查看更多>>摘要：Bile salts were first tested as epithelial permeation enhancers (PEs) for the intestine and buccal routes over 20 years ago. They are not as popular as other PEs due to their non-specific mechanism of action and perceived toxicity potential. We revisited two of them by comparing efficacy and toxicity of sodium glycodeoxycholate (SGC) and sodium deoxycholate (DC) for both routes using in vitro and ex vivo methods. Cytotoxicity assays in Caco-2 cells revealed that both agents altered cellular parameters at concentrations >2 mM over 60 min. Both agents reduced the transepithelial resistance (TEER) and doubled the Papp of [H-3]-octreotide across isolated rat colonic mucosae mounted in Ussing chambers at 10 mM concentrations. In some studies, 10 mM GDC also increased the Papp of the paracellular marker, FITC-dextran 4000 (FD4) and the fluorescent peptide, FITC-LKP, across colonic mucosae. Tissue histology was intact despite some mild perturbation at 10 mM. In the buccal epithelial cell line, TR146, changes in cell parameters were also seen at 1.5 mM over 60 min for both agents, with slightly more sensitivity seen for DC. In isolated porcine buccal epithelial mucosae, GDC was slightly more potent and efficacious than DC at increasing the Papp of [C-14]-mannitol. It also increased the Papp of [H-3]-octreotide and FITC-LKP by similar to 3-fold across porcine buccal tissue without causing damage. Overall, GDC and DC were efficacious in intestinal and buccal models. Both cause mild perturbation leading to an increase in paracellular fluxes for hydrophilic molecules including peptides. Their moderate efficacy, low potency, and low toxicity in these models are similar to that of more established PEs in clinical trials.
查看更多>>摘要：Background and Purpose: RC18 is a novel recombinant fusion protein targeting on B lymphocyte stimulator (BLyS). We aimed to develop and qualify a population pharmacokinetics (PopPK) model for RC18 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process.
Martinez-Chavez, AlejandraBroeders, JelleLebre, Maria C.Tibben, Matthijs T....
10页
查看更多>>摘要：The promising anticancer drug milciclib potently inhibits cyclin-dependent kinase (CDK) 2 and tropomyosin receptor kinase (TRK) A, and is currently in phase II clinical studies. To characterize factors affecting milciclib pharmacokinetics, we investigated whether milciclib is a substrate of the multidrug efflux and uptake transporters ABCB1 (P-gp), ABCG2 (BCRP), and OATP1A/1B, and the drug-metabolizing enzyme CYP3A, using genetically-modified mouse models and Madin-Darby Canine Kidney (MDCK-II) cells. In vitro , milciclib was transported by mAbcg2, and this was inhibited by the ABCG2 inhibitor Ko143. Upon oral administration of milciclib, its plasma exposure in Abcb1a/1b(-/-) , Abcg2(-/-) , and Abcb1a/1b;Abcg2(-/-) mice was similar to that found in wild-type mice. Milciclib showed good brain penetration even in wild-type mice (brain-to-plasma ratio of 1.2), but this was further increased by 5.2-fold when both Abcb1 and Abcg2 were ablated, and to a lesser extent in single Abcb1- or Abcg2-deficient mice. Oatp1a/1b deficiency had only a minor impact on the milciclib plasma AUC(0-24h) and C-max. The milciclib AUC(0-8h) increased 1.9-fold in Cyp3a(-/-) mice but decreased only 1.3fold upon overexpression of human CYP3A4. Thus, ABCB1 and ABCG2 cooperatively limit milciclib brain penetration. The low impact of OATP1 and CYP3A could be clinically favorable for milciclib, reducing the risks of unintended drug-drug interactions or interindividual variation in CYP3A4 activity.
Mascarello, AlessandraAzevedo, HatylasJunior, Marcos Antonio FerreiraIshikawa, Eloisa Eriko...
13页
查看更多>>摘要：The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver 59 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them pmdrugs, but bearing only the AT1 pharmacophore.
查看更多>>摘要：Research on intravenous emulsions has been ongoing for several decades, and their unique advantages bring many opportunities for insoluble drugs. However, emulsions cannot withstand freezing in practical applications because their quality is severely affected. In this study, we used coenzyme Q10 as a model drug to prepare emulsions. Monosialotetrahexosylganglioside (GM1) was used to modify the emulsion to solve the freeze-thaw intolerance problem. The particle size, sterilization and freeze-thaw stability were affected by the oil content, phospholipid content, drug loading and homogenization conditions, which showed significant effects on the preparation properties. Emulsions prepared with a high oil content (30%, W/V) withstood three freeze-thaw cycles when the GM1 content was 0.2%-1.0% (W/V). In addition, pharmacokinetic studies indicated that emulsions modified with high-density GM1 had a long circulation time. Compared with the coenzyme Q10 solution, the emulsions showed different degrees of heart, liver, spleen and brain targeting. The relative uptake rate of the 0.2% GM1-modified emulsion in the heart was 37.06, while that of the 1.0% GM1-modified emulsion in the brain was 17.43. These results strongly suggest that coenzyme Q10 emulsions coated with GM1 can tolerate freeze-thaw cycles and are excellent for treatment of cardiac and neurodegenerative diseases.
