Formulation Design Research Articles

Impact of vaccination with the Anaplasma phagocytophilum MSP4 chimeric antigen on gene expression in the rabbit host

There are currently no vaccines available to prevent and control of Anaplasma phagocytophilum, an intracellular bacterial pathogen transmitted by ticks that occurs in many regions of the world and causes disease in a wide range of domestic and wild hosts, including humans. Vaccines induce long-lasting immunity and could prevent or reduce transmission of this pathogen.Understanding how vaccines induce a protective response can be difficult due to the complexity of the immune system, which operates at many levels throughout the organism. New perspectives in vaccinology, based on systems biology approaches, integrate many scientific disciplines to fully understand the biological responses to vaccination, where a transcriptomic approach could reveal relevant information of the host immune system, allowing profiling for rational design of vaccine formulations, administration, and potential protection.In the present study we report the gene expression profiles by RNA-seq followed by functional analysis using whole blood samples from rabbits immunized with a recombinant chimeric protein containing peptides from the MSP4 protein of A. phagocytophilum, which showed satisfactory results in terms of potential protection. Transcriptomic analysis revealed differential expression of 720 genes, with 346 genes upregulated and 374 genes downregulated. Overrepresentation of biological and metabolic pathways correlated with immune response, protein signaling, cytoskeleton organization and protein synthesis were found. These changes in gene expression could provide a complete and unique picture of the biological response to the epitope candidate vaccine against A. phagocytophilum in the host.

Effect of different food matrices on the bioaccessibility of vitamin D3 in beverage systems: Comparison between juice and liquid milk

Vitamin D plays a crucial role in bone, immunology, and neurophysiological functions but has inadequate bioavailability in the human body. In this paper, six different liquid beverages were used for vitamin D3 fortification, investigating the effect of different food matrices on the bioaccessibility of vitamin D. Not from concentrate (NFC) apple juice (9.34%) and NFC orange juice (8.12%) presented about 20% higher bioaccessibility of vitamin D3 than soybean and skim milk, and achieved a similar value of whole milk (8.04%). Meanwhile, the bioaccessibility of NFC apple and orange juice was markedly about 120% higher than that of apple clear juice. From the correlation analysis, the bioaccessibility of VD3 indicated significant correlations with small intestine retention (0.82) and viscosity (0.66). But small intestinal particle size showed a negative effect on bioaccessibility (−0.78). Therefore, food components, delivery matrices, and physicochemical properties of digesta were key factors to achieve higher bioaccessibility for guiding formulation design.

Replication in random translation designs

Replication is a commonly recommended feature of experimental designs. However, its impact in model-robust design is relatively under-explored; indeed, replication is impossible within the current formulation of random translation designs, which were introduced recently for model-robust prediction. Here we extend the framework of random translation designs to allow replication, and quantify the resulting performance impact. The extension permits a simplification of our earlier heuristic for constructing random translation strategies from a traditional V-optimal design. Namely, in the previous formulation any replicates of the V-optimal design first had to be split up before a random translation can be applied to the design points. With the new framework we can instead preserve the replicates instead if we so wish. Surprisingly, we find that in low-dimensional problems it is often substantially more efficient to continue to split replicates, while in high-dimensional problems it can be substantially better to retain replicates.

Vat photopolymerization of silica reinforced styrene-butadiene rubber elastomeric nanocomposites

