Pharmaceutics最新文献

Background: Gliadins have aroused significant interest in the last decade as suitable biomaterials for food and pharmaceutical applications. In particular, the oral route is the preferred method of administration for gliadin-based formulations, due to the affinity of this biomaterial for the gut mucosa. However, up to now, this has been demonstrated only by means of in vivo or ex vivo studies.

Methods: This is why, in this study, various in vitro techniques were employed in order to evaluate the ability of polymeric nanoparticles, made up of a commercial grade of the protein and an etheric surfactant, to interact with porcine gastric mucin. The nanosystems were also used for the encapsulation of thiamine hydrochloride, used as a model of a micronutrient.

Results: The resulting systems were characterized by a mean diameter of ~160-170 nm, a narrow size distribution when 0.2-0.6 mg/mL of thiamine was used, and an encapsulation efficiency between 30 and 45% of the drug initially employed. The incubation of the gliadin nanosystems with various concentrations of porcine gastric mucin evidenced the ability of the carriers to interact with the mucus glycoprotein, showing a decreased Zeta potential after a 4 h incubation (from ~-30 to -40 mV), while demonstrating that the encapsulation of the drug did not affect its bioadhesive features.

Conclusions: Altogether, these data support the conceivable application of gliadin nanoparticles as formulations for the oral administration of bioactive compounds.

Background/objectives: Implementing model-informed precision dosing (MIPD) strategies guided by population pharmacokinetic/pharmacodynamic (PK/PD) models could enhance the management of inflammatory diseases such as psoriasis. However, the extent of individual experimental data gathered during MIPD significantly influences the uncertainty in estimating individual PK/PD parameters, affecting clinical dose selection decisions.

Methods: This study proposes a methodology to individualize ustekinumab (UTK) dosing strategies for 23 Spanish patients with moderate to severe chronic plaque psoriasis., considering the uncertainty of individual parameters within a population PK/PD model.

Results: An indirect response model from previous research was used to describe the PK/PD relationship between UTK serum concentrations and the Psoriasis Area and Severity Index (PASI) score. A maximum inhibition drug effect (I_max) model was selected, and a first-order remission constant rate of psoriatic skin lesion (k_out = 0.016 d^-1) was estimated.

Conclusions: The MIPD approach predicted that 35% and 26% of the patients would need an optimized and intensified dosage regimen, respectively, compared to the regimen typically used in clinical practice. This analysis demonstrated its utility as a tool for selecting personalized UTK dosing regimens in clinical practice in order to optimize the probability of achieving targeted clinical outcomes in patients with psoriasis.

Background/objectives:Apodanthera glaziovii is an endemic species from the semi-arid Brazilian, which has limited toxicological and pharmacological studies. This species belongs to a well-studied family known for its bioactive compounds used in treating inflammatory. This study aimed to identify secondary metabolites in the stems from A. glaziovii, evaluate toxicity, and investigate the anti-inflammatory potential of the stem hydroalcoholic extract (SHE-Ag). Methods: qualitative and quantitative assays were employed to identify secondary metabolites, along with chromatographic analyses and ¹H and ¹³C NMR. Toxicity was assessed through in vitro hemolytic toxicity, in vivo genotoxicity, and oral acute toxicity tests before the pharmacological assays were conducted. Results: phytochemical screening, HPLC and NMR analyses suggested the presence of saponins of the norcucurbitacin class. The SHE-Ag exhibited no hemolytic activity and no mutagenic potential. However, in vivo toxicity at a dose of 2000 mg/kg revealed hematological and biochemical alterations, while the 500 mg/kg dose was safe. In the anti-inflammatory assays, SHE-Ag at 100 mg/kg reduced paw edema by 55.8%, and leukocyte and neutrophil migration by 62% and 68% in the peritonitis model, respectively; inflammatory cell migration by 70% in the air pouch model, outperforming indomethacin, which showed a 54% reduction. Conclusions: these findings indicate that SHE-Ag is rich in saponins, confirmed through HPLC and ¹H and ¹³C NMR analyses. The SHE-Ag also demonstrated low toxicity. The inflammation models used showed a reduction in inflammation, pro-inflammatory cells, and edema, highlighting the significant anti-inflammatory activity of hydroethanolic extract A. glaziovii stems.

