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Acta Biomaterialia Sep 2023Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate...
Matrix mechanics regulate essential cell behaviors through mechanotransduction, and as one of its most important elements, substrate stiffness was reported to regulate cell functions such as viability, communication, migration, and differentiation. Neutrophils (Neus) predominate the early inflammatory response and initiate regeneration. The activation of Neus can be regulated by physical cues; however, the functional alterations of Neus by substrate stiffness remain unknown, which is critical in determining the outcomes of engineered tissue mimics. Herein, a three-dimensional (3D) culture system made of hydrogels was developed to explore the effects of varying stiffnesses (1.5, 2.6, and 5.7 kPa) on the states of Neus. Neus showed better cell integrity and viability in the 3D system. Moreover, it was shown that the stiffer matrix tended to induce Neus toward an anti-inflammatory phenotype (N2) with less adhesion molecule expression, less reactive oxygen species (ROS) production, and more anti-inflammatory cytokine secretion. Additionally, the aortic ring assay indicated that Neus cultured in a stiffer matrix significantly increased vascular sprouting. RNA sequencing showed that a stiffer matrix could significantly activate JAK1/STAT3 signaling in Neus and the inhibition of JAK1 ablated the stiffness-dependent increase in the expression of CD182 (an N2 marker). Taken together, these results demonstrate that a stiffer matrix promotes Neus to shift to the N2 phenotype, which was regulated by JAK1/STAT3 pathway. This study lays the groundwork for further research on fabricating engineered tissue mimics, which may provide more treatment options for ischemic diseases and bone defects. STATEMENT OF SIGNIFICANCE.
Topics: Bone Marrow; Neutrophils; Mechanotransduction, Cellular; Hydrogels; Cell Differentiation
PubMed: 37467837
DOI: 10.1016/j.actbio.2023.07.012 -
International Journal of Pharmaceutical... 2024Aspirin is a non-steroidal, anti-inflammatory drug used for a range of indications. For patients with aspirin hypersensitivities, a desensitization procedure may be...
Aspirin is a non-steroidal, anti-inflammatory drug used for a range of indications. For patients with aspirin hypersensitivities, a desensitization procedure may be prescribed, and the initial low doses of <81 mg need to be provided by compounded preparations. Compounding with aspirin is associated with stability challenges due to its poor chemical stability. Additionally, low-strength preparations often exhibit dosage accuracy and uniformity issues. This study was designed to assess the feasibility of compounding low-strength aspirin capsules for the use in desensitization protocols. Aspirin capsules of 40-mg, 10-mg, 3-mg, and 1-mg strengths were prepared by manual filling of dry powders. Formulations were kept as simple as possible for ease of compounding, and the ingredients and compounding procedures were carefully selected to minimize the moisture content and to optimize the dosage accuracy. For the 40-mg and 10-mg capsules, two formulations were tested, using pure drug or crushed tablet powder. For the 3-mg and 1-mg capsules, only one formulation was tested, using a 5% mixture of pure drug and cellulose. All formulations were filled into hydroxypropyl methylcellulose capsule shells and stored at room temperature for 90 days. A stability indicating, high-performance liquid chromatography method was used to analyze the quality of the capsules. The initial potency results of all capsule formulations were within 100% to 105% of the label claim, and the standard deviation was <3% for all formulations except the 1-mg strength (7%). The use of crushed tablet powder over pure drug powder appeared to reduce the potency variability, probably due to the larger fill weight per capsule. Upon storage at room temperature, the 40-mg and 10-mg formulations retained >90% of the label claim for up to 90 days, but the 3-mg and 1-mg formulations retained >90% of the label claim for up to only 31 days. Low-strength aspirin capsules were prepared successfully by compounding with a beyond-use date of at least 31 days at room temperature. However, the overall trend confirmed the challenges of achieving dosage uniformity and aspirin stability at 3-mg and 1-mg strengths. For general application in compounding pharmacies, trial batches are recommended with proper analytical testing.