Compared to their unfilled counterparts, elastomeric nanocomposites offer tailorable combinations of properties, including improved mechanical properties, increased durability, and enhanced thermal and electrical conductivity. However, the high viscosity caused by the presence of both the high molecular weight elastomer and the inclusion of fillers complicates additive manufacturing (AM) of elastomeric nanocomposites. This is especially challenging in vat photopolymerization (VP) AM, which requires resins that possess low viscosity (< 10 Pa·s) and exhibit sufficient storage modulus (∼ 104 Pa) when photocured. To address this process limitation, the authors have previously demonstrated decoupling the relationship between viscosity and molecular weight via VP of a photocurable composite latex resin. In this approach, a photocurable matrix is photocured as a scaffold around the latex particles, which provides sufficient modulus for the printed "green" part. Following a dehydration post-processing step, the latex particles coalesce to provide the final elastomeric mechanical properties without compromising feature resolution.In this work, the authors explore the effects of the addition of silica nanoparticles (10, 15, and 20 wt.%) on (i) the printability of photocurable styrene-butadiene rubber (SBR) latex resin and (ii) the mechanical properties of the resultant printed composites. The printable photocurable silica-SBR colloidal resin is realized by balancing the viscosity of the resin, the modulus of the cured green body, the silica nanoparticles content for reinforcement, and the high SBR content for elastomeric behavior. Specifically, the photocurable colloidal resin's viscosity is controlled by formulation design, while high silica nanoparticle content in the final part is achieved through evaporation of unreactive diluent. Characterization of the printed SBR nanocomposites with 20 wt.% silica reinforcement elucidated significant enhancements in the tensile strength (53 % increase), Young's modulus (671 % increase), and Shore A hardness (108 % increase) compared to printed SBR without filler reinforcement. To the authors' knowledge, this is the first report of 3D printing rubber nanocomposite using VP.

Assessing the Compatibility of Menatetrenone with Excipients: A Spectroscopic Approach and Implication in Drug Formulation Development.

An experiment was conducted to evaluate the compatibility of menatetrenone with selected pharmaceutical excipients. Fourier Transform Infrared Spectroscopy (FTIR) was used to assess drug-excipient compatibility. The present research systematically investigates the FTIR spectrum of each chemical compound separately and their physical blends, analyzing for possible shifts, alterations or novel peak that may indicate chemical interactions. This study aims to utilize spectral data interpretation to detect potential compatibility problems that may occur while design and production of menatetrenone containing dosage forms ensuring their increased stability and effectiveness. The FTIR results demonstrated that all the pharmaceutical excipients were compatible with menatetrenone. In conclusion, the compatibility of pharmaceutical excipients with menatetrenone was successfully assessed using FTIR that will aid in future design of formulations containing menatetrenone as therapeutic moiety.

Mechanism, Formulation, and Efficacy Evaluation of Natural Products for Skin Pigmentation Treatment.

Skin pigmentation typically arises from the excessive secretion and accumulation of melanin, resulting in a darker complexion compared to normal skin. Currently, the local application of chemical drugs is a first-line strategy for pigmentation disorders, but the safety and efficacy of drugs still cannot meet clinical treatment needs. For long-term and safe medication, researchers have paid attention to natural products with higher biocompatibility. This article begins by examining the pathogenesis and treatment approaches of skin pigmentation diseases and summarizes the research progress and mechanism of natural products with lightening or whitening effects that are clinically common or experimentally proven. Moreover, we outline the novel formulations of natural products in treating pigmentation disorders, including liposomes, nanoparticles, microemulsions, microneedles, and tocosomes. Finally, the pharmacodynamic evaluation methods in the study of pigmentation disorder were first systematically analyzed. In brief, this review aims to collect natural products for skin pigmentation treatment and investigate their formulation design and efficacy evaluation to provide insights for the development of new products for this complex skin disease.

Smart Polymer Systems: A Futuristic Approach to Enhance Therapeutic Efficacy

Abstract: Recently, pharmaceutical industries have placed considerable emphasis on formulating drug delivery systems that precisely target specific sites, optimize drug utilization, minimize excipient usage, and mitigate side effects. Smart polymers hold tremendous promise in the design of innovative formulations tailored to deliver drugs with enhanced precision, efficacy, and therapeutic benefits while minimizing adverse effects. Within drug delivery, smart polymers demonstrate exceptional potential in achieving controlled and targeted release profiles, ensuring drug delivery to specific receptors, and minimizing offtarget effects. This comprehensive review article focuses on the latest developments in smart polymers, primarily in the domains of drug delivery. By intelligently responding to external stimuli, smart polymer-based materials offer various applications, making them pivotal in modern pharmaceutical research. By utilizing the remarkable attributes of smart polymers, researchers and industry stakeholders can forge a path toward personalized, efficient, and patient-centric therapies with reduced side effects, propelling the pharmaceutical field into an era of unprecedented advancements.

Advancing Ocular Medication Delivery with Nano-Engineered Solutions: A Comprehensive Review of Innovations, Obstacles, and Clinical Impact.

