variable. The process of gas phase ions formation was verified by both flow injection and column analysis. The models derived are proven reliable for the study of such mechanisms, with small number of components and good linearity (R(2)>83%, Q(2)>70%). The present study showed that parameters as pKa, ionization percentage of the analyte, PSA, HBA, COOH, water solubility and surface tension of a solid are affecting ion formation. At the same time, slight differentiations of the influence of certain parameters were observed on column injection analysis due to the chromatographic delay of some analytes.