Topics: Humans; Drug Compounding; Drug Stability; Aspirin; Powders; Tablets; Capsules
PubMed: 38306624
DOI: No ID Found -
Physical Chemistry Chemical Physics :... Aug 2023Multicompartment structures have the potential for biomedical applications because they can act as multifunctional systems and provide simultaneous delivery of drugs and... (Review)
Review
Multicompartment structures have the potential for biomedical applications because they can act as multifunctional systems and provide simultaneous delivery of drugs and diagnostics agents of different types. Moreover, some of them mimic biological cells to some extent with organelles as separate sub-compartments. This article analyses multicompartment colloidal structures with smaller sub-units covered with lipid or polymer membranes that provide additional protection for the encapsulated substances. Vesosomes with small vesicles encapsulated in the inner pools of larger liposomes are the most studied systems to date. Dendrimer molecules are enclosed by a lipid bilayer shell in dendrosomes. Capsosomes, polymersomes-in-polymer capsules, and cubosomes-in-polymer capsules are composed of sub-compartments encapsulated within closed multilayer polymer membranes. Janus or Cerberus emulsions contain droplets composed of two or three phases: immiscible oils in O/W emulsions and aqueous polymer or salt solutions that are separated into two or three phases and form connected droplets in W/O emulsions. In more cases, the external surface of engulfed droplets in Janus or Cerberus emulsions is covered with a lipid or polymer monolayer. eLiposomes with emulsion droplets encapsulated into a bilayer shell have been given little attention so far, but they have very great prospects. In addition to nanoemulsion droplets, solid lipid nanoparticles, nanostructured lipid carriers and inorganic nanoparticles can be loaded into eLiposomes. Molecular engineering of the external membrane allows the creation of ligand-targeted and stimuli-responsive multifunctional systems. As a result, the efficacy of drug delivery can be significantly enhanced.
Topics: Polymers; Emulsions; Capsules; Drug Delivery Systems; Lipid Bilayers
PubMed: 37565484
DOI: 10.1039/d3cp01984e -
Journal of Pharmaceutical Sciences Jul 2024The production of paediatric pharmaceutical forms represents a unique challenge within the pharmaceutical industry. The primary goal of these formulations is to ensure... (Review)
Review
The production of paediatric pharmaceutical forms represents a unique challenge within the pharmaceutical industry. The primary goal of these formulations is to ensure therapeutic efficacy, safety, and tolerability in paediatric patients, who have specific physiological needs and characteristics. In recent years, there has been a significant increase in attention towards this area, driven by the need to improve drug administration to children and ensure optimal and specific treatments. Technological innovation has played a crucial role in meeting these requirements, opening new frontiers in the design and production of paediatric pharmaceutical forms. In particular, three emerging technologies have garnered considerable interest and attention within the scientific and industrial community: 3D printing, prilling/vibration, and microfluidics. These technologies offer advanced approaches for the design, production, and customization of paediatric pharmaceutical forms, allowing for more precise dosage modulation, improved solubility, and greater drug acceptability. In this review, we delve into these cutting-edge technologies and their impact on the production of paediatric pharmaceutical forms. We analyse their potential, associated challenges, and recent developments, providing a comprehensive overview of the opportunities that these innovative methodologies offer to the pharmaceutical sector. We examine different pharmaceutical forms generated using these techniques, evaluating their advantages and disadvantages.
Topics: Printing, Three-Dimensional; Humans; Child; Microfluidics; Dosage Forms; Technology, Pharmaceutical; Pediatrics; Pharmaceutical Preparations; Drug Compounding; Chemistry, Pharmaceutical; Solubility
PubMed: 38582283
DOI: 10.1016/j.xphs.2024.04.001 -
International Journal of Biological... Dec 2023There are many studies on specific macromolecules and their contributions to tissue repair. Macromolecules have supporting and protective effects in organisms and can... (Review)
Review
There are many studies on specific macromolecules and their contributions to tissue repair. Macromolecules have supporting and protective effects in organisms and can help regrow, reshape, and promote self-repair and regeneration of damaged tissues. Macromolecules, such as proteins, nucleic acids, and polysaccharides, can be constructed into hydrogels for the preparation of slow-release drug agents, carriers for cell culture, and platforms for gene delivery. Hydrogels and microspheres are fabricated by chemical crosslinking or mixed co-deposition often used as scaffolds, drug carriers, or cell culture matrix, provide proper mechanical support and nutrient delivery, a well-conditioned environment that to promote the regeneration and repair of damaged tissues. This review provides a comprehensive overview of recent developments in the construction of macromolecules into hydrogels and microspheres based on the proteins, nucleic acids, polysaccharides and other polymer and their application in tissue repair. We then discuss the latest research trends regarding the advantages and disadvantages of these composites in repair tissue. Further, we examine the applications of microspheres/hydrogels in different tissue repairs, such as skin tissue, cartilage, tumor tissue, synovial, nerve tissue, and cardiac repair. The review closes by highlighting the challenges and prospects of microspheres/hydrogels composites.
