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Biomedicine & Pharmacotherapy =... Jul 2023No medical interventions for noise induced hearing loss (NIHL) are approved by the Food and Drug Administration (USA). Here, we evaluate statins in CBA/CaJ mice as...
No medical interventions for noise induced hearing loss (NIHL) are approved by the Food and Drug Administration (USA). Here, we evaluate statins in CBA/CaJ mice as potential drugs for hearing loss. Direct delivery of fluvastatin to the cochlea and oral delivery of lovastatin were evaluated. Baseline hearing was assessed using Auditory Brain Stem Responses (ABRs). For fluvastatin, a cochleostomy was surgically created in the basal turn of the cochlea by a novel, laser-based procedure, through which a catheter attached to a mini-osmotic pump was inserted. The pump was filled with a solution of 50 µM fluvastatin+carrier or with the carrier alone for continuous delivery to the cochlea. Mice were exposed to one octave band noise (8-16 kHz x 2 h x 110 dB SPL). In our past work with guinea pigs, fluvastatin protected in the contralateral cochlea. In this study in CBA/CaJ mice, hearing was also assessed in the contralateral cochlea 1-4 weeks after noise exposure. At two weeks post exposure, ABR thresholds at 4, 8, 12, 16, and 32 kHz were elevated, as expected, in the noise+carrier alone treated mice by approximately 9-, 17-, 41-, 29-, and 34-dB, respectively. Threshold elevations were smaller in mice treated with noise+fluvastatin to about 2-, 6-, 20-,12- and 12-dB respectively. Survival of inner hair cell synapses were not protected by fluvastatin over these frequencies. Lovastatin delivered by gavage showed lower threshold shifts than with carrier alone. These data show that direct and oral statin delivery protects mice against NIHL.
Topics: United States; Mice; Animals; Guinea Pigs; Mice, Inbred CBA; Hearing Loss, Noise-Induced; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Fluvastatin; Lovastatin; Excipients
PubMed: 37435721
DOI: 10.1016/j.biopha.2023.114674 -
Advanced Drug Delivery Reviews Nov 2023Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical... (Review)
Review
Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical excipients, food additives, emulsifiers in cosmetics, and as household/industrial detergents. This review outlines the interaction of surfactant-type excipients present in oral pharmaceutical dosage forms with the intestinal epithelium of the gastrointestinal (GI) tract. Many surfactants permitted for human consumption in oral products reduce intestinal epithelial cell viability in vitro and alter barrier integrity in epithelial cell monolayers, isolated GI tissue mucosae, and in animal models. This suggests a degree of mis-match for predicting safety issues in humans from such models. Recent controversial preclinical research also infers that some widely used emulsifiers used in oral products may be linked to ulcerative colitis, some metabolic disorders, and cancers. We review a wide range of surfactant excipients in oral dosage forms regarding their interactions with the GI tract. Safety data is reviewed across in vitro, ex vivo, pre-clinical animal, and human studies. The factors that may mitigate against some of the potentially abrasive effects of surfactants on GI epithelia observed in pre-clinical studies are summarised. We conclude with a perspective on the overall safety of surfactants in oral pharmaceutical dosage forms, which has relevance for delivery system development.
Topics: Animals; Humans; Excipients; Drug Compounding; Pharmaceutical Preparations; Intestines; Surface-Active Agents
PubMed: 37739041
DOI: 10.1016/j.addr.2023.115086 -
International Journal of Molecular... Oct 2023Food colorants are commonly used as excipients in pharmaceutical and nutraceutical fields, but they have a wide range of other potential applications, for instance, as...