Recent advancements in ocular drug delivery have led to the introduction of a range of nanotechnology-based systems, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, inorganic nanoparticles, niosomes, liposomes, nanosuspensions, dendrimers, nanoemulsions, and microemulsions. These systems enhance drug retention, penetration, bioavailability, and targeted delivery, promising prolonged drug release, and improved patient compliance. However, their interactions with biological systems pose potential toxicity risks, necessitating a careful evaluation of nanoparticle size, shape, surface charge, and coating. Traditional ocular drug delivery methods, like topical applications and injections, face challenges due to anatomical and physiological barriers, leading to frequent dosing and systemic toxicity risks. Nanocarriers offer solutions by improving drug permeation and targeted delivery, yet translating these innovations from research to clinical practice involves overcoming hurdles related to manufacturing scale-up, quality control, regulatory approval, and cost-effectiveness. The quality by design (QbD) framework provides a systematic approach to optimize nanocarrier formulation and process design, ensuring safety and efficacy. Assessing the safety of nanocarriers through in vivo and in vitro studies is crucial for their clinical application. This review explores the use of various nanomedicines in ocular drug delivery, highlighting the current state of ocular medication delivery and considering critical aspects such as scaling up and clinical applications.

Biological Fate Tracking of Nitric Oxide-Propelled Microneedle Delivery System Using an Aggregation-Caused Quenching Probe.

Nanoparticle-loaded dissolving microneedles (DMNs) have attracted increasing attention due to their ability to provide high drug loading, adjustable drug release behavior, and enhanced therapeutic efficiency. However, such delivery systems still face unsatisfied drug delivery efficiency due to insufficient driving force to promote nanoparticle penetration and the lack of in vivo fate studies to guide formulation design. Herein, an aggregation-caused quenching (ACQ) probe (P4) was encapsulated in l-arginine (l-Arg)-based nanomicelles, which was further formulated into nitric oxide (NO)-propelled nanomicelle-integrated DMNs (P4/l-Arg NMs@DMNs) to investigate their biological fate. The P4 probe could emit intense fluorescence signals in intact nanomicelles, while quenching with the dissociation of nanomicelles, providing a "distinguishable" method for tracking the fate of nanomicelles at a different status. l-Arg was demonstrated to self-generate NO under the tumor microenvironment with excessive reactive oxygen species (ROS), providing a pneumatic force to promote the penetration of nanomicelles in both three-dimensional (3D)-cultured tumor cells and melanoma-bearing mice. Compared with passive microneedles (P4 NMs@DMNs) without a NO propellant, the P4/l-Arg NMs@DMNs possessed a good NO production performance and higher nanoparticle penetration capacity. In conclusion, this study offered an ACQ probe-based biological fate tracking approach to demonstrate the potential of NO-propelled nanoparticle-loaded DMNs in penetration enhancement for topical tumor therapy.

Optimization of mechanical and safety properties by designing interface characteristics within energetic composites

The interfacial structure has an important effect on the mechanical properties and safety of the energetic material. In this work, a mesostructure model reflecting the real internal structure of PBX is established through image digital modeling and vectorization processing technology. The microscopic molecular structure model of PBX is constructed by molecular dynamics, and the interface bonding energy is calculated and transferred to the mesostructure model. Numerical simulations are used to study the influence of the interface roughness on the dynamic compression and impact ignition response of PBX, and to regulate and optimize the mechanical properties and safety of the explosive to obtain the optimal design of the surface roughness of the explosive crystal. The results show that the critical hot spot density of PBX ignition under impact loading is 0.68 mm−2. The improvement of crystal surface roughness can improve the mechanical properties of materials, but at the same time it can improve the impact ignition sensitivity and reduce the safety of materials. The optimal friction coefficient range for the crystal surface that satisfies both the mechanical properties and safety of PBX is 0.06–0.12. This work can provide a reference basis for the formulation design and production processing of energetic materials.

