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European Journal of Pharmaceutics and... Aug 2023Pharmaceutical excipients are an important part of biological products. However, few attempts have been made to distinguish between the risk of inflammation associated...
BACKGROUND
Pharmaceutical excipients are an important part of biological products. However, few attempts have been made to distinguish between the risk of inflammation associated with the biological products themselves and that associated with excipients. The analysis of early immune response risk associated with excipients added to biological products is an important step in exploring the complex mechanism of side effects in susceptible patients.
METHODS AND RESULTS
In this study, nanoparticle impurities (NPIs) were extracted from trehalose and characterized. A mouse popliteal lymph node cell (PLNA) model, a mouse spleen lymphocyte model, a human peripheral blood mononuclear cell cytokine release model, and a macrophage complement activation model were established to comprehensively evaluate the early immune risk related to impurities in the trehalose excipient. Although popliteal lymph node cell counts in mice did not show significant differences, all other models indicated possible immune risk. In the PLNA model, NPIs caused significant toe thickening in mice, whereby the content of IgE and MCP-1 increased significantly. NPIs significantly increased the proliferation and differentiation of spleen lymphocytes according to the CCK-8 assay and flow cytometry. After treatment with NPIs, the release of IgE and a variety of cytokines (MIP-1α, IFN-γ, IL-2, IL-8, TNF-α, IL-6, IL-1α) in human peripheral blood cells was significantly increased according to ELISA, while a concomitant increase of C3a/C5a as well as C4a/Bb proved that NPIs activated the complement system.
CONCLUSION
NPIs from trehalose elicited an immune response in vitro, and the immune response to trehalose may be related to NPIs and not the excipient itself. Different batches of trehalose showed different immune response effects. The currents research suggests that when trehalose is applied in high-risk administration routes, NPIs should be assessed and reasonably controlled.
Topics: Humans; Mice; Animals; Excipients; Trehalose; Leukocytes, Mononuclear; Cytokines; Immunity; Immunoglobulin E; Biological Products
PubMed: 37354998
DOI: 10.1016/j.ejpb.2023.06.011 -
Drug Development and Industrial Pharmacy Dec 2023The present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma (HCC)...
OBJECTIVE
The present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma (HCC) treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs.
SIGNIFICANCE
The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations.
METHODS
The non-oncology drugs (alone and in combinations) were screened for anticancer effect (against HepG2 cells) using (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as ketoconazole (KCZ), disulfiram (DSR), tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin US2 (adsorbent carrier), which was developed and characterized.
RESULTS
The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 pmol), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The DTX inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm), and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss).
CONCLUSION
The current study revealed a non-oncology drug combination effective against HCC. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.
Topics: Humans; Carcinoma, Hepatocellular; Emulsions; Caco-2 Cells; Drug Repositioning; Liver Neoplasms; Drug Delivery Systems; Excipients; Docetaxel; Administration, Oral; Solubility
PubMed: 37216496
DOI: 10.1080/03639045.2023.2216785 -
International Journal of Pharmaceutics Jul 2023Powder flow is a critical attribute of pharmaceutical blends to ensure tablet weight uniformity and production of tablets with consistent and reproducible properties....
Powder flow is a critical attribute of pharmaceutical blends to ensure tablet weight uniformity and production of tablets with consistent and reproducible properties. This study aims at characterizing different powder blends with a number of different rheologic techniques, in order to understand how particles' attributes and interaction between components within the formulation generate different responses when analysed by different rheological tests. Furthermore, this study intends on reducing the number of tests in early development phases, by selecting the ones that provide the best information about the flowability attributes of the pharmaceutical blends. This work considered two cohesive powders - spray-dried hydroxypropyl cellulose (SD HPMC) and micronized indomethacin (IND) - formulated with other four commonly used excipients [(lactose monohydrated (LAC), microcrystalline cellulose (MCC), magnesium stearate (MgSt) and colloidal silica (CS)]. The experimental results showed that powder flowability may be affected by materials particles' size, bulk density, morphology, and interactions with lubricant. In detail, parameters, such as angle of repose (AoR), compressibility percentage (CPS), and flow function coefficient (ff) have shown to be highly affected by the particle size of the materials present in the blends. On the other hand, the Specific Energy (SE) and the effective angle of internal friction (φe) showed to be more related with particle morphology and materials interaction with the lubricant. Since both ff and φe parameters are generated from the yield locus test, data suggest that a number of different powder flow features may be understood only by applying this test, avoiding redundant powder flow characterization, as well as extensive time and material spent in early development formulation stages.