Food colorants are commonly used as excipients in pharmaceutical and nutraceutical fields, but they have a wide range of other potential applications, for instance, as cytotoxic drugs or mediators of physical antimicrobial treatments. The photodynamic antibacterial activity of several edible food colorants is reported here, including E127, E129, E124, E122, E133, and E150a, alongside Rhein, a natural lipophilic antibacterial and anticancer compound found in medicinal plants. Minimal inhibitory concentration (MIC) values for and showed that E127 and Rhein were effective against both bacteria, while other colorants exhibited low activity against . In some cases, dark pre-incubation of the colorants with Gram-positive increased their photodynamic activity. Adding Rhein to E127 increased the photodynamic activity of the latter in a supportive mode. Optional sensing mechanism pathways of combined E127/Rhein action were suggested. The antibacterial activity of the studied colorants can be ranged as follows: E127/Rhein >> E127 >> E150a > E122 > E124 >> E129 ≈ E133. E127 was also found to exhibit photodynamic properties. Short ultrasonic treatment before illumination caused intensification of E127 photodynamic activity against when applied alone and especially in combination with Rhein. Food colorants exhibiting photo- and sonodynamic properties may have good potential in food preservation.
Topics: Food Coloring Agents; Staphylococcus aureus; Escherichia coli; Anti-Bacterial Agents
PubMed: 37894807
DOI: 10.3390/ijms242015126 -
PLoS Biology Sep 2023Dietary emulsifiers, including carboxymethylcellulose (CMC) and polysorbate 80 (P80), perturb gut microbiota composition and gene expression, resulting in a microbiota...
Dietary emulsifiers, including carboxymethylcellulose (CMC) and polysorbate 80 (P80), perturb gut microbiota composition and gene expression, resulting in a microbiota with enhanced capacity to activate host pro-inflammatory gene expression and invade the intestine's inner mucus layer. Such microbiota alterations promote intestinal inflammation, which can have a variety of phenotypic consequences including increased adiposity. Bacterial flagellin is a key mediator of emulsifiers' impact in that this molecule enables motility and is itself a pro-inflammatory agonist. Hence, we reasoned that training the adaptive mucosal immune system to exclude microbes that express flagellin might protect against emulsifiers. Investigating this notion found that immunizing mice with flagellin elicited an increase in mucosal anti-flagellin IgA and IgA-coated microbiota that would have otherwise developed in response to CMC and P80 consumption. Yet, eliciting these responses in advance via flagellin immunization prevented CMC/P80-induced increases in microbiota expression of pro-inflammatory agonists including LPS and flagellin. Furthermore, such immunization prevented CMC/P80-induced microbiota encroachment and deleterious pro-inflammatory consequences associated therewith, including colon shortening and increased adiposity. Hence, eliciting mucosal immune responses to pathobiont surface components, including flagellin, may be a means of combatting the array of inflammatory diseases that are promoted by emulsifiers and perhaps other modern microbiota stressors.
Topics: Animals; Mice; Vaccination; Immunization; Diet; Microbiota; Obesity; Flagellin; Polysorbates; Immunoglobulin A
PubMed: 37725584
DOI: 10.1371/journal.pbio.3002289 -
Acta Pharmaceutica Sinica. B Aug 2023Chemotherapy has occupied the critical position in cancer therapy, especially towards the post-operative, advanced, recurrent, and metastatic tumors. Paclitaxel... (Review)
Review
Chemotherapy has occupied the critical position in cancer therapy, especially towards the post-operative, advanced, recurrent, and metastatic tumors. Paclitaxel (PTX)-based formulations have been widely used in clinical practice, while the therapeutic effect is far from satisfied due to off-target toxicity and drug resistance. The caseless multi-components make the preparation technology complicated and aggravate the concerns with the excipients-associated toxicity. The self-assembled PTX nanoparticles possess a high drug content and could incorporate various functional molecules for enhancing the therapeutic index. In this work, we summarize the self-assembly strategy for diverse nanodrugs of PTX. Then, the advancement of nanodrugs for tumor therapy, especially emphasis on mono-chemotherapy, combinational therapy, and theranostics, have been outlined. Finally, the challenges and potential improvements have been briefly spotlighted.
