Formulating biopharmaceuticals using three-dimensional printing.

Additive manufacturing, commonly referred to as three-dimensional (3D) printing, has the potential to initiate a paradigm shift in the field of medicine and drug delivery. Ever since the advent of the first-ever United States Food and Drug Administration (US FDA)-approved 3D printed tablet, there has been an increased interest in the application of this technology in drug delivery and biomedical applications. 3D printing brings us one step closer to personalized medicine, hence rendering the "one size fits all" concept in drug dosing obsolete. In this review article, we focus on the recent developments in the field of modified drug delivery systems in which various types of additive manufacturing technologies are applied.

[Research practice and development direction of intelligent manufacturing of presonalized traditional Chinese medicine preparations].

In recent years, as people's living standards continue to improve, and the pace of life accelerates dramatically, the demand and quality of traditional Chinese medicine(TCM) services from patients continue to rise. As an essential supplement to the existing forms of TCM application, such as Chinese patent medicine, decoction, and formulated granules, presonalized TCM preparations is facing an increasing market demand. Currently, manual and semi-mechanized production are the primary production ways in presonalized TCM preparations. However, the production process control level is low, and digitalization and informatization need to be improved, which restricts the automated and intelligent development of presonalized TCM preparations. Presonalized TCM preparations faces a significant opportunity and challenge in integrating with intelligent manufacturing through research and development of intelligent equipment and core technology. This paper overviews the connotation and characteristics of intelligent manufacturing and summarizes the application of intelligent manufacturing technologies such as "Internet of things" "big data", and "artificial intelligence" in the TCM industry. Based on the innovative research and development model of "intelligent classification of TCM materials, intelligent decision making of prescription and process, and online control and intelligent production" of presonalized TCM preparations, the research practice and achievements from our research group in the field of intelligent manufacturing of presonalized TCM preparations are introduced. Ultimately, the paper proposes the direction for developing intelligent manufacturing of presonalized TCM preparations, which will provide a reference for the research and application of automation and intelligence of presonalized TCM preparations.

Polymer Characteristics for Drug Layering on Particles Using a Novel Melt Granulation Technology, MALCORE®.

MALCORE®, a novel manufacturing technology for drug-containing particles (DCPs), relies on the melt granulation method to produce spherical particles with high drug content. The crucial aspect of particle preparation through MALCORE® involves utilizing polymers that dissolve in the melt component, thereby enhancing viscosity upon heating. However, only aminoalkyl methacrylate copolymer E (AMCE) has been previously utilized. Therefore, this study aims to discover other polymers and comprehend the essential properties these polymers need to possess. The results showed that polyvinylpyrrolidone (PVP) was soluble in the stearic acid (SA) melt component. FTIR examination revealed no interaction between SA and polymer. The phase diagram was used to analyze the state of the SA and polymer mixture during heating. It revealed the mixing ratio and temperature range where the mixture remained in a liquid state. The viscosity of the mixture depended on the quantity and molecular weight of the polymer dissolved in SA. Furthermore, the DCPs prepared using PVP via MALCORE® exhibited similar pharmaceutical properties to those prepared with AMCE. In conclusion, understanding the properties required for polymers in the melt granulation process of MALCORE® allows for the optimization of manufacturing conditions, such as temperature and mixing ratios, for efficient and consistent drug layering.

Machine learning modeling for ultrasonic quality attribute assessment of pharmaceutical tablets for continuous manufacturing and real-time release testing.

In in-process quality monitoring for Continuous Manufacturing (CM) and Critical Quality Attributes (CQA) assessment for Real-time Release (RTR) testing, ultrasonic characterization is a critical technology for its direct, non-invasive, rapid, and cost-effective nature. In quality evaluation with ultrasound, relating a pharmaceutical tablet's ultrasonic response to its defect state and quality parameters is essential. However, ultrasonic CQA characterization requires a robust mathematical model, which cannot be obtained with traditional first principles-based modeling approaches. Machine Learning (ML) using experimental data is emerging as a critical analytical tool for overcoming such modeling challenges. In this work, a novel Deep Neural Network-based ML-driven Non-Destructive Evaluation (ML-NDE) modeling framework is developed, and its effectiveness for extracting and predicting three CQAs, namely defect states, compression force levels, and amounts of disintegrant, is demonstrated. Using a robotic tablet handling experimental rig, each attribute's distinct waveform dataset was acquired and utilized for training, validating, and testing the respective ML models. This study details an advanced algorithmic quality assessment framework for pharmaceutical CM in which automated RTR testing is expected to be critical in developing cost-effective in-process real-time monitoring systems. The presented ML-NDE approach has demonstrated its effectiveness through evaluations with separate (unused) test datasets.

