Breast Milk Excretion of Dinalbuphine Sebacate Injection Administered After Cesarean Section.

Ensuring the safety of analgesics during lactation is crucial for women of childbearing potential. Available data regarding the transfer of nalbuphine for postoperative acute pain via breast milk are limited to the postmarketing experience. This lactation study aimed to assess nalbuphine and dinalbuphine sebacate concentrations in breast milk from lactating women with postoperative pain treated with dinalbuphine sebacate extended-release injection (150 mg dinalbuphine sebacate/2 mL Naldebain). Breast milk was collected throughout the 5-day posthospitalization interval from 20 mothers injected with one dose of extended-release dinalbuphine sebacate intramuscularly. Maternal safety was assessed during the study period. Nalbuphine was detectable in 71% of milk samples collected from all mothers, whereas dinalbuphine sebacate was undetectable or below the quantitation limit (0.1 ng/mL). The mean nalbuphine concentration in milk was approximately 10.55 ng/mL, with the peak concentration reaching up to 12.7 ng/mL. The mean relative infant dose was 0.39% (coefficient of variation, 65%). The mean pain intensity at rest was reduced to mild pain from Day 2 morning to discharge. Overall, the maternal safety profile was tolerable. The breast milk of women who receive one dose of dinalbuphine sebacate injection postpartum contains low nalbuphine concentration. In addition, dinalbuphine sebacate injection potentially reduces maternal pain intensity during the first postpartum week and offers low toxicity risk among breastfed infants.

Needles to Spheres: Evaluation of inkjet printing as a particle shape enhancement tool.

Active pharmaceutical ingredients (APIs) often reveal shapes challenging to process, e.g. acicular structures, and exhibit reduced bioavailability induced by slow dissolution rate. Leveraging the API particles' surface and bulk properties offers an attractive pathway to circumvent these challenges. Inkjet printing is an attractive processing technique able to tackle these limitations already in initial stages when little material is available, while particle properties are maintained over the entire production scale. Additionally, it is applicable to a wide range of formulations and offers the possibility of co-processing with a variety of excipients to improve the API's bioavailability. This study addresses the optimization of particle shapes for processability enhancement and demonstrates the successful application of inkjet printing to engineer spherical lacosamide particles, which are usually highly acicular. By optimizing the ink formulation, adapting the substrate-liquid interface and tailoring the heat transfer to the particle, spherical particles in the vicinity of 100 µm, with improved flow properties compared to the bulk material, were produced. Furthermore, the particle size was tailored reproducibly by adjusting the deposited ink volume per cycle and the number of printing cycles. Therefore, the present study shows a novel, reliable, scalable and economical strategy to overcome challenging particle morphologies by co-processing an API with suitable excipients.

Development of a Workflow to Engineer Tailored Microparticles Via Inkjet Printing.

PURPOSE: New drug development and delivery approaches result in an ever-increasing demand for tailored microparticles with defined sizes and structures. Inkjet printing technologies could be promising new processes to engineer particles with defined characteristics, as they are created to precisely deliver liquid droplets with high uniformity. METHODS: D-mannitol was used as a model compound alone or co-processed with the pore former agent ammonium bicarbonate, and the polymer polyethylene glycol 200. Firstly, a drop shape analyzer was used to characterize and understand ink/substrate interactions, evaporation, and solidification kinetics. Consequently, the process was transferred to a laboratory-scale inkjet printer and the resulting particles collected, characterized and compared to others obtained via an industrial standard technique. RESULTS: The droplet shape analysis allowed to understand how 3D structures are formed and helped define the formulation and process parameters for inkjet printing. By adjusting the drop number and process waveform, spherical particles with a mean size of approximately 100 µm were obtained. The addition of pore former and polymer allowed to tailor the crystallization kinetics, resulting in particles with a different surface (i.e., spike-like surface) and bulk (e.g. porous and non-porous) structure. CONCLUSION: The workflow described enabled the production of 3D structures via inkjet printing, demonstrating that this technique can be a promising approach to engineer microparticles.

Can Liposomes Survive Inkjet Printing? The Effect of Jetting on Key Liposome Attributes for Drug Delivery Applications.