PubMed: 37655323
DOI: 10.1016/j.apsb.2023.02.021 -
European Journal of Pharmaceutical... Mar 2024Microparticles have unique benefits in the formulation of multiparticulate and multi-unit type pharmaceutical dosage forms allowing improved drug safety and efficacy... (Review)
Review
Microparticles have unique benefits in the formulation of multiparticulate and multi-unit type pharmaceutical dosage forms allowing improved drug safety and efficacy with favorable pharmacokinetics and patient centricity. On the other hand, the above advantages are served by high and well reproducible quality attributes of the medicinal product where even flexible design and controlled processability offer success as well as possible longer product life-cycle for the manufacturers. Moreover, the specific demands of patients can be taken into account, including simplified dosing regimens, flexible dosage, drug combinations, palatability, and ease of swallowing. In the more than 70 years since the first modified-release formulation appeared on the market, many new formulations have been marketed and many publications have appeared in the literature. More unique and newer pharmaceutical technologies and excipients have become available for producing tailor-made particles with micrometer dimensions and beyond. All these have contributed to the fact that the sub-units (e.g. minitablets, pellets, microspheres) that make up a multiparticulate system can vary widely in composition and properties. Some units have mucoadhesive properties and others can float to contribute to a suitable release profile that can be designed for the multiparticulate formula as a whole. Nowadays, there are some available formulations on the market, which are able to release the active substance even for several months (3 or 6 months depending on the type of treatment). In this review, the latest developments in technologies that have been used for a long time are presented, as well as innovative solutions such as the applicability of 3D printing to produce subunits of multiparticulate systems. Furthermore, the diversity of multiparticulate systems, different routes of administration are also presented, touching the ones which are capable of carrying the active substance as well as the relevant, commercially available multiparticle-based medical devices. The versatility in size from 1 µm and multiplicity of formulation technologies promise a solid foundation for the future applications of dosage form design and development.
Topics: Humans; Drug Delivery Systems; Pharmaceutical Preparations; Excipients
PubMed: 38228279
DOI: 10.1016/j.ejps.2024.106704 -
Materials (Basel, Switzerland) Jul 2023Palygorskite is an aluminum and magnesium silicate characterized by its fibrous morphology, providing it with great versatility in industrial applications, including...
Palygorskite is an aluminum and magnesium silicate characterized by its fibrous morphology, providing it with great versatility in industrial applications, including pharmaceuticals. Although most of the reserves are in the United States, in recent years occurrences of commercially exploited deposits in Brazil have been recorded, mainly in the country's northeast region. This has motivated this study, which analyzes raw Brazilian palygorskite compared to a commercial sample (Pharmasorb colloidal) to demonstrate its pharmaceutical potential. The chemical and mineral composition of the samples were evaluated for surface properties, granulometry, morphology, crystallography, thermal analysis, and spectroscopy. Raw palygorskite presented 67% purity, against 74% for Pharmasorb colloidal. The percentage purity relates to the presence of contaminants, mainly carbonates and quartz (harmless under conventional conditions of pharmaceutical use). Furthermore, it was possible to confirm the chemical composition of these phyllosilicates, formed primarily of silicon, aluminum, and magnesium oxides. The crystallographic and spectroscopic profiles were consistent in both samples, showing characteristic peaks for palygorskite (2θ = 8.3°) and bands attributed to fibrous phyllosilicates below 1200 cm, respectively. The thermal analysis allowed the identification of the main events of palygorskite, with slight differences between the evaluated samples: loss of water adsorbed onto the surface (~85 °C), removal of water contained in the channels (~200 °C), coordinated water loss (~475 °C), and, finally, the dehydroxylation (>620 °C). The physicochemical characteristics of raw palygorskite align with pharmacopeial specifications, exhibiting a high specific surface area (122 m/g), moderately negative charge (-13.1 mV), and compliance with the required limits for heavy metals and arsenic. These favorable technical attributes indicate promising prospects for its use as a pharmaceutical ingredient in the production of medicines and cosmetics.
PubMed: 37512238
DOI: 10.3390/ma16144962 -
Pharmaceuticals (Basel, Switzerland) Aug 2023To investigate the effects of (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000 succinate...