Background/Objectives: Brick dust molecules exhibit high melting points and ultralow solubility. Overcoming this solubility issue is challenging. Previously, we formulated a co-amorphous system for a neuropeptide Y5 receptor antagonist (NP) as a brick dust drug using sodium taurocholate (ST) to improve its dissolution profile. In this study, we have designed a ternary amorphous system involving polymer addition to further improve a co-amorphous system. Methods: The amorphous samples were prepared by the ball milling. The thermal and spectroscopic analyses were performed, and the isothermal crystallization and dissolution profiles were evaluated. Results: The ball milling of NPs, ST, and each of the three types of polymers successfully converted crystalline NPs to amorphous NPs. Thermal analysis confirmed the formation of a single amorphous phase. The infrared spectra revealed a specific interaction between an NP and ST in the co-amorphous system. Moreover, the intermolecular interactions of NP-ST were maintained in the ternary amorphous systems, suggesting the miscible dispersion of the co-amorphous system into the polymer via weak interactions as co-amorphous solid dispersions. The dissolution profile of co-amorphous NP-ST was 4.1- and 6.7-fold higher than that of crystalline NPs in pH 1.2 and 6.8 buffers, respectively. The drug concentration in the ternary amorphous system in pH 1.2 and 6.8 buffers became 1.1-1.2- and 1.4-2.7-fold higher than that seen in the co-amorphous system, respectively. Conclusions: Co-amorphous solid dispersion is a promising method for enhancing the solubility of brick dust molecules.

Low oral bioavailability is a common feature in most drugs, including antibiotics, due to low solubility in physiological media and inadequate cell permeability, which may limit their efficacy or restrict their administration in a clinical setting. Cefuroxime is usually administered in its prodrug form, cefuroxime axetil. However, its preparation requires further reaction steps and additional metabolic pathways to be converted into its active form. The combination of Active Pharmaceutical Ingredients (APIs) with biocompatible organic molecules as salts is a viable and documented method to improve the solubility and permeability of a drug. Herein, the preparations of five organic salts of cefuroxime as an anion with enhanced physicochemical characteristics have been reported. These were prepared via buffer-assisted neutralization methodology with pyridinium and imidazolium cations in quantitative yields and presented as solids at room temperature. Cell viability studies on 3T3 cells showed that only the cefuroxime salts combined with longer alkyl chain cations possess higher cytotoxicity than the original drug, and while most salts lost in vitro antibacterial activity against E. coli, P. aeruginosa and B. subtilis, one compound, [PyC₁₀Py][CFX]₂, retained the activity. Cefuroxime organic salts have a water solubility 8-to-200-times greater than the original drug at 37 °C. The most soluble compounds have a very low octanol-water partition, similar to cefuroxime, while more lipophilic salts partition predominantly to the organic phase.

Background: During the dissolution of amorphous solid dispersion (ASD) formulations, the drug load (DL) often impacts the release mechanism and the occurrence of loss of release (LoR). The ASD/water interfacial gel layer and its specific phase behavior in connection with DL strongly dictate the release mechanism and LoR of ASDs, as reported in the literature. Thermodynamically driven liquid-liquid phase separation (LLPS) and/or drug crystallization at the interface are the key phase transformations that drive LoR.

Methods: In this study, a combination of Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) thermodynamic modeling and in silico molecular simulation was applied to investigate the release mechanism and the occurrence LoR of an ASD formulation consisting of ritonavir as the active pharmaceutical ingredient (API) and the polymer, polyvinylpyrrolidone-co-vinyl acetate (PVPVA64). A thermodynamically modeled ternary phase diagram of ritonavir (PVPVA64) and water was applied to predict DL-dependent LLPS in the ASD/water interfacial gel layer. Microscopic Erosion Time Testing (METT) was used to experimentally validate the phase diagram predictions. Additionally, in silico molecular simulation was applied to provide further insights into the phase separation, the release mechanism, and aggregation behavior on a molecular level.

Results: Thermodynamic modeling, molecular simulation, and experimental results were consistent and complementary, providing evidence that ASD/water interactions and phase separation are essential factors driving the dissolution behavior and LoR at 40 wt% DL of the investigated ritonavir/PVPVA64 ASD system, consistent with previous studies.

Conclusions: This study provides insights into the potential of blending thermodynamic modeling, molecular simulation, and experimental research to comprehensively understand ASD formulations. Such a combined approach can be leveraged as a computational framework to gain insights into the ASD dissolution mechanism, thereby facilitating in silico screening, designing, and optimization of formulations with the benefit of significantly reducing the number of experimental tests.