Purpose: Inkjet printing has the potential to enable novel personalized and tailored drug therapies based on liposome and lipid nanoparticles. However, due to the significant shear force exerted on the jetted fluids, its suitability for shear-sensitive materials such as liposomes, has not been verified. We have conducted a proof-of-concept study to examine whether the particle concentration and size distribution of placebo liposomes are affected by common inkjet/dispensing technologies. Methods: We have subjected three types of liposome-containing fluids ("inks") to two different commercial dispensing/jetting technologies, which are relevant to most drug printing approaches. The liposome jetting processes were observed in real-time using strobographic imaging techniques. The phospholipid concentrations and particle size distributions were determined before and after jetting via enzymatic colorimetric and dynamic light scattering methods, respectively. Results: Our results have shown that the jetting dynamics of the liposome inks are well predicted by the established inkjet printing regime map based on their physical properties and the jetting conditions. Importantly, although significant shear forces were confirmed during jetting, the liposome concentrations and particle size distributions in the collected samples remain largely unaffected. Conclusion: These findings, we believe, provide the essential proof-of-concept to encourage further development in this highly topical research area.

Near-Infrared Hyperspectral Imaging as a Monitoring Tool for On-Demand Manufacturing of Inkjet-Printed Formulations.

This study evaluates the potential use of near-infrared hyperspectral imaging (NIR-HSI) for quantitative determination of the drug amount in inkjet-printed dosage forms. We chose metformin hydrochloride as a model active pharmaceutical ingredient (API) and printed it onto gelatin films using a piezoelectric inkjet printing system. An industry-ready NIR-HSI sensor combined with a motorized movable linear stage was applied for spectral acquisition. Initial API-substrate screening revealed best printing results for gelatin films with TiO2 filling. For calibration of the NIR-HSI system, escalating drug doses were printed on the substrate. After spectral pre-treatments, including standard normal variate (SNV) and Savitzky-Golay filtering for noise reduction and enhancement of spectral features, principal component analysis (PCA) and partial least squares (PLS) regression were applied to create predictive models for the quantification of independent printed metformin hydrochloride samples. It could be shown that the concentration distribution maps provided by the developed HSI models were capable of clustering and predicting the drug dose in the formulations. HSI model prediction showed significant better correlation to the reference (HPLC) compared to on-board monitoring of dispensed volume of the printer. Overall, the results emphasize the capability of NIR-HSI as a fast and non-destructive method for the quantification and quality control of the deposited API in drug-printing applications.

Fluidization characterization in the ConSigma 25 dryer via process data - A method of advanced quality assurance in continuous manufacturing.

Wet granulation lines in pharmaceutical manufacturing facilities typically comprise a dryer that removes the excess moisture content after wet granulation. In this study, a semi-continuous dryer installed in the ConsiGma 25 wet granulation line was investigated. The goal was to highlight specific characteristics of this type of dryer, utilizing the available process data and the corresponding data obtained via material characterization. This paper addresses typical effects and issues associated with the dryer's setup and operation (e.g., unexpected cell temperature profiles, the effects of air flow and temperature on the granule properties, variations in the granule moisture between the dryer cells). Since in many situations the liquid-to-solid ratio is based on the properties of granules after the granulation step, the selection of inlet air flow rate and the inlet air temperature of the dryer as well as the overall line throughput (affecting the cell fill level in the dryer) are of particular interest from a practical point of view. This paper discusses these issues and provides suggestions on how to address them when setting up the process. A novel approach for characterizing the fluidization inside the dryer by means of quantifying the "smoothness" of the temperature profile is proposed. The paper should be viewed as a hands-on guideline, which highlights possible pitfalls during the process setup and offers solutions.

Deep convolutional neural networks: Outperforming established algorithms in the evaluation of industrial optical coherence tomography (OCT) images of pharmaceutical coatings.