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.

Fabrication of 3D-Printed Hydrocortisone Triple Pulsatile Tablet Using Fused Deposition Modelling Technology.

Hydrocortisone (HC) is the optimal drug for adolescents diagnosed with congenital adrenal hyperplasia (CAH). Because traditional dosage regimens HC are inconvenient, our study used fused deposition modeling (FDM) three-dimensional (3D) printing technology to solve the problems caused by traditional preparations. First, we designed a core-shell structure tablet with an inner instant release component and an outer delayed release shell. The instant release component was Kollicoat IR: glycerol (GLY): HC = 76.5:13.5:10. Then, we used Affinisol® HPMC 15LV to realize delayed release. Furthermore, we investigated the relationship between the thickness of the delayed release shell and the delayed release time, and an equation was derived through binomial regression analysis. Based on that equation, a novel triple pulsatile tablet with an innovative structure was devised. The tablet was divided into three components, and the drug was released multiple times at different times. The dose and release rate of the tablets can be adjusted by modifying the infill rate of the printing model. The results indicated that the triple pulsatile tablet exhibited desirable release behavior in vitro. Moreover, the physicochemical properties of the drug, excipients, filaments, and tablets were characterized. All these results indicate that the FDM 3D printing method is a convenient technique for producing preparations with intricate structures.

Development of a simple paste for 3D printing of drug formulations containing a mesoporous material loaded with a poorly water-soluble drug.

Poorly soluble drugs represent a substantial portion of emerging drug candidates, posing significant challenges for pharmaceutical formulators. One promising method to enhance the drug's dissolution rate and, consequently, bioavailability involves transforming them into an amorphous state within mesoporous materials. These materials can then be seamlessly integrated into personalized drug formulations using Additive Manufacturing (AM) techniques, most commonly via Fused Deposition Modeling. Another innovative approach within the realm of AM for mesoporous material-based formulations is semi-solid extrusion (SSE). This study showcases the feasibility of a straightforward yet groundbreaking hybrid 3D printing system employing SSE to incorporate drug-loaded mesoporous magnesium carbonate (MMC) into two different drug formulations, each designed for distinct administration routes. MMC was loaded with the poorly water-soluble drug ibuprofen via a solvent evaporation method and mixed with PEG 400 as a binder and lubricant, facilitating subsequent SSE. The formulation is non-aqueous, unlike most pastes which are used for SSE, and thus is beneficial for the incorporation of poorly water-soluble drugs. The 3D printing process yielded tablets for oral administration and suppositories for rectal administration, which were then analyzed for their dissolution behavior in biorelevant media. These investigations revealed enhancements in the dissolution kinetics of the amorphous drug-loaded MMC formulations. Furthermore, an impressive drug loading of 15.3 % w/w of the total formulation was achieved, marking the highest reported loading for SSE formulations incorporating mesoporous materials to stabilize drugs in their amorphous state by a wide margin. This simple formulation containing PEG 400 also showed advantages over other aqueous formulations for SSE in that the formulations did not exhibit weight loss or changes in size or form during the curing process post-printing. These results underscore the substantial potential of this innovative hybrid 3D printing system for the development of drug dosage forms, particularly for improving the release profile of poorly water-soluble drugs.

[Current situation and development trend of digital traditional Chinese medicine pharmacy].

The 21st century is a highly information-driven era, and traditional Chinese medicine(TCM) pharmacy is also moving towards digitization and informatization. New technologies such as artificial intelligence and big data with information technology as the core are being integrated into various aspects of drug research, manufacturing, evaluation, and application, promoting interaction between these stages and improving the quality and efficiency of TCM preparations. This, in turn, provides better healthcare services to the general population. The deep integration of emerging technologies such as artificial intelligence, big data, and cloud computing with the TCM pharmaceutical industry will innovate TCM pharmaceutical technology, accelerate the research and industrialization process of TCM pharmacy, provide cutting-edge technological support to the global scientific community, boost the efficiency of the TCM industry, and promote economic and social development. Drawing from recent developments in TCM pharmacy in China, this paper discussed the current research status and future trends in digital TCM pharmacy, aiming to provide a reference for future research in this field.

