Search Results (2,169)

Combined oral contraceptives (COCs) remain one of the most popular reversible contraceptive methods worldwide. Still, regardless of the drug composition and duration of therapy, almost all COCs are associated with the risk of venous thrombosis. This review highlights the main pathogenetic mechanisms of thrombosis development during oral contraceptive use. Increase the production of certain clotting factors; a decrease in antithrombin and protein S levels; acquired resistance to activated protein C; a reduction in tissue factor pathway inhibitor (TFPI); indirect endothelial activation; inhibition of endogenous fibrinolysis; regulation of tissue factor by estradiol-sensitive microRNA; homocysteine imbalance caused by decreased intestinal reabsorption of folates and vitamin B-12; reduced bioavailability of nitric oxide (NO) due to high homocysteine levels; higher blood pressure, water retention, insulin resistance, increased levels of pro-inflammatory C-reactive protein (CRP) and uric acid, and antifibrinolytic (plasminogen activator inhibitor 1 type, PAI-1) biomarkers as consequences of NO deficiency; increased platelet adhesiveness and ADP-induced aggregation, which promote fibrinogen binding; and increased expression of pro-inflammatory cytokines are the main thrombotic effects of COCs use. Clinicians should carefully evaluate each patient’s individual risk factors when prescribing COCs and conduct regular monitoring to reduce the risk of complications. Full article

In this study, we review the use of cyclodextrin-based formulations to develop oral tablets of cladribine by enhancing its bioavailability and to improve the solubility and stability of retrometabolic chemical delivery systems (CDSs) in general and estredox, a brain-targeting estradiol-CDS, in particular. Cyclodextrins (CDs), cyclic oligosaccharides that can form host–guest inclusion complexes with a variety of molecules, are widely utilized in pharmaceuticals to increase drug solubility, stability, bioavailability, etc. The stability of the complex depends on how well the guest fits within the cavity of the CD host; a model connecting this to the size of the guest molecules is briefly discussed. Modified CDs, and particularly 2-hydroxypropyl-β-cyclodextrin (HPβCD), provided dramatically increased water solubility and oxidative stability for estredox (estradiol-CDS, E₂-CDS), making its clinical development possible and highlighting the potential of our brain-targeted CDS approach for CNS-targeted delivery with minimal peripheral exposure. A unique HPβCD-based formulation also provided an innovative solution for the development of orally administrable cladribine. The corresponding complex dual CD-complex formed by an amorphous admixture of inclusion- and non-inclusion cladribine–HPβCD complexes led to the development of tablets that provide adequate oral bioavailability for cladribine, as demonstrated in both preclinical and clinical studies. Cladribine–HPβCD tablets (Mavenclad) offer a convenient, effective, and well-tolerated oral therapy for multiple sclerosis, achieving worldwide approval and significant clinical success. Overall, the developments summarized here underscore the importance of tailored cyclodextrin-based approaches for overcoming barriers in drug formulation for compounds with challenging physicochemical properties, and demonstrate the versatility and clinical impact of CD inclusion complexes in modern pharmaceutical development. Full article

Imatinib (IMT) is a small-molecule tyrosine kinase inhibitor that primarily targets platelet-derived growth factor receptor-β and related kinases. Beyond its established efficacy in chronic myeloid leukemia, IMT has also demonstrated therapeutic benefits in gastrointestinal stromal tumors, dermatofibrosarcoma, acute lymphoblastic leukemia, and as a second-line treatment for aggressive systemic mastocytosis or as an anti-Mycobacterium agent. From a physicochemical perspective, IMT exhibits poor aqueous solubility but high membrane permeability, classifying it as a Biopharmaceutics Classification System Class II compound. Pharmacokinetically, IMT shows variable oral absorption and a prolonged terminal half-life, resulting in dose-dependent systemic exposure. Despite relatively high oral bioavailability, its clinical use requires large doses to achieve therapeutic efficacy, underscoring the need for advanced drug delivery strategies. Nano- and microscale delivery systems offer promising approaches to enhance tumor-specific accumulation through the enhanced permeability and retention effect while mitigating resistance mechanisms. However, achieving high drug loading introduces formulation challenges, such as controlling particle size distribution, polydispersity, and scalability. Moreover, designing carriers capable of controlled release without premature leakage remains crucial for maintaining systemic bioavailability and therapeutic performance. Emerging delivery platforms—including polymeric, lipid-based, carbon-derived, and stimuli-responsive nanocarriers—have shown significant potential in overcoming these limitations. Such systems can enhance IMT’s bioavailability, improve selective tumor targeting, and minimize systemic toxicity, thereby advancing its translational potential. This review aims to highlight the different biomedical applications of IMT and off-label uses, and to discuss current advances in drug delivery to optimize its clinical efficacy and safety profile. Full article