Topics: Microspheres; Hydrogels; Nucleic Acids; Delayed-Action Preparations; Polysaccharides; Tissue Engineering; Tissue Scaffolds
PubMed: 37652329
DOI: 10.1016/j.ijbiomac.2023.126611 -
Drugs in R&D Sep 2023The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism.
OBJECTIVE
The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin.
METHODS
In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters.
RESULTS
The observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak (C: 2332 ± 950 pg/mL; T: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak (C: 1151 ± 565 pg/mL; T: 64.2 ± 44.2 min; p < 0.001 for comparison of C and T) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated.
CONCLUSIONS
The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form.
TRIAL REGISTRY
Registration number: NCT04574141.
Topics: Humans; Male; Biological Availability; Cross-Over Studies; Melatonin; Tablets; Volunteers; Administration, Oral; Area Under Curve
PubMed: 37438493
DOI: 10.1007/s40268-023-00431-9 -
International Journal of Nanomedicine 2023The aim of this study was to develop a liposome gel containing -tetrahydropalmatine (-THP) and evaluate its transdermal properties.
PURPOSE
The aim of this study was to develop a liposome gel containing -tetrahydropalmatine (-THP) and evaluate its transdermal properties.
METHODS
A L (4) orthogonal experiment was conducted to optimize the preparation of -THP liposomes and assess their characterization and stability in a gel. The transdermal features were analyzed through in vivo and in vitro experiments on rats and Strat-M membrane, respectively. The metabolism of -THP in liver and skin S9 fractions was also studied.
RESULTS
The optimization of the orthogonal experiment revealed that the ideal mass ratio of phosphatidylcholine, cholesterol, and -THP during preparation was 10:1:3. The resulting liposome exhibited a particle size of 68 nm, a PDI of 0.27, a drug loading of 4.33%, an encapsulation of 18.79%, and a zeta potential of -41.27 mV. Both the -THP and its liposome-gel formulation were found to be stable for a duration of 45 days at 4 °C and 30 °C. During the in vivo transdermal study, the maximum concentration (C) of -THP from the liposome gel was 0.16 μg/mL, and the time to reach this maximum concentration (t) was 1.2 hours. The relative bioavailability of -THP in the liposome gel was 233.8% compared to the emulsion. The concentration of -THP (prepared in PBS) decreased at a rate of 0.0067 μg/mL/min in the liver S9 fraction and 0.0027 μg/mL/min in the skin S9 fraction, however, this difference was not observed when -THP was encapsulated in liposomes. -THP passed through the Strat-M membrane at a rate of 0.0032 mg/cm/h and 0.002 mg/cm/h for the emulsion and liposome gel, respectively.
CONCLUSION
The optimal process for the preparation of -THP liposomes was obtained. Compared to the emulsion, the liposomes provided greater bioavailability when used transdermally. The liposomes also provided greater stability for -THP during storage.
Topics: Animals; Rats; Liposomes; Emulsions; Skin; Lecithins
PubMed: 37600118
DOI: 10.2147/IJN.S422305 -
Molecular Pharmaceutics Nov 2023Dry powder inhaler (DPI) products are commonly formulated as a mixture of micronized drug particles and large carrier particles, with or without additional fine particle... (Review)
Review
Dry powder inhaler (DPI) products are commonly formulated as a mixture of micronized drug particles and large carrier particles, with or without additional fine particle excipients, followed by final powder filling into dose containment systems such as capsules, blisters, or reservoirs. DPI product manufacturing consists of a series of unit operations, including particle size reduction, blending, and filling. This review provides an overview of the relevant critical process parameters used for jet milling, high-shear blending, and dosator/drum capsule filling operations across commonly utilized instruments. Further, this review describes the recent achievements regarding the application of empirical and mechanistic models, especially discrete element method (DEM) simulation, in DPI process development. Although to date only limited modeling/simulation work has been accomplished, in the authors' perspective, process design and development are destined to be more modeling/simulation driven with the emphasis on evaluating the impact of material attributes/process parameters on process performance. The advancement of computational power is expected to enable modeling/simulation approaches to tackle more complex problems with better accuracy when dealing with real-world DPI process operations.