Topics: Powders; Excipients; Rheology; Tablets; Particle Size; Lubricants
PubMed: 37279868
DOI: 10.1016/j.ijpharm.2023.123107 -
Molecular Pharmaceutics Aug 2023Small extracellular vesicles (sEVs) are produced by most cells and play an important role in cell-to-cell communication and maintaining cellular homeostasis. Their... (Review)
Review
Small extracellular vesicles (sEVs) are produced by most cells and play an important role in cell-to-cell communication and maintaining cellular homeostasis. Their ability to transfer biological cargo to target cells makes them a promising tool for cancer drug delivery. Advances in sEV engineering, EV mimetics, and ligand-directed targeting have improved the efficacy of anticancer drug delivery and functionality. EV-based RNA interference and hybrid miRNA transfer have also been extensively used in various preclinical cancer models. Despite these developments, gaps still exist in our understanding of using sEVs to treat solid tumor malignancies effectively. This article provides an overview of the last five years of sEV research and its current status for the efficient and targeted elimination of cancer cells, which could advance cancer research and bring sEV formulations into clinical use.
Topics: Medical Oncology; Extracellular Vesicles; Cell Communication; Drug Delivery Systems; Excipients
PubMed: 37410017
DOI: 10.1021/acs.molpharmaceut.3c00363 -
International Journal of Biological... Dec 2023For the drug delivery system, drug carriers' selection is critical to the drug's success in reaching the desired target. Drug carriers from natural biopolymers are... (Review)
Review
For the drug delivery system, drug carriers' selection is critical to the drug's success in reaching the desired target. Drug carriers from natural biopolymers are preferred over synthetic materials due to their biocompatibility. The use of polysaccharide gums in the drug delivery system has received considerable attention in recent years. Polysaccharide gums are renewable resources and abundantly found in nature. They could be isolated from marine algae, microorganisms, and higher plants. In terms of carbohydrates, the gums are water-soluble, non-starch polysaccharides with high commercial value. Polysaccharide gums are widely used for controlled-release products, capsules, medicinal binders, wound healing agents, capsules, and tablet excipients. One of the essential applications of polysaccharide gum is drug delivery systems. The various kinds of polysaccharide gums obtained from different plants, marine algae, and microorganisms for the drug delivery system application are discussed comprehensively in this review paper.
Topics: Polysaccharides; Drug Delivery Systems; Drug Carriers; Excipients; Plant Gums
PubMed: 37741484
DOI: 10.1016/j.ijbiomac.2023.127020 -
Biomaterial-enabled therapeutic modulation of cGAS-STING signaling for enhancing antitumor immunity.Molecular Therapy : the Journal of the... Jul 2023cGAS-STING signaling is a central component in the therapeutic action of most existing cancer therapies. The accumulated knowledge of tumor immunoregulatory network in... (Review)
Review
cGAS-STING signaling is a central component in the therapeutic action of most existing cancer therapies. The accumulated knowledge of tumor immunoregulatory network in recent years has spurred the development of cGAS-STING agonists for tumor treatment as an effective immunotherapeutic strategy. However, the clinical translation of these agonists is thus far unsatisfactory because of the low immunostimulatory efficacy and unrestricted side effects under clinically relevant conditions. Interestingly, the rational integration of biomaterial technology offers a promising approach to overcome these limitations for more effective and safer cGAS-STING-mediated tumor therapy. Herein, we first outline the cGAS-STING signaling axis and generally discuss its association with tumors. We then symmetrically