Background/Objectives: Propofol is frequently used as an intravenous anesthetic and is rapidly metabolized. Therefore, if it could be administered non-invasively (e.g., orally) as premedication, it might hasten emergence from anesthesia, thereby improving patient safety. However, it undergoes extensive first-pass metabolism in the liver and intestines, limiting the route for premedication. We evaluated whether intranasal delivery of a propofol-encapsulated liposome solution improves systemic exposure and bioavailability in rabbits. Methods: A propofol-encapsulated liposome solution was administered to rabbits via the intravenous, oral, and intranasal routes. Blood propofol concentrations were measured for up to 60 min after administration and the area under the concentration–time curve (AUC_0–60) and bioavailability of the propofol-encapsulated liposome solution were compared with those of the non-encapsulated propofol formulation. The differences were tested by two-way analysis of variance (ANOVA) with Šidák’s post hoc multiple-comparisons test and the Mann–Whitney test (α = 0.05). Results: The AUC_0–60 for blood propofol concentrations after intravenous administration was significantly higher with the propofol-encapsulated liposome solution than with the non-encapsulated propofol formulation (3038.8 ± 661.5 vs. 1929.8 ± 58.2 ng·min/mL; p = 0.0286). By contrast, no increase in blood propofol concentrations was observed after oral administration, whereas intranasal administration increased blood propofol concentrations and yielded significantly higher bioavailability compared with the non-encapsulated propofol formulation (16.4 ± 7.3% vs. 2.0 ± 1.2%; p = 0.0286). Conclusions: The findings of the present study suggest that intranasal liposomal propofol increased systemic availability compared with a non-encapsulated formulation, supporting further evaluation as a candidate premedication approach for propofol. Full article

Therapeutic peptides have gained significant attention due to their high specificity, potency, and safety profiles in treating various diseases. However, their clinical application via the oral route remains challenging. Peptides are inherently unstable in the gastrointestinal environment, where they are rapidly degraded by proteolytic enzymes and acidic pH, leading to poor bioavailability. Additionally, their large molecular size and hydrophilicity restrict passive diffusion across the epithelial barriers of the gastrointestinal tract. These limitations have traditionally necessitated parenteral administration, which reduces patient compliance and convenience. The oral cavity, comprising the buccal and sublingual mucosa, offers a promising alternative for peptide delivery. Its rich vascularization allows for rapid systemic absorption while bypassing hepatic first-pass metabolism. Furthermore, the mucosal surface provides a relatively permeable and accessible site for drug administration. However, the oral cavities also present significant barriers: the mucosal epithelium limits permeability, the presence of saliva causes rapid clearance, and enzymes in saliva contribute to peptide degradation. Therefore, innovative strategies are essential to enhance peptide stability, retention, and permeation in this environment. Nanoparticle-based delivery systems, including lipid-based carriers such as liposomes and niosomes, as well as polymeric nanoparticles like chitosan and PLGA, offer promising solutions. These nanocarriers protect peptides from enzymatic degradation, enhance mucoadhesion to prolong residence time, and facilitate controlled release. Their size and surface properties can be engineered to improve mucosal penetration, including through receptor-mediated endocytosis or by transiently opening tight junctions. Among these, niosomes have shown high encapsulation efficiency and sustained release potential, making them particularly suitable for oral peptide delivery. Despite advances, challenges remain in translating these technologies clinically, including ensuring biocompatibility, scalable manufacturing, and patient acceptance. Nevertheless, the oral cavity’s accessibility, combined with nanotechnological innovations, offers a compelling platform for personalized, non-invasive peptide therapies that could significantly improve treatment outcomes and patient quality of life. Full article