This paper presents a novel evaluation approach for optical coherence tomography (OCT) image analysis of pharmaceutical solid dosage forms based on deep convolutional neural networks (CNNs). As a proof of concept, CNNs were applied to image data from both, in- and at-line OCT implementations, monitoring film-coated tablets as well as single- and multi-layered pellets. CNN results were compared against results from established algorithms based on ellipse-fitting, as well as to human-annotated ground truth data. Performance benchmarks used include, efficiency (computation speed), sensitivity (number of detections from a defined test set) and accuracy (deviation from the reference method). The results were validated by comparing the output of several algorithms to data manually annotated by human experts and microscopy images of cross-sectional cuts of the same dosage forms as a reference method. In order to guarantee comparability for all results, the algorithms were executed on the same hardware. Since modern OCT systems must operate under real-time conditions in order to be implemented in-line into manufacturing lines, the necessary steps are discussed on how to achieve this goal without sacrificing the algorithmic performance and how to tailor a deep CNN to cope with the high amount of image noise and alterations in object appearance. The developed deep learning approach outperforms static algorithms currently available in pharma applications with respect to performance benchmarks, and represents the next level in real time evaluation of challenging industrial OCT image data.

Can 3D printing of oral drugs help fight the current COVID-19 pandemic (and similar crisis in the future)?

The ongoing COVID-19 crisis has highlighted the importance of a robust drug supply chain which can be quickly and flexibly ramped up to produce life-saving drug treatments. 3D printing (3DP) of oral solid dosage forms (OSDF) could be a viable part of the emergency drug production response to support vulnerable patients in rural regions and other isolated locations. In the context of the current pandemic, the suitability of different 3DP technologies will depend on the physicochemical properties, unit dose strength and BCS classification of the repurposed drug compounds currently being trialed for COVID-19. Furthermore, the deployment strategy should focus on simplifying dosage forms and formulations, scaling down the size and complexity of the printing systems and real-time quality assurance via process analytical technologies (PAT).

Feeding of particle-based materials in continuous solid dosage manufacturing: a material science perspective.

The pharmaceutical industry today is experiencing a paradigm shift from batch to continuous manufacturing, which promises greater flexibility to target diverse populations, as well as more-consistent product quality to ensure best efficacy. However, shifting to continuous processing means that even basic process steps, such as feeding, can become unexpected but are crucially important. In this review, we will present the fundamental differences between dispensing (batch) and feeding (continuous) and how they impact the formulation design space. We will further outline our rational development approach, applicable to continuous unit operations in general, which includes standardized material and process characterization, as well as predictive modeling based on advanced, multidomain simulation tools.

Model-based approach to the design of pharmaceutical roller-compaction processes.

This work presents a new model based approach to process design and scale-up within the same equipment of a roller compaction process. The prediction of the operating space is not performed fully in-silico, but uses low-throughput experiments as input. This low-throughput data is utilized in an iterative calibration routine to describe the behavior of the powder in the roller compactor and improves the predictive quality of the mechanistic models at low and high-throughput. The model has been validated with an experimental design of experiments of two ibuprofen formulations. The predicted sweet spots in the operating space are in good agreement with the experimental results.

Measurement of residence time distributions and material tracking on three continuous manufacturing lines.

Over the recent decade, benefits of continuous manufacturing (CM) of pharmaceutical products have been acknowledged widely. In contrast to batch processes, the product is not physically separated into batches in CM, which creates a few challenges. Product release is done for batches that should have a uniform quality over time, materials need to be tracked along the line, and locations to reject product must be established. To enable these, the residence time distributions (RTDs) of all unit operations must be known. In this paper, three CM tableting lines, each employing a different granulation technique, were investigated. The RTDs of their main unit operations were characterized, utilizing different measurement techniques successfully. All of these RTD measurement techniques could have been performed in any of the lines. The differences were related to the techniques themselves. Overall, external tracer with in-line Near-Infrared detection or color tracer with video recording proved most usable techniques, with few limitations. The RTDs for full lines were calculated by convoluting the unit operation RTDs, which enables material tracking through entire lines. The lines exhibited both truly continuous and quasi-continuous unit operations. Quasi-continuous unit operations divide the material stream into lots that can be utilized for tracking and rejection.

Key acceptability attributes of orodispersible films.

