Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.

First-in-human study of CPL207280, a novel G-protein-coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration.

AIM: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G-protein-coupled receptor 40 agonist developed to treat type 2 diabetes (T2D). METHODS: The phase 1 study in healthy volunteers (White, age 18-55 years, body mass index 18.5-29.9 kg/m2 ) was performed after single (24 subjects, 5-480 mg) and multiple (32 subjects, 60-480 mg) once-daily administration of CPL207280.  The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C-peptide, proinsulin, glucagon levels) observed during the 14-day treatment period. RESULTS: No deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (Cmax ) or area under the plasma concentration-time curve up to 24 h. However, dose-normalized Cmax decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half-life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed. CONCLUSIONS: CPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single-daily administration and justifies further development of this therapy for patients with T2D.

Hydration Patterns in Sodium Alginate Polymeric Matrix Tablets-The Result of Drug Substance Incorporation.

The purpose was to show, using destructive/nondestructive methods, that the interplay between water, tablet structure, and composition determine the unique spatiotemporal hydration pattern of polymer-based matrices. The tablets containing a 1:1 w/w mixture of sodium alginate with salicylic acid (ALG/SA) or sodium salicylate (ALG/SNA) were studied using Karl Fischer titration, differential scanning calorimetry, X-ray microtomography, and magnetic resonance imaging. As the principal results, matrix specific features were detected, e.g., "locking" of the internal part of the matrix (ALG/SA); existence of lamellar region associated with detection of free/freezing water (ALG/SA); existence of water penetrating the matrix forming specific region preceding infiltration layer (ALG/SNA); switch in the onset temperature of endothermic water peak associated with an increase in the fraction of non-freezing water weight per dry matrix weight in the infiltration layer (ALG/SNA). The existence of complicated spatiotemporal hydration patterns influenced by matrix composition and molecular properties of constituents has been demonstrated.

Development and Bio-Predictive Evaluation of Biopharmaceutical Properties of Sustained-Release Tablets with a Novel GPR40 Agonist for a First-in-Human Clinical Trial.

Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the present study, we describe the development of a robust SR matrix tablet with a novel G-protein-coupled receptor 40 (GPR40) agonist for first-in-human studies and introduce a general workflow for the successful development of SR formulations for innovative APIs. The hydrophilic matrix tablets containing the labeled API dose of 5, 30, or 120 mg were evaluated with several methods: standard USP II dissolution, bio-predictive dissolution tests, and the texture and matrix formation analysis. The standard dissolution tests allowed preselection of the prototypes with the targeted dissolution rate, while the subsequent studies in physiologically relevant conditions revealed unwanted and potentially harmful effects, such as dose dumping under an increased mechanical agitation. The developed formulations were exceptionally robust toward the mechanical and physicochemical conditions of the bio-predictive tests and assured a comparable drug delivery rate regardless of the prandial state and dose labeled. In conclusion, the introduced development strategy, when implemented into the development cycle of SR formulations with innovative APIs, may allow not only to reduce the risk of formulation-related failure of phase I clinical trial but also effectively and timely provide safe and reliable medicines for patients in the trial and their further therapy.

Spatiotemporal Analysis of Hydration Mechanism in Sodium Alginate Matrix Tablets.

Methods of spatiotemporal characterization of nonequilibrated polymer based matrices are still immature and imperfect. The purpose of the study was to develop the methodology for the spatiotemporal characterization of water transport and properties in alginate tablets under hydration. The regions of low water content were spatially and temporally sampled using Karl Fisher and Differential Scanning Callorimetry (spatial distribution of freezing/nonfreezing water) with spatial resolution of 1 mm. In the regions of high water content, where sampling was infeasible due to gel/sol consistency, magnetic resonance imaging (MRI) enabled characterization with an order of magnitude higher spatial resolution. The minimally hydrated layer (MHL), infiltration layer (IL) and fully hydrated layer (FHL) were identified in the unilaterally hydrated matrices. The MHL gained water from the first hour of incubation (5-10% w/w) and at 4 h total water content was 29-39% with nonfreezing pool of 28-29%. The water content in the IL was 45-47% and at 4 h it reached ~50% with the nonfreezing pool of 28% and T2 relaxation time < 10 ms. The FHL consisted of gel and sol layer with water content of 85-86% with a nonfreezing pool of 11% at 4 h and T2 in the range 20-200 ms. Hybrid destructive/nondestructive analysis of alginate matrices under hydration was proposed. It allowed assessing the temporal changes of water distribution, its mobility and interaction with matrices in identified layers.

The Relationship Between the Evolution of an Internal Structure and Drug Dissolution from Controlled-Release Matrix Tablets.

In the last decade, imaging has been introduced as a supplementary method to the dissolution tests, but a direct relationship of dissolution and imaging data has been almost completely overlooked. The purpose of this study was to assess the feasibility of relating magnetic resonance imaging (MRI) and dissolution data to elucidate dissolution profile features (i.e., kinetics, kinetics changes, and variability). Commercial, hydroxypropylmethyl cellulose-based quetiapine fumarate controlled-release matrix tablets were studied using the following two methods: (i) MRI inside the USP4 apparatus with subsequent machine learning-based image segmentation and (ii) dissolution testing with piecewise dissolution modeling. Obtained data were analyzed together using statistical data processing methods, including multiple linear regression. As a result, in this case, zeroth order release was found to be a consequence of internal structure evolution (interplay between region's areas-e.g., linear relationship between interface and core), which eventually resulted in core disappearance. Dry core disappearance had an impact on (i) changes in dissolution kinetics (from zeroth order to nonlinear) and (ii) an increase in variability of drug dissolution results. It can be concluded that it is feasible to parameterize changes in micro/meso morphology of hydrated, controlled release, swellable matrices using MRI to establish a causal relationship between the changes in morphology and drug dissolution. Presented results open new perspectives in practical application of combined MRI/dissolution to controlled-release drug products.

Geometry of modified release formulations during dissolution--influence on performance of dosage forms with diclofenac sodium.

The objectives of the work included: presentation of magnetic resonance imaging (MRI) and fractal analysis based approach to comparison of dosage forms of different composition, structure, and assessment of the influence of the compositional factors i.e., matrix type, excipients etc., on properties and performance of the dosage form during drug dissolution. The work presents the first attempt to compare MRI data obtained for tablet formulations of different composition and characterized by distinct differences in hydration and drug dissolution mechanisms. The main difficulty, in such a case stems from differences in hydration behavior and tablet's geometry i.e., swelling, cracking, capping etc. A novel approach to characterization of matrix systems i.e., quantification of changes of geometrical complexity of the matrix shape during drug dissolution has been developed. Using three chosen commercial modified release tablet formulations with diclofenac sodium we present the method of parameterization of their geometrical complexity on the base of fractal analysis. The main result of the study is the correlation between the hydrating tablet behavior and drug dissolution - the increase of geometrical complexity expressed as fractal dimension relates to the increased variability of drug dissolution results.