Thymol gastro-resistant self-emulsifying pellets were used to achieve thymol targeted release on the side of the intestine with the most intensive absorption to enhance its oral bioavailability. Forty-eight rabbits (35 d of age) were divided into two groups fed with a standard diet containing gastro-resistant enteric pellets (control, CG; without thymol, initial live weight 1350.0 ± 18.0, and experimental, EG; with thymol 250 mg/kg, initial live weight 1352.0 ± 19.9 g). The experiment lasted 28 days: thymol was administered for 21 days and then withdrawn for 7 days. Thymol was significantly higher in duodenal wall (DW) than in plasma during both periods (p = 0.0053, p < 0.0001). Significant correlation was established between thymol concentration in plasma and DW during its application (r_s = 0.9333, p < 0.001). Thymol was below the limit of quantitation in plasma, spleen and muscle only after its withdrawal, and its significantly higher concentration in kidney and fat than in plasma (p = 0.0182, p = 0.0003) and muscle (p = 0.0236, p = 0.0004) indicates its efficient accumulation. Thymol in gastro-resistant form prevented its degradation due to adverse conditions in the stomach and ensured its release at the site of greatest absorption in the small intestine. Full article

Background: Epigallocatechin-3-gallate (EGCG), a potent green tea polyphenol, possesses significant therapeutic potential, but its clinical application is limited by poor gastrointestinal stability and low oral bioavailability. To address this, a novel herbal nanomedicine-based delivery system was developed utilizing D-α-tocopheryl polyethylene glycol succinate (TPGS) and Poloxamer 407. Objectives: This study aims to develop and characterize EGCG-loaded TPGS/Poloxamer 407 micelles, evaluating their physicochemical properties, storage stability, in vitro drug release profile, in vivo oral bioavailability, and preliminary tolerability observation. Methods: The micelles were prepared using the film hydration method followed by lyophilization. Results: The optimized 2:2 TPGS-to-poloxamer 407 weight ratio yielded EGCG-loaded micelles, displaying a mean particle size of 15.4 nm, a polydispersity index (PDI) of 0.16, a zeta potential of −17.7 mV, an encapsulation efficiency of 82.7%, and a drug loading capacity of 7.6%. The critical micelle concentration (CMC) was determined to be 0.00125% w/v. Transmission electron microscopy (TEM) confirmed the micelles’ uniform spherical morphology. In vitro release studies demonstrated a sustained release profile in both simulated gastric and intestinal fluids. EGCG formulation remained stable for at least six months when stored at 4 °C. No adverse clinical signs were noted during the 28-day tolerability observation. In vivo pharmacokinetic evaluation in mice revealed a significant elevation in oral bioavailability, achieving a 2.27-fold increase in area under the curve (AUC) and a 1.8-fold increase in peak plasma concentration (Cmax) compared to free EGCG. Conclusions: Collectively, these findings underscore the potential of the TPGS/poloxamer 407-based micelle system as a promising oral delivery platform for EGCG, enhancing its stability and pharmacokinetic performance. Full article

Peptide drug development has emerged as a prominent area in pharmaceutical research due to its high specificity and therapeutic potential. However, their biological activity, stability, and bioavailability are significantly influenced by interactions with counter-ions, which electrostatically bind to charged residues on peptide surfaces. This review systematically examines the multifaceted roles of counter-ions in modulating peptide structure and function. Counter-ions are classified into organic/inorganic and anionic/cationic categories, with their selection critically impacting peptide solubility, conformational stability, and activity. Inorganic counter-ions could enhance structural integrity, while organic counter-ions could mitigate toxicity risks. Notably, counter-ions can induce secondary structural transitions, directly affecting biological efficacy. Furthermore, counter-ions play pivotal roles in drug delivery systems, including nanoemulsions, self-emulsifying formulations, and lipid-based nanoparticles, where hydrophobic ion pairing improves encapsulation efficiency and oral bioavailability. In chromatography, ion-pairing reagents optimize peptide separation but may compromise mass spectrometry compatibility. Emerging analytical techniques, such as capillary electrophoresis and liquid chromatography–tandem mass spectrometry (LC-MS/MS), enhance counter-ion detection precision, addressing challenges in pharmaceutical quality control. Despite advancements, gaps remain in understanding ion-specific binding mechanisms and long-term safety profiles. This review underscores the necessity of tailoring counter-ion selection to balance efficacy, stability, and biocompatibility. Future research should prioritize elucidating molecular interaction dynamics and developing safer, high-affinity counter-ions to overcome current limitations in peptide drug development. Full article