Fortification of local fruit parijoto on soy yogurt drink and economy analysis

Background: The food and beverage industry is a leading industry that is the government's focus in the Industrial Revolution 4.0. Culinary is the most popular economic sub-sector.. As a food product from biotechnology, yoghurt always manages to occupy a global market share. Yoghurt is proven to maintain the digestive system. Therefore innovation is needed, especially regarding materials, to boost product competitiveness. Animal milk substrate can be substituted with soy milk which is cheap but rich in protein. The addition of natural fortification is projected to improve product quality. Parijoto fruit (Medinilla speciosa) typical of the slopes of Mount Muria, Colo Village, Kab. Kudus was chosen as a fortificant because it is rich in antioxidants and antibacterial pathogens. At the same time, this adds to the usability and economic value of Parijoto, which is still low so far. Method: The research was conducted experimentally, referring to previous research methods. The formulation design was varied regarding adding Parijoto fruit extract to 100 ml of the product. Findings: From the results of the organoleptic test, the F1 formula (addition of 5 ml of Parijoto fruit extract) received the best acceptance from the panellists, with a preference level of 4.89. The product characteristics are liquid texture, alcoholic sweet taste, cream colour, and the aroma of Parijoto fruit tends to be faint. Conclusion:Parijoto Yogurt has advantages in terms of locality, price and nutrition. However, further research is needed based more collaboration to increase this product's health and economic impact local society. Novelty/Originality of this article: This study creates new functional food products and opens up opportunities to revitalize local economies and conserve biodiversity.

COSMOPharm: Drug-Polymer Compatibility of Pharmaceutical Amorphous Solid Dispersions from COSMO-SAC.

The quantum mechanics-aided COSMO-SAC activity coefficient model is applied and systematically examined for predicting the thermodynamic compatibility of drugs and polymers. The drug-polymer compatibility is a key aspect in the rational selection of optimal polymeric carriers for pharmaceutical amorphous solid dispersions (ASD) that enhance drug bioavailability. The drug-polymer compatibility is evaluated in terms of both solubility and miscibility, calculated using standard thermodynamic equilibrium relations based on the activity coefficients predicted by COSMO-SAC. As inherent to COSMO-SAC, our approach relies only on quantum-mechanically derived σ-profiles of the considered molecular species and involves no parameter fitting to experimental data. All σ-profiles used were determined in this work, with those of the polymers being derived from their shorter oligomers by replicating the properties of their central monomer unit(s). Quantitatively, COSMO-SAC achieved an overall average absolute deviation of 13% in weight fraction drug solubility predictions compared to experimental data. Qualitatively, COSMO-SAC correctly categorized different polymer types in terms of their compatibility with drugs and provided meaningful estimations of the amorphous-amorphous phase separation. Furthermore, we analyzed the sensitivity of the COSMO-SAC results for ASD to different model configurations and σ-profiles of polymers. In general, while the free volume and dispersion terms exerted a limited effect on predictions, the structures of oligomers used to produce σ-profiles of polymers appeared to be more important, especially in the case of strongly interacting polymers. Explanations for these observations are provided. COSMO-SAC proved to be an efficient method for compatibility prediction and polymer screening in ASD, particularly in terms of its performance-cost ratio, as it relies only on first-principles calculations for the considered molecular species. The open-source nature of both COSMO-SAC and the Python-based tool COSMOPharm, developed in this work for predicting the API-polymer thermodynamic compatibility, invites interested readers to explore and utilize this method for further research or assistance in the design of pharmaceutical formulations.

Design of multicomponent thermosetting polymers with enhanced tensile properties through active learning

Multicomponent thermosets can simultaneously achieve high strength, modulus, and toughness inaccessible by single-component materials, but efficiently designing those with exceptional mechanical properties relies on serendipity because knowledge-guided methodologies often fail in high-dimensional spaces and multi-objective problems. We proposed a multi-objective Bayesian-optimization-based active learning method enhanced by a dual-driver acquisition function to accelerate the formulation design of multicomponent epoxy resins. After several iterative experiments, we identified a multicomponent formulation of ultra-strong and high-tough samples that was much better than currently available epoxy resins. The molecular dynamic simulations and synchrotron radiation wide-angle X-ray scattering revealed that the exceptional mechanical properties of multicomponent thermosetting polymers originate from the larger meshes of crosslinking networks and the homogeneity of cured structures. The closed-loop, dual-driver Bayesian optimization strategy can be generalized for the fast discovery of high-performance materials that involve time-intensive experiments and multi-dimensional parameter spaces.

Molecular dynamics study on the physical compatibility of SEBS/plasticizer blend systems.