Application of Raman spectroscopy during pharmaceutical process development for determination of critical quality attributes in Protein A chromatography.

Raman spectroscopy is considered a Process Analytical Technology (PAT) tool in biopharmaceutical downstream processes. In the past decade, researchers have shown Raman spectroscopy's feasibility in determining Critical Quality Attributes (CQAs) in bioprocessing. This study verifies the feasibility of implementing a Raman-based PAT tool in Protein A chromatography as a CQA monitoring technique, for the purpose of accelerating process development and achieving real-time release in manufacturing. A system connecting Raman to a Tecan liquid handling station enables high-throughput model calibration. One calibration experiment collects Raman spectra of 183 samples with 8 CQAs within 25 h. After applying Butterworth high-pass filters and k-nearest neighbor (KNN) regression for model training, the model showed high predictive accuracy for fragments (Q2 = 0.965) and strong predictability for target protein concentration, aggregates, as well as charge variants (Q2≥ 0.922). The model's robustness was confirmed by varying the elution pH, load density, and residence time using 19 external validation preparative Protein A chromatography runs. The model can deliver elution profiles of multiple CQAs within a set point ± 0.3 pH range. The CQA readouts were presented as continuous chromatograms with a resolution of every 28 s for enhanced process understanding. In external validation datasets, the model maintained strong predictability especially for target protein concentration (Q2 = 0.956) and basic charge variants (Q2 = 0.943), except for overpredicted HCP (Q2 = 0.539). This study demonstrates a rapid, effective method for implementing Raman spectroscopy for in-line CQA monitoring in process development and biomanufacturing, eliminating the need for labor-intensive sample pooling and handling.

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation-Where Are We Now?

Hot-melt extrusion (HME) is a globally recognized, robust, effective technology that enhances the bioavailability of poorly soluble active pharmaceutical ingredients and offers an efficient continuous manufacturing process. The twin-screw extruder (TSE) offers an extremely resourceful customizable mixer that is used for continuous compounding and granulation by using different combinations of conveying elements, kneading elements (forward and reverse configuration), and distributive mixing elements. TSE is thus efficiently utilized for dry, wet, or melt granulation not only to manufacture dosage forms such as tablets, capsules, or granule-filled sachets, but also for designing novel formulations such as dry powder inhalers, drying units for granules, nanoextrusion, 3D printing, complexation, and amorphous solid dispersions. Over the past decades, combined academic and pharmaceutical industry collaborations have driven novel innovations for HME technology, which has resulted in a substantial increase in published articles and patents. This article summarizes the challenges and models for executing HME scale-up. Additionally, it covers the benefits of continuous manufacturing, process analytical technology (PAT) considerations, and regulatory requirements. In summary, this well-designed review builds upon our earlier publication, probing deeper into the potential of twin-screw extruders (TSE) for various new applications.

Application of 3D printing in early phase development of pharmaceutical solid dosage forms.

Three-dimensional printing (3DP) is an emerging technology, offering the possibility for the development of dose-customized, effective, and safe solid oral dosage forms (SODFs). Although 3DP has great potential, it does come with certain limitations, and the traditional drug manufacturing platforms remain the industry standard. The consensus appears to be that 3DP technology is expected to benefit personalized medicine the most, but that it is unlikely to replace conventional manufacturing for mass production. The 3DP method, on the other hand, could prove well-suited for producing small batches as an adaptive manufacturing technique for enabling adaptive clinical trial design for early clinical studies. The purpose of this review is to discuss recent advancements in 3DP technologies for SODFs and to focus on the applications for SODFs in the early clinical development stages, including a discussion of current regulatory challenges and quality controls.

Application of 3D printing technology for the development of dose adjustable geriatric and pediatric formulation of celecoxib.