Background: This work aimed to enhance the solubility of Tadalafil (TDL), a BCS Class II drug, by preparing Type IV lipid-based formulations. Methods: Type IV formulations were prepared using surfactants and/or hydrophilic co-surfactants, resulting in oil-free systems. Results: Based on the solubility test, Transcutol^® HP exhibited the highest solubility for TDL (48.33 ± 0.004 mg/mL) and was selected as the co-surfactant. Among surfactants, Kolliphor^® PS80 (42.74 ± 2.29 mg/mL), Kolliphor^® EL (41.87 ± 2.50 mg/mL), Kollisolv^® PEG 400 (40.70 ± 0.30 mg/mL), and Kolliphor^® HS15 (31.40 ± 3.63 mg/mL) demonstrated high solubilization capacity. These were used to prepare formulations without the addition of an oil phase. The developed formulations resulted in a system with a nano-droplet size (<50 nm) and PDI values < 0.3, which was clear, transparent, and resistant to pH dilutions. The optimum Type IV lipid formulations were further characterized and demonstrated good thermodynamic stability under temperature and pH changes. The optimized formulation was adsorbed onto different carriers and transformed into solid TDL-loaded formulations. The in vitro dissolution rate of the drug from the solidified lipid formulations was studied in various dissolution media. It was observed that the solid formulations prepared with Neusilin US2^® (2:1) exhibited a significantly higher dissolution of over 95% within 5 min compared to the marketed product. The in vitro lipolysis studies demonstrated that F2 formulation maintained TDL in a supersaturated state throughout digestion, with limited enzymatic degradation of the excipients. Cytotoxicity evaluation using the MTT assay in Caco-2 cells confirmed the biocompatibility of both drug-free and TDL-loaded formulations, with IC₅₀ values of 19.55 µg/mL and 17.55 µg/mL, respectively. Conclusions: The overall results suggested that the developed solid Type IV lipid formulations can improve the dissolution rate of TDL, which would potentially lead to an improvement in its oral bioavailability and, consequently, a reduction in the treatment dose as a safe delivery system. Full article

Sinomenine (SIN) is a promising candidate for the treatment of rheumatoid arthritis (RA). Although it possesses the advantage of being non-addictive, its poor aqueous solubility and low oral bioavailability have limited its clinical application. To address these issues, SIN was encapsulated into lipid cubic liquid crystal nanoparticles (LCNPs) and systematically characterized. Molecular dynamics (MD) simulations were first employed to screen suitable excipients for formulation development. Combined with single-factor optimization and Box–Behnken response surface design, the optimal composition and preparation process were determined. The resulting SIN-LCNPs exhibited a particle size of 149.7 ± 0.9 nm, a polydispersity index (PDI) of 0.223 ± 0.01, a zeta potential of −18.9 mV, and an encapsulation efficiency (EE%) of 92.2%. Spectroscopic analyses confirmed successful incorporation of SIN into the lipid matrix. Pharmacodynamic studies revealed that SIN-LCNPs enhanced targeted drug delivery to inflamed joints, significantly alleviating inflammation and suppressing disease progression in rats. In vivo single-pass intestinal perfusion (SPIP) experiments further demonstrated that SIN was primarily absorbed through the small intestine and that the LCNP carrier effectively improved its intestinal permeability. Collectively, this study provides a novel strategy and theoretical foundation for developing efficient formulations of poorly water-soluble drugs, highlighting the potential clinical application of SIN-LCNPs in RA therapy. Full article