查看更多>>摘要：Background: : Ammoxetine is a novel selective serotonin and norepinephrine reuptake inhibitor. Preclinical studies have indicated the potential utility of ammoxetine for therapy in major depressive disorder.
Zolotov, Sergey A.Demina, Natalia B.Zolotova, Anna S.Shevlyagina, Natalia V....
13页
查看更多>>摘要：The aim of this work was to compare mesopomus carriers based on silica and magnesium aluminosilicate in the amorphous solid dispersion production. Darunavir has been selected as an active pharmaceutical ingredient that is classified as a Class 2 BCS substance and exists in two commercially available forms: crystalline ethanolate and amorphous. In the course of the study, the conditions for the preparation of amorphous samples with the selected carriers were evaluated within the framework of the most common methods for obtaining solid dispersions - hot-melt extrusion, solvent wetting, and spray drying. It was determined that the obtained dispersion properties almost completely repeat the properties of the corresponding carriers. The resulting dispersions were examined in a dissolution test and the best ones was used to formulate tablets, which were studied in an in vitro dissolution test with the original Prezista. The proposed tablet formulation showed improved dissolution compared to the original one. It was also found that silica supports have a greater positive contribution to darunavir dissolution - both ethanolate or amorphous forms.
Zaidi, Syed A. M.Elkes, RichardAcharya, ShreyasTruong, Triet...
12页
查看更多>>摘要：Due to the complexity in the interactions of variables and mechanisms leading to blend segregation, quantifying the segregation propensity of an Active Pharmaceutical Ingredient (API) has been challenging. A high-throughput segregation risk prediction workflow for early drug product development has been developed based on the dispensing mechanism of automated powder dispensing technology. The workflow utilized liquid handling robots and high-performance liquid chromatography (HPLC) with a well-plate autosampler for sample preparation and analysis. Blends containing three different APIs of varying concentrations and particle sizes of different constituents were evaluated through this automated workflow. The workflow enabled segregation evaluation of different API blends in very small quantities (similar to 7g) compared to other common segregation testers that consume hundreds of grams. Segregation patterns obtained were well explained with vibration induced percolation-based segregation phenomena. Segregation risk was translated quantitatively using relative standard deviation (RSD) calculations, and the results matched well with large-scale segregation studies. The applied approach increased the throughput, introduced a simple and clean walk-up method with minimized equipment space and API exposures to conduct segregation studies. Results obtained can provide insights about optimizing particle size distributions, as well as selecting appropriate formulation constituents and secondary processing steps in early drug product development when the amount of available API is very limited.
查看更多>>摘要：In the present study, the three functions, including enhanced permeability and retention (EPR) effect, deep penetration within tumor, and receptor-mediated endocytosis, were integrated into a single platform in order to improve antitumor efficiency. A novel nanoparticle (dendrigraft poly-L-lysine@glycyrrhetinic acid@cyclohexane dicarboxylic anhydride@doxorobicin@ hyaluronic acid composite) has been successfully developed and was denoted as DGL-GA-CDA-DOX-HA. The transmission electron microscope (TEM), dynamic light scattering (DLS), polymer dispersity index (PDI), fourier transform infrared spectrometer (FTIR), and zeta potentials were used to characterize the physicochemical properties of the nanoparticles. According to the results of TEM and DLS, the DGL-GA-CDA-DOX-HA nanoparticles could be rapidly degraded with a size shrink from 182.5 nm to 47.7 nm by hyaluronidase (HAase) added in the medium. The loading amount of DOX reached 252.03 +/- 36.38 mg/g for DGL-GA-CDA-DOX nanoparticles. When the nanoparticles were in a medium with HAase at pH 5.0, the drug quickly released. However, when the nanoparticles were exposed to a medium without HAase at pH 5.0, or a neutral medium containing HAase, drug release slowed down. The modification of GA on nanoparticles significantly enhanced their affinity and cytotoxicity to hepatocellular carcinoma HepG2 cells. The study showed that the penetrability of DGL-GA-CDA-DOX and DGL-GA-CDA DOX-HA nanoparticles pre-degraded by HAase in vitro multicellular tumor spheroids were always better than that of DGL-GA-CDA-DOX-HA nanoparticles untreated by HAase. The imaging in vivo and ex vivo exhibited that DGL-GA-CDA-DOX-HA nanoparticles could preferentially accumulate in the tumor site. Correspondingly, the DGL-GA-CDA-DOX-HA displayed the preferable antitumor efficiency to other experimental groups in H22 tumor-bearing mice, with a tumor inhibition rate of 71.6%. In short, these results suggested that DGL-GA-CDA-DOX-HA nanoparticles could promote therapeutic effects by modulating particle size and GA receptor-mediated endocytosis.
NSTL
Elsevier