Topics: Powders; Drug Compounding; Administration, Inhalation; Drug Carriers; Computer Simulation; Dry Powder Inhalers; Particle Size; Aerosols
PubMed: 37783568
DOI: 10.1021/acs.molpharmaceut.3c00557 -
International Journal of Pharmaceutics Nov 2023A compressed pharmaceutical oral solid dosage (OSD) form is a strongly micro-viscoelastic material composite arranged as a network of agglomerated particles due to its...
A compressed pharmaceutical oral solid dosage (OSD) form is a strongly micro-viscoelastic material composite arranged as a network of agglomerated particles due to its constituent powders and their bonding and fractural mechanical properties. An OSD product's Critical Quality Attributes, such as disintegration, drug release (dissolution) profile, and structural strength ("hardness"), are influenced by its micro-scale properties. Ultrasonic evaluation is direct, non-destructive, rapid, and cost-effective. However, for practical process control applications, the simultaneous extraction of the micro-viscoelastic and scattering properties from a tablet's ultrasonic response requires a unique solution to a challenging inverse mathematical wave propagation problem. While the spatial progression of a pulse traveling in a composite medium with known micro-scale properties is a straightforward computational task when its dispersion relation is known, extracting such properties from the experimentally acquired waveforms is often non-trivial. In this work, a novel Machine Learning (ML)-based micro-property extraction technique directly from waveforms, based on Multi-Output Regression models and Neural Networks, is introduced and demonstrated. Synthetic waveforms with a given set of micro-properties of virtual tablets are computationally generated to train, validate, and test the developed ML models for their effectiveness in the inverse problem of recovering specified micro-scale properties. The effectiveness of these ML models is then tested and demonstrated for a set of physical OSD tablets. The micro-viscoelastic and micro-structural properties of physical tablets with known properties have been extracted through experimentally acquired waveforms to exhibit their consistency with the generated ML-based attenuation results.
Topics: Technology, Pharmaceutical; Drug Compounding; Tablets; Pressure; Ultrasonics
PubMed: 37797783
DOI: 10.1016/j.ijpharm.2023.123477 -
Advances in Colloid and Interface... Nov 2023Although fat is one of the indispensable components of food flavor, excessive fat consumption could cause obesity, metabolism syndromes and an imbalance in the... (Review)
Review
Although fat is one of the indispensable components of food flavor, excessive fat consumption could cause obesity, metabolism syndromes and an imbalance in the intestinal flora. In the pursuit of a healthy diet, designing fat reducing foods by inhibiting lipid digestion and calorie intake is a promising strategy. Altering the gastric emptying rates of lipids as well as acting on the lipase by suppressing the enzymatic activity or limiting lipase diffusion via interfacial modulation can effectively decrease lipolysis rates. In this review, we provide a comprehensive overview of colloid-based strategies that can be employed to retard lipid hydrolysis, including pancreatic lipase inhibitors, emulsion-based interfacial modulation and fat substitutes. Plants-/microorganisms-derived lipase inhibitors bind to catalytic active sites and change the enzymatic conformation to inhibit lipase activity. Introducing oil-in-water Pickering emulsions into the food can effectively delay lipolysis via steric hindrance of interfacial particulates. Regulating stability and physical states of emulsions can also affect the rate of hydrolysis by altering the active hydrolysis surface. 3D network structure assembled by fat substitutes with high viscosity can not only slow down the peristole and obstruct the diffusion of lipase to the oil droplets but also impede the transportation of lipolysis products to epithelial cells for adsorption. Their applications in low-calorie bakery, dairy and meat products were also discussed, emphasizing fat intake reduction, structure and flavor retention and potential health benefits. However, further application of these strategies in large-scale food production still requires more optimization on cost and lipid reducing effects. This review provides a comprehensive review on colloidal approaches, design, principles and applications of fat reducing strategies to meet the growing demand for healthier diet and offer practical insights for the low-calorie food industry.
Topics: Lipids; Fat Substitutes; Colloids; Lipase; Emulsions; Digestion
PubMed: 37826977
DOI: 10.1016/j.cis.2023.103011