Iron deficiency anaemia (IDA) affects 25% of the global population, with detrimental effects on the health of women and children. Treatments with iron supplements offer temporary relief but often yield adverse effects, hindering patient adherence. Additionally, IDA is associated with oxidative stress, which becomes significantly exacerbated during iron supplementation. Our study aimed to address this challenge by developing a plant-based nutritional formula rich in bioavailable iron and antioxidants devoid of adverse effects. Chemical analysis of edible plants, focused on the content of iron and iron absorption inhibitors, guided formula development. In vivo studies on rats with IDA evaluated iron bioavailability from the formulated plant-based nutraceuticals. Results of animal studies showed significant improvements in IDA-associated blood parameters after 28 days of oral administration of the nutraceuticals. Additionally, the nutraceuticals did not impede the benefits of iron supplementation. These findings strongly indicate that plant-based nutraceuticals can serve as an effective source of bioavailable iron, potentially improving treatment adherence and at the same time aligning with ongoing WHO and UNICEF initiatives to enhance IDA management. Full article

Background: Betulins (betulin, betulinic acid and lupeol) demonstrated antitumor and chemopreventive activity but showed low bioavailability due to their self-aggregation in hydrophilic environments. To overcome these disadvantages, their incorporation into lipid nanoformulations (PEGylated liposomes and Lipid Nanostructured Carriers (NLCs)) has proven to represent a viable solution. Objectives: The purpose of this study is to evaluate the size and incorporation rate of these molecules in nanoformulations, as well as their delivery and metabolic fate (pure betulinic acid versus a standardized extract, TT) relative to Doxorubicin using an in vivo protocol. The investigation extended our previous in vitro investigations towards an in vivo evaluation of antitumor activity, metabolic fate and toxicity in Wistar rats bearing Walker 256 carcinoma tumors over 21 days. Since previous studies used oral or intratumor administration, this exploratory study applied intravenous administration via microbubble-assisted sonoporation, considering its higher relevance for translational studies. Methods: The delivery and metabolic fate of the parent molecules, the identification of their fragments and metabolites using UHPLC-QTOF-ESI⁺MS were investigated, along with the identification of some toxicity biomarkers in rat plasma, tumor tissues and urine. Results: Preferential accumulation of Doxorubicin in tumors was observed compared to betulinic acid and TT components, as well as their persistence in plasma or elimination in urine. Compared to PEGylated liposomes, NLC formulations (especially NLC Doxo) induced a lower survival rate, a decreased bioavailability and increased toxicity by around 20%. Conclusions: These data are a starting point and complement the contrast-enhanced imaging and histology evaluations, which may contribute to the actual knowledge about the in vivo fate of betulins. Full article

Porcelain-fused-to-metal (PFM) crowns continue to serve as a cornerstone of restorative dentistry owing to their strength, affordability, and esthetics. However, late-onset complications such as oral burning and lichenoid reactions have been observed in long-serving PFMs, suggesting complex host–material interactions that extend beyond simple mechanical wear. This Perspective introduces the Nallan–Nickel Effect, a theoretical model proposing that a host- and environment-dependent threshold of bioavailable nickel ions (Ni²⁺), once exceeded, may trigger a neuro-immune cascade culminating in a burning phenotype. Within this framework, slow corrosion at exposed PFM interfaces releases Ni²⁺ into saliva and crevicular fluid, facilitating epithelial uptake and activation of innate immune sensors such as TLR4 and NLRP3. The resulting cytokine milieu (IL-1β, IL-6, TNF-α) drives NF-κB, mediated inflammation and T-cell activation, while neurogenic mediators—including nerve growth factor (NGF), substance P, and CGRP—sensitize TRPV1/TRPA1 nociceptors, establishing feedback loops of persistent burning and neurogenic inflammation. Modifying factors such as low salivary flow, acidic oral pH, mixed-metal galvanic coupling, and parafunctional stress can lower this threshold, whereas replacement with high-noble or all-ceramic materials may restore tolerance. The model generates testable predictions: elevated local free Ni²⁺ levels and increased expression of TLR4 and TRPV1 in symptomatic mucosa, along with clinical improvement following substitution of nickel-containing restorations. Conceptually, the Nallan–Nickel Effect reframes PFM-associated burning and lichenoid lesions as threshold-governed, neuro-immune phenomena rather than nonspecific irritations. By integrating corrosion chemistry, mucosal immunology, and sensory neurobiology, this hypothesis offers a coherent, testable framework for future translational research and patient-centered management of PFM-related complications. Full article