Thermoplastic elastomer styrene-ethylene-butylene-styrene block copolymer (SEBS) has excellent mechanical properties and aging resistance, so it has good application prospects in thermoplastic solid propellants. The selection of plasticizer is one of the keys to the formulation design of thermoplastic solid propellant. The compatibility of the plasticizer with the polymer determines the plasticizer's ability to plasticize the polymer's molecular chain segments. Herein, the compatibility of four plasticizers with SEBS was investigated, and the results declared that the order of compatibility between SEBS and the four plasticizers is SEBS/WO > SEBS/DOS > SEBS/DEP > SEBS/TA. Physical compatibility of SEBS binder with plasticizer triacetin (TA), diethyl phthalate (DEP), dioctyl sebacate (DOS), and 26# industrial white oil (WO) was simulated using molecular dynamics (MD) method via Materials Studio 8.0, and the simulation results were verified experimentally. The results showed that the compatibility of SEBS with these plasticizers can be comprehensively evaluated by analyzing solubility parameters, radial distribution functions, and blend miscibility simulations.

Examine stability polyvinyl alcohol-stabilized nanosuspensions to overcome the challenge of poor drug solubility utilizing molecular dynamic simulation

The pharmaceutical industry faces a significant challenge from the low water solubility of nearly 90% of newly developed Active Pharmaceutical Ingredients (APIs). Despite extensive efforts to improve solubility, approximately 40% of these APIs encounter commercialization hurdles, impacting drug efficacy. In this context, a promising strategy will be introduced in which nanosuspensions, particularly polyvinyl alcohol (PVA) as a stabilizer, are applied to increase drug solubility. In this work using molecular dynamics simulations, the nanosuspension of four poorly water-soluble drugs (flurbiprofen, bezafibrate, miconazole, and phenytoin) stabilized with PVA is investigated. The simulation data showed van der Waals energies between polyvinyl alcohol with flurbiprofen and bezafibrate are − 101.12 and − 58.42 kJ/mol, respectively. The results indicate that PVA is an effective stabilizer for these drugs, and superior interactions are obtained with flurbiprofen and bezafibrate. The study also explores the impact of PVA on water molecule diffusion, providing insights into the stability of nanosuspensions. Obtained results also provide valuable insights into hydrogen bond formation, diffusion coefficients, and nanosuspension stability, contributing to the rational design and optimization of pharmaceutical formulations.

Effects of different natural soundscapes on human psychophysiology in national forest park

Most of the current soundscape research content is limited to the discussion of the restoration effect of single-element soundscapes, but it is the combination of sounds that is common in outdoor activities, and there is no evidence that the restoration of natural soundscapes is better with multi-element combinations. In this study, the Zhangjiajie National Forest Park in China was used as the research object, and the physiological indices of the subjects were collected through electroencephalogram signals, and the POMS short-form psychological scale was used to understand the subjective psychological responses of the subjects to the soundscape. The results showed that (1) The psychophysiological restorative ability of the natural soundscape of the National Forest Park was confirmed, and the subjects’ psychological and physiological indices changed significantly and positively after listening to each section of the natural soundscape (p = 0.001). (2) The restorative effect of the multi-natural sound combination was ranked first in the overall ranking of the five natural soundscapes, and the multi-natural sound combination did indeed provide better restorative effects than the single-element sounds. (3) Gender does not usually have a significant effect on the restoration effect, and only Windy Sound among the four single-element nature sound landscapes and one multi-element combination of nature sound landscapes showed a significant gender difference, so in general, the effect of gender on the restoration effect of nature sound landscapes is not significant. In terms of research methodology, this study used cluster analysis to cluster the five types of natural soundscapes according to psychological and physiological recovery ability, and used ridge regression to construct mathematical models of the psychological and physiological recovery of each of the four natural soundscapes. The study of human physiological and psychological recovery from different types of natural soundscapes in China’s national forest parks will provide a basis for soundscape planning, design, and policy formulation in national forest parks.