The features rendering orodispersible films (ODFs) patient-centric formulations are widely discussed in the scientific literature. However there is a lack of research studies exploring ODF characteristics with a potential impact on end-user acceptability. The aim of this study was to identify the key ODF characteristics affecting end-user acceptability by developing in vitro test methods for the prediction of ODFs acceptability and correlate these formulation characteristics with the data obtained from a human panel study. Four drug-free single-polymer films were prepared by solvent casting. Solutions of poly(vinyl) alcohol (PVOH) 39 KDa (P1), PVOH 197 KDa (P2), carboxymethylcellulose (CMC) 395 KDa (C1), and CMC 725 KDa (C2) were prepared. Texture analysis and Dynamic Mechanical Analysis (DMA) were used to assess film tack. Petri dish and drop methods were used to assess disintegration time. A human panel of 24 healthy young adults was employed to identify end-user acceptability criteria of the four study film samples. Texture analysis data of ODF tack were not found to be in agreement with the in vivo perceived stickiness in the mouth. However, measurement of the area under the adhesive force curve obtained by DMA correlated with in vivo perceived stickiness data for all samples. The disintegration times obtained by drop method were more comparable to human panel data than the petri dish method. Hence DMA and drop methods proved to be promising methodologies for the prediction of the end-user acceptability. The type and molecular weight of the film-forming polymer had a strong influence on stickiness perception, whereas only polymeric molecular weight influenced perceived disintegration time. The human panel study showed that Participant Reported Outcomes (PROs) for the perceived stickiness in the mouth and disintegration time of test films received significantly different scores between samples, and thus were identified as the key attributes with the potential to affect the end-user acceptability. ODF stickiness and disintegration time should therefore be evaluated at an early stage of the drug product design.

Orodispersible films: Towards drug delivery in special populations.

Orodispersible films (ODF) hold promise as a novel delivery method, with the potential to deliver tailored therapies to different patient populations. This article reviews the current strides of ODF technology and some of its unmet quality and manufacturing aspects. A topic highlights opportunities and limitations of inkjet printed ODF as a population-specific drug delivery. Overall, this article aims to stimulate further research to fill the current knowledge gap between manufacturing and administration requirements of ODF targeting specific patient subpopulations such as geriatrics.

Three-dimensional printing of the retina.

PURPOSE OF REVIEW: Biological three-dimensional printing has received a lot of media attention over recent years with advances made in printing cellular structures, including skin and heart tissue for transplantation. Although limitations exist in creating functioning organs with this method, the hope has been raised that creating a functional retina to cure blindness is within reach. The present review provides an update on the advances made toward this goal. RECENT FINDINGS: It has recently been shown that two types of retinal cells, retinal ganglion cells and glial cells, can be successfully printed using a piezoelectric inkjet printer. Importantly, the cells remained viable and did not change certain phenotypic features as a result of the printing process. In addition, recent advances in the creation of complex and viable three-dimensional cellular structures have been made. SUMMARY: Some first promising steps toward the creation of a functional retina have been taken. It now needs to be investigated whether recent findings can be extended to other cells of the retina, including those derived from human tissue, and if a complex and viable retinal structure can be created through three-dimensional printing.

Printing stable liquid tracks on a surface with finite receding contact angle.

We have used high-speed imaging to study the formation of liquid tracks on a surface with nonzero receding contact angle, by the sequential deposition of liquid drops. For small drop spacing we found good agreement with the track morphology predicted by an existing line stability model. In addition, we confirmed definitively the preferential drop-to-bead fluid flow and the predicted drop spreading variation in the scalloped line and paired bead formation regimes. However, we found that without accounting for drop impact inertia, the model underestimated the maximum drop spreading radii and, hence, the instantaneous track width. In addition, the printed track became stable at larger drop spacing, in contrast to the expected behavior. We believe that the destabilizing effect of a receding contact line may be minimized when track radii, as predicted by volume conservation and drop-bead coalescence dynamics, converge as the drop spacing increases. An increase in viscous dissipation and a reduction of the capillary-driven flow may be the additional stabilization mechanisms. The latter may also be responsible for achieving a stable and symmetrical track when printing with a shorter interval (higher print frequency) at a given drop spacing.