Developing safe and effective formulations for the geriatric and pediatric population is a challenging task due to issues of swallowability and palatability. The lack of standardized procedures for pediatric formulations further complicates the process. Manipulating adult formulations for children can lead to suboptimal efficacy and safety concerns. To overcome these challenges, minitablets or spinklets are preferred for the geriatric and pediatric population due to their smaller size and flexible dose adjustment. The aim of this study is the development of a 3D printed spinklets formulation of celecoxib, a nonsteroidal anti-inflammatory drug, using hot melt extrusion to address the limitations of traditional manufacturing methods. Three different formulations of celecoxib were prepared using Poly-2-ethyl-tetra-oxazoline (Aquazol) with and without surfactant. Subsequently, the mechanical properties and solubility of the drug-loaded filaments were evaluated. Solid state characterization confirmed the drug conversion into an amorphous form during the extrusion process, Computer-aided design software facilitate sprinklets design for fused deposition modeling and scanning electron microscopy assess the surface morphology. Sophorolipids plasticize better than TPGS, resulting in lowering processing temperatures during melt extrusion. In vitro drug release showed successful enhancements in the dissolution of oral medications for pediatric patients, considering their distinctive physiological characteristics. Overall, this study demonstrates the successful development of PEtOx-based 3D printed celecoxib sprinklets by coupling hot-melt extrusion and 3D printing technology. Future exploration holds the potential to revolutionize pharmaceutical production and advance personalized medication formulations.

Systematic screening of photopolymer resins for stereolithography (SLA) 3D printing of solid oral dosage forms: Investigation of formulation factors on printability outcomes.

Pharmaceutical three-dimensional printing (3DP) is now in its golden age. Recent years have seen a dramatic increase in the research in 3D printed pharmaceuticals due to their potential to deliver highly personalised medicines, thus revolutionising the way medicines are designed, manufactured, and dispensed. A particularly attractive 3DP technology used to manufacture medicines is stereolithography (SLA), which features key advantages in terms of printing resolution and compatibility with thermolabile drugs. Nevertheless, the enthusiasm for pharmaceutical SLA has not been followed by the introduction of novel excipients specifically designed for the fabrication of medicines; hence, the choice of biocompatible polymers and photoinitiators available is limited. This work provides an insight on how to maximise the usefulness of the limited materials available by evaluating how different formulation factors affect printability outcomes of SLA 3D printed medicines. 156 photopolymer formulations were systematically screened to evaluate the influence of factors including photoinitiator amount, photopolymer molecular size, and type and amount of liquid filler on the printability outcomes. Collectively, these factors were found highly influential in modulating the print quality of the final dosage forms. Findings provide enhanced understanding of formulation parameters informing the future of SLA 3D printed medicines and the personalised medicines revolution.

Tailoring drug release in bilayer tablets through droplet deposition modeling and injection molding.

This study explores the innovative production of personalized bilayer tablets, integrating two advanced manufacturing techniques: Droplet Deposition Modeling (DDM) and Injection Molding (IM). Unlike traditional methods limited to customizing dense bilayer medicines, our approach uses Additive Manufacturing (AM) to effectively adjust drug release profiles. Focusing on Caffeine and Paracetamol, we found successful processing for both DDM and IM using Caffeine formulation. The high viscosity of Paracetamol formulation posed challenges during DDM processing. Integrating Paracetamol formulation for the over-molding process proved effective, demonstrating IM's versatility in handling complex formulations. Varying infill percentages in DDM tablets led to distinct porosities affecting diverse drug release profiles in DDM-fabricated tablets. In contrast, tablets with high-density structures formed through the over-molding process displayed slower and more uniform release patterns. Combining DDM and IM techniques allows for overcoming the inherent limitations of each technique independently, enabling the production of bilayer tablets with customizable drug release profiles. The study's results offer promising insights into the future of personalized medicine, suggesting new pathways for the development of customized oral dosage forms.

Perspectives on 3D printed personalized medicines for pediatrics.

In recent years, the rapid advancement of three-dimensional (3D) printing technology has yielded distinct benefits across various sectors, including pharmaceuticals. The pharmaceutical industry has particularly experienced advantages from the utilization of 3D-printed medications, which have invigorated the development of tailored drug formulations. The approval of 3D-printed drugs by the U.S. Food and Drug Administration (FDA) has significantly propelled personalized drug delivery. Additionally, 3D printing technology can accommodate the precise requirements of pediatric drug dosages and the complexities of multiple drug combinations. This review specifically concentrates on the application of 3D printing technology in pediatric preparations, encompassing a broad spectrum of uses and refined pediatric formulations. It compiles and evaluates the fundamental principles associated with the application of 3D printing technology in pediatric preparations, including its merits and demerits, and anticipates its future progression. The objective is to furnish theoretical underpinning for 3D printing technology to facilitate personalized drug delivery in pediatrics and to advocate for its implementation in clinical settings.

Accelerating attribute-focused process and product development through the development and deployment of autonomous process analytical technology platform system.