Background/Objectives: Plasma levels of 4β-hydroxycholesterol (4β-OHC), a CYP3A-specific metabolite of cholesterol, are elevated after administration of CYP3A inducers like rifampicin and carbamazepine. To simulate such plasma 4β-OHC increase, we developed a physiologically based pharmacokinetic (PBPK) model of cholesterol and 4β-OHC in the Simcyp PBPK Simulator (Version 23, Certara UK Ltd.) using a middle-out approach. Methods: Relevant physicochemical properties and metabolic pathway data for CYP3A and CYP27A1 was incorporated in the model. Results: The PBPK model recovered the observed baseline plasma 4β-OHC levels in Caucasian, Japanese, and Korean populations. The model also captured the higher baseline 4β-OHC levels in females compared to males, indicative of sex-specific differences in CYP3A abundance. More importantly, the model recapitulated the increased 4β-OHC plasma levels after multiple-dose rifampicin treatment in six independent studies, indicative of hepatic CYP3A induction. The verified model also captured the altered 4β-OHC levels in CYP3A4/5 polymorphic populations and with other CYP3A inducers. The model is limited by scant data on relative contributions of CYP3A and CYP27A1 pathways and does not account for regulatory mechanisms that control plasma cholesterol and 4β-OHC levels. Conclusion: This study provides a quantitative fit-for-purpose and framed-for-future modelling framework for an endogenous biomarker to evaluate the DDI risk with hepatic CYP3A induction.

Background: The SARS-CoV-2 pandemic has highlighted niclosamide (NIC) as a promising treatment for COVID-19. However, its clinical application is limited due to its poor water solubility, resulting in low bioavailability. Methods: To address this issue, we developed a AuNP-HA-NIC system, which combines gold nanoparticles with hyaluronic acid to enhance drug delivery. Our comprehensive characterization of the system revealed that hyaluronic acid with specific molecular weights, particularly those exposed to electron-beam irradiation between 2 and 20 kGy, produced the most stable nanoparticles for efficient drug loading and delivery. Results: Additionally, the AuNP-HA-NIC system exhibits a significant sensitivity to pH changes, which is a critical feature for targeted drug release. Under acidic conditions mimicking the stomach and small intestine, minimal drug release was observed, indicating the effective prevention of premature drug release in the gastrointestinal tract. Furthermore, the integration of a targeting aptamer established specific binding abilities towards the SARS-CoV-2 spike protein, distinguishing it from other coronaviruses. Conclusions: As research progresses, and with further in vivo testing and optimization, the AuNP-HA-NIC-aptamer system holds great promise as a game-changer in the field of antiviral therapeutics, particularly in the battle against COVID-19.

Background/objectives: The pharmacy profession has undergone significant changes driven by advancements in patient care and healthcare systems. The FDA approval of Spritam^® (levetiracetam), the first 3D-printed drug, has sparked increased interest in the use of Fused Deposition Modeling (FDM) 3D printing for pharmaceutical applications, particularly in the production of polypills.

Methods: This review provides an overview of FDM 3D printing in the development of pharmaceutical dosage forms, focusing on its operation, printing parameters, materials, additives, advantages, and limitations. Key aspects, such as the ability to personalize medication and the challenges associated with the technique, including drug stability at high temperatures, are discussed.

Results: Fourteen studies relevant to FDM 3D-printed polypills were analyzed from an initial pool of 60. The increasing number of publications highlights the growing global interest in this technology, with the UK contributing the highest number of studies.

Conclusions: FDM 3D printing offers significant potential for personalized medicine by enabling precise control over dosage forms and tailoring treatments to individual patient needs. However, limitations such as high printing temperatures and the lack of standardized GMP guidelines for large-scale production must be addressed to fully realize its potential in pharmaceutical manufacturing.

Background/Objectives: Conventional anticancer therapies often lack specificity, targeting both cancerous and normal cells, which reduces efficacy and leads to undesired off-target effects. An additional challenge is the presence of hypoxic regions in tumors, where the Hypoxia Inducible Factor (HIF) transcriptional system drives the expression of pro-survival and drug resistance genes, leading to radio- and chemo-resistance. This study aims to explore the efficacy of targeted nanoparticle (NP)-based small interfering RNA (siRNA) therapies in downregulating these genes to enhance treatment outcomes in pancreatic cancer, a tumor type characterized by high CD44 expression and hypoxia. Methods: We utilized hyaluronic acid (HA)-displaying nanoparticles composed of positively charged chitosan (CS) complexed with siRNA to target and knock down HIF-1α in pancreatic cancer cells. Two NP formulations were prepared using either low molecular weight (LMW) or high molecular weight (HMW) CS. These formulations were evaluated for their internalization by cells and their effectiveness in gene silencing, both in vitro and in vivo. Results: The study found that the molecular weight (MW) of CS influenced the interaction between HA and CD44, as well as the release of siRNA upon internalization. The LMW CS formulation shows faster uptake kinetics, while HMW CS is more effective in gene knockdown across different cell lines in vitro. In vivo, both were able to significantly knockdown HIF-1α and some of its downstream genes. Conclusions: The results suggest that HMW and LMW CS-based NPs exhibit distinct characteristics, showing that both MWs have potential for targeted pancreatic cancer therapy by influencing different aspects of delivery and gene silencing, particularly in the hypoxic tumor microenvironment.