Background/Objectives: Grape seed oil (GSO) is a potent source of dietary phytochemicals, particularly polyphenols and flavonoids, known for their health-promoting properties. This study aims to investigate the anticancer and hepatoprotective effects of a nanoemulsion formulation of grape seed oil (GSONE), to enhance the efficacy and bioavailability of its phytochemical constituents against solid tumors. Methods: Ninety female Swiss albino mice were divided into six groups: control, alone, GSONE alone, Ehrlich solid tumor (EST), EST treated with GSO, and EST treated with GSONE. Tumor development, growth performance, serum biochemistry, antioxidant status, hepatic histopathology, apoptotic gene expression, and flow cytometry analyses were assessed following 30 days of daily oral treatment. Results: GSONE significantly reduced tumor weight and volume (52.9%) and more effectively counteracted tumor-induced body weight loss than crude GSO. Treatment with GSONE normalized serum protein levels and improved liver function markers (AST, ALT, ALP, total bilirubin) to near-control values. Tumor markers (AFP, CEA) and oxidative stress indices (MDA, 8-OHdG) were markedly decreased, while activities of hepatic antioxidants (SOD, CAT, GPx, GSH) were restored. GSONE enhanced gene expression of pro-apoptotic markers (Bax, TP53, caspase-3, caspase-9), suppressed anti-apoptotic Bcl-2, and significantly increased the proportion of p53- and cleaved caspase-3-positive tumor cells. Liver histopathology and ultrastructure demonstrated normalized morphology and reduced damage in GSONE-treated mice. Multivariate analyses confirmed GSONE’s restorative effect compared to raw GSO. Conclusions: The delivery of dietary phytochemicals via nanoemulsion significantly enhances antitumor and hepatoprotective actions in a preclinical solid tumor model. These findings support the potential of phytochemical-rich edible oils, enhanced by nanotechnology, for dietary prevention and adjunctive management of cancer. Full article

Chrysin is a dietary flavonoid with antioxidant and anti-inflammatory activity, but its clinical potential is limited by poor oral bioavailability. This randomized double-blind three period crossover trial evaluated the pharmacokinetics of a novel micellar chrysin formulation co-encapsulated with quercetin and rutin (LMC) compared with a non-micellar chrysin formulation (NMC) and unformulated chrysin (UFC). Secondary objectives included in vitro permeability (Caco-2) and a 30-day safety assessment of daily LMC supplementation. Sixteen healthy adults received a single oral dose of each formulation in randomized order separated by a 7-day washout. Plasma chrysin was quantified over 24 h to determine pharmacokinetic parameters. In vitro Caco-2 assays evaluated permeability, and clinical biochemistry of 15 participants were assessed weekly during 30 days of daily LMC use. LMC achieved >2-fold higher systemic exposure than unformulated chrysin (AUC_0–24 = 914.8 ± 697.5 ng·h/mL; C_max = 87.3 ± 59.4 ng/mL; both p < 0.05) and >2.6-fold higher than NMC, supported by >10-fold higher in vitro permeability. Daily LMC supplementation was well tolerated, with only mild, reversible adverse events and no clinically relevant safety changes, despite higher systemic exposure. Small, but significant, reductions in fasting glucose were observed in both sexes. The novel micellar chrysin–quercetin–rutin formulation substantially improved bioavailability and was well tolerated during 30 days of daily use, supporting its potential as an advanced delivery strategy for flavonoids with poor oral absorption and identifying glucose regulation as a physiological effect of interest. Full article