Adult rat retinal ganglion cells and glia can be printed by piezoelectric inkjet printing.

We have investigated whether inkjet printing technology can be extended to print cells of the adult rat central nervous system (CNS), retinal ganglion cells (RGC) and glia, and the effects on survival and growth of these cells in culture, which is an important step in the development of tissue grafts for regenerative medicine, and may aid in the cure of blindness. We observed that RGC and glia can be successfully printed using a piezoelectric printer. Whilst inkjet printing reduced the cell population due to sedimentation within the printing system, imaging of the printhead nozzle, which is the area where the cells experience the greatest shear stress and rate, confirmed that there was no evidence of destruction or even significant distortion of the cells during jet ejection and drop formation. Importantly, the viability of the cells was not affected by the printing process. When we cultured the same number of printed and non-printed RGC/glial cells, there was no significant difference in cell survival and RGC neurite outgrowth. In addition, use of a glial substrate significantly increased RGC neurite outgrowth, and this effect was retained when the cells had been printed. In conclusion, printing of RGC and glia using a piezoelectric printhead does not adversely affect viability and survival/growth of the cells in culture. Importantly, printed glial cells retain their growth-promoting properties when used as a substrate, opening new avenues for printed CNS grafts in regenerative medicine.

Intramarrow bone morphogenetic protein 4 gene delivery enhances early implant stability in femurs of ovariectomized rabbits.

BACKGROUND: Sufficient early implant stability is critical to prevent excessive micromovement of the implant during peri-implant healing and to ensure the success of osseointegration. Implants placed in osteoporotic bones are often associated with low early implant stability. The purpose of this study is to determine the effects of intramarrow bone morphogenetic protein 4 (BMP4) gene delivery on early implant stability and peri-implant healing. METHODS: Adenoviruses encoding human BMP4 or LacZ were introduced into the femoral osteotomy sites immediately before implant placement in ovariectomized rabbits. The implant stability was determined by resonance frequency analysis at weeks 0, 4, and 8. Changes in cortical bone thickness and intrascrew bone formation at weeks 4 and 8 were evaluated by microcomputed tomography analysis and undecalcified histologic examination, respectively. RESULTS: Intramarrow BMP4 gene delivery resulted in more improvement in implant stability at both weeks 4 and 8. Increased increment in peri-implant cortical bone thickness and better intrascrew bone formation were found in the BMP4 group compared to the LacZ group. CONCLUSION: The results of this study suggest that intramarrow adenoviral gene delivery of BMP4 enhances peri-implant bone healing and improves early implant stability in osteoporotic rabbit femurs.

Intramarrow bone morphogenetic protein 4 gene delivery improves local bone quality in femurs of ovariectomized rabbits.

BACKGROUND: Poor bone quality at implant recipient site is a major risk factor for implant failure. The purpose of this study is to examine the potential of intramarrow bone morphogenetic protein 4 (BMP4) gene delivery for local bone quality improvement. METHODS: Adenoviral vector encoding human BMP4 (Ad-BMP4) was constructed. Adenovirus encoding ß-galactosidase (Ad-LacZ) was used as a control virus. Ad-BMP4 and Ad-LacZ were injected into femurs of ovariectomized rabbits. The temporal changes in bone mineral density at injected areas were determined by repeated measurements by dual-energy x-ray absorptiometry at 0, 1, 2, 4, and 8 weeks after injection. The effects of gene delivery on cortical bone and cancellous bone were evaluated by microcomputed tomography analysis and histologic examination at 8 weeks. RESULTS: The bone mineral density of the BMP4 group was significantly higher than the LacZ group at 4 and 8 weeks by 61% and 35%, respectively. Results from microcomputed tomography analysis and histologic examination at 8 weeks indicated thicker cortical bone and denser cancellous bone in the BMP4 group compared to the LacZ group. CONCLUSIONS: Intramarrow gene delivery of BMP4 effectively improved local bone quality for at least 8 weeks. The sustained delivery of osteogenic factors via local gene therapy approach may reduce implant failures associated with poor local bone quality.