Enabling real-time monitoring and control of the biomanufacturing processes through product quality insights continues to be an area of focus in the biopharmaceutical industry. The goal is to manufacture products with the desired quality attributes. To realize this rigorous attribute-focused Quality by Design approach, it is critical to support the development of processes that consistently deliver high-quality products and facilitate product commercialization. Time delays associated with offline analytical testing can limit the speed of process development. Thus, developing and deploying analytical technology is necessary to accelerate process development. In this study, we have developed the micro sequential injection process analyzer and the automatic assay preparation platform system. These innovations address the unmet need for an automatic, online, real-time sample acquisition and preparation platform system for in-process monitoring, control, and release of biopharmaceuticals. These systems can also be deployed in laboratory areas as an offline analytical system and on the manufacturing floor to enable rapid testing and release of products manufactured in a good manufacturing practice environment.

Development of multiple structured extended release tablets via hot melt extrusion and dual-nozzle fused deposition modeling 3D printing.

The study aims to fabricate extended release (ER) tablets using a dual-nozzle fused deposition modeling (FDM) three-dimensional (3D) printing technology based on hot melt extrusion (HME), using caffeine as the model compound. Three different ER tablets were developed, which obtained "delayed-release", "rapid-sustained release", and "release-lag-release" properties. Each type of tablet was printed with two different formulations. A novel printing method was employed in this study, which is to push the HME filament from behind with polylactic acid (PLA) to prevent sample damage by gears during the printing process. Powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC) results showed that caffeine was predominately amorphous in the final tablets. The dissolution of 3D printed tablets was assessed using a USP-II dissolution apparatus. ER tablets containing PVA dissolved faster than those developed with Kollicoat IR. Overall, this study revealed that ER tablets were successfully manufactured through HME paired with dual-nozzle FDM 3D printing and demonstrated the power of 3D printing in developing multi-layer tablets with complex structures.

Optimizing twin-screw melt granulation: The role of overflight clearance on granulation behavior.

Twin-screw melt granulation (TSMG) relies on the dispersive and distributive mixing at the kneading zone for granule growth to happen highlighting the critical role played by the kneading elements in TSMG. Despite extensive research conducted on the impact of screw geometry in melt compounding, there is not enough literature for TSMG. Disc width for the kneading elements was 2 mm, contrary to the standard 5 mm. The objective of this study was to evaluate if varying overflight clearance (OC) can alter the paradigm for TSMG. The new elements reduce the peak shear at kneading zone however a higher barrel temperature and degree of fill (DoF) is required to compensate to attain similar granule attributes. The change in DoF was achieved through a combination of modified screw configuration to pre-densify powders before kneading and processing at a lower screw speed. Despite the higher barrel temperature, process optimization of thermally unstable gabapentin was carried out. Using the new elements, compressible granules (Tensile strength > 2 MPa) with low % GABA-L content were manufactured despite increasing OC to 0.4 mm. Granule stability at 40 °C, ambient humidity for 6 months indicated gabapentin was stable (% GABA-L ≪0.4 %) despite a high barrel temperature of 120 °C.

Cutaneous Pharmacokinetics of Topically Applied Novel Dermatological Formulations.

Novel formulations are developed for dermatological applications to address a wide range of patient needs and therapeutic challenges. By pushing the limits of pharmaceutical technology, these formulations strive to provide safer, more effective, and patient-friendly solutions for dermatological concerns, ultimately improving the overall quality of dermatological care. The article explores the different types of novel dermatological formulations, including nanocarriers, transdermal patches, microsponges, and microneedles, and the techniques involved in the cutaneous pharmacokinetics of these innovative formulations. Furthermore, the significance of knowing cutaneous pharmacokinetics and the difficulties faced during pharmacokinetic assessment have been emphasized. The article examines all the methods employed for the pharmacokinetic evaluation of novel dermatological formulations. In addition to a concise overview of earlier techniques, discussions on novel methodologies, including tape stripping, in vitro permeation testing, cutaneous microdialysis, confocal Raman microscopy, and matrix-assisted laser desorption/ionization mass spectrometry have been conducted. Emerging technologies like the use of microfluidic devices for skin absorption studies and computational models for predicting drug pharmacokinetics have also been discussed. This article serves as a valuable resource for researchers, scientists, and pharmaceutical professionals determined to enhance the development and understanding of novel dermatological drug products and the complex dynamics of cutaneous pharmacokinetics.