Cocrystal formulation design of 4-Aminosalicylic acid and isoniazid via spray-drying based on a ternary phase diagram toward simultaneous pulmonary delivery

Cocrystal engineering is a potent strategy for enhancing drug properties, but its application in spray-drying has been limited. Furthermore, concurrently introducing two drugs and realizing simultaneous pharmacological effects at the target site is challenging. This is particularly evident for oral formulations designed for systemic use, but the local administration of drugs at the target site displays the potential to overcome this problem. Herein, we investigated the potential of cocrystallization principles for use in developing dry powder inhaler formulations of anti-tuberculosis drugs. We focused on the formation of cocrystals of 4-aminosalicylic acid (PAS) and isoniazid (INH), which are crucial components of tuberculosis treatment. Via spray-drying, we successfully produced spray-dried particles of PAS-INH that exhibited hydrogen bonding interactions between the molecules. Aerosolization performance evaluation with an Andersen Cascade Impactor (ACI) confirmed the concurrent deposition of both drugs, highlighting the potential of our particle design for use in the co-delivery of PAS-INH. Furthermore, simulated lung dissolution studies using the ACI and Transwell inserts revealed synchronized dissolution patterns, indicating promising prospects for use in effective drug delivery. This innovative approach to tuberculosis therapy has significant implications for improving treatment efficacy and enhancing patient adherence, potentially revolutionizing tuberculosis treatment.

Smarter facility layout design: leveraging worker localisation data to minimise travel time and alleviate congestion

This paper introduces a novel methodology leveraging worker localisation data from ultrawide-band sensors to formulate alternative facility layouts aimed at minimising travel time and congestion in labour-intensive manufacturing systems. The system preprocesses sensor data to discern flow patterns between existing stations within the production facility, such as machine tools, workbenches, and stores. This information about the movement of people and materials informs the generation of optimised layouts through scenario-based optimisation. We explored two methods to devise these new layouts: a mixed-integer linear programming method and a simulated annealing metaheuristic, the latter being specifically developed to find high-quality solutions to the quadratic layout design formulation. Both methods employ biobjective formulations, focussing on the minimisation of travel time and the reduction of congestion risk on the manufacturing floor, an aspect often neglected in prior studies. Our methodology, applied to a real-world manual assembly line case study, demonstrated the potential to reduce travel time by a minimum of 32% and alleviate congestion while maintaining significant safety distances between facilities. This was achieved by automatically identifying design features that position high-traffic facilities closely and align them to eliminate movement overlaps.

Fractional-Order Robust Control Design under parametric uncertain approach

This paper presents a novel methodology that combines fractional-order control theory with robust control under a parametric uncertainty approach to enhance the performance of linear time-invariant uncertain systems with integer or fractional order, referred to as Fractional-Order Robust Control (FORC). In contrast to traditional approaches, the proposed methodology introduces a novel formulation of inequalities-based design, thus expanding the potential for discovering improved solutions through linear programming optimization. As a result, fractional order controllers are designed to guarantee desired transient and steady-state performance in a closed-loop system. To enable the digital implementation of the designed controller, an impulse response invariant discretization of fractional-order differentiators (IRID-FOD) is employed to approximate the fractional-order controllers to an integer-order transfer function. Additionally, Hankel’s reduction order method is applied, thus making it suitable for hardware deployment. Experimental tests carried out in a thermal system and the assessment results, based on time-domain responses and robustness analysis supported by performance indices and set value analysis in a thermal system test-bed, demonstrate the improved and robust performance of the proposed FORC methodology compared to classical robust control under parametric uncertainty.

Optimal Design of Plane Elastic Membranes Using the Convexified Föppl’s Model

This work puts forth a new optimal design formulation for planar elastic membranes. The goal is to minimize the membrane’s compliance through choosing the material distribution described by a positive Radon measure. The deformation of the membrane itself is governed by the convexified Föppl’s model. The uniqueness of this model lies in the convexity of its variational formulation despite the inherent nonlinearity of the strain–displacement relation. It makes it possible to rewrite the optimization problem as a pair of mutually dual convex variational problems. The primal variables are displacement functions, whilst in the dual one seeks stresses being Radon measures. The pair of problems is analysed: existence and regularity results are provided, together with the system of optimality criteria. To demonstrate the computational potential of the pair, a finite element scheme is developed around it. Upon reformulation to a conic-quadratic & semi-definite programming problem, the method is employed to produce numerical simulations for several load case scenarios.