To investigate the effects of (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000 succinate (TPGS), sodium desoxycholate (SDOCH), trimethyl chitosan (TMC), and sodium caprate (C10) on the plasma concentration and the oral bioavailability of tigecycline in broiler chickens. To test the effects of the excipients on absorption of tigecycline, a tetracycline that is poorly absorbed from the gastrointestinal tract, broiler chickens were used as an animal model. Tigecycline (10 mg/kg body weight) was administered intravenously, orally, and orally with one of the excipients. Plasma samples were taken after administration. To measure tigecycline concentrations, high-performance liquid chromatography coupled with tandem mass spectrometry was used. Compartmental and non-compartmental analyses were used for pharmacokinetic analyses of mean plasma concentrations versus time. With the exception of sodium caprate, all the excipients significantly increased the area under the curve and bioavailability of tigecycline ( < 0.05). These parameters were approximately doubled by HP-β-CD, TPGS, and SDOCH, with 95% confidence intervals (95% CIs) for the difference that included only increases of 1.5-fold or higher (bioavailability: control, 1.67%; HP-β-CD, 3.24%; TPGS, 3.30%; and SDOCH, 3.24%). The increases in these parameters were smaller with DM-β-CD and TMC (DM-β-CD, 2.41%; TMC, 2.55%), and the 95% CIs ranged from close to no difference to nearly double the values in the control group. These results indicate that HP-β-CD, TPGS, and SDOCH substantially increase the area under the curve and oral bioavailability of tigecycline. They suggest that DM-β-CD and TMC may also substantially increase these parameters, but more research is needed for more precise estimates of their effects.
PubMed: 37631025
DOI: 10.3390/ph16081111 -
Molecules (Basel, Switzerland) Jul 2023Cyclodextrins (CDs) are a family of carrier molecules used to improve the pharmacokinetic parameters of therapeutic molecules. These cyclic oligosaccharides have medical... (Review)
Review
Cyclodextrins (CDs) are a family of carrier molecules used to improve the pharmacokinetic parameters of therapeutic molecules. These cyclic oligosaccharides have medical and pharmaceutical applications by being able to form inclusion complexes with molecules that are poorly soluble in water. The benefits of these complexes are directed towards improving the chemical and biological properties-i.e., solubility, bioavailability, stability, non-toxicity and shelf life of drug molecules. Since the 1960s, the first inclusion complexes used in therapeutics were those with α-, β- and γ-CD, which proved their usefulness, but had certain degrees of particularly renal toxicity. Currently, to correct these deficiencies, β-CD derivatives are most frequently used, such as sulfobutylether-β-CD, hydroxypropyl-β-CD, etc. Therefore, it is of interest to bring to the attention of those interested the diversity of current and potential future clinical applications of inclusion complexes in veterinary medicine and to present the contribution of these inclusion complexes in improving drug efficacy. The most important biological activities of β-CD complexed molecules in the veterinary field are summarized in this short review.
Topics: Cyclodextrins; Excipients; Solubility; Biological Availability; Water; 2-Hydroxypropyl-beta-cyclodextrin
PubMed: 37513437
DOI: 10.3390/molecules28145565 -
Journal of Pharmaceutical Sciences Jul 2023N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework... (Review)
Review
N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of N-nitrosamines in drug products. One strategy to inhibit the formation of N-nitrosamines during the manufacture and storage of drug products involves the incorporation of nitrite scavengers in the formulation. Diverse molecules have been tested in screening studies including the antioxidant vitamins ascorbic acid and α-tocopherol, amino acids, and other antioxidants used in foods or drugs, for inclusion into drug products to mitigate N-nitrosamine formation. This review article outlines key considerations for the inclusion of nitrite scavengers in oral drug product formulations.
Topics: Humans; Nitrosamines; Nitrites; Antioxidants; Ascorbic Acid; Pharmaceutical Preparations
PubMed: 37023856
DOI: 10.1016/j.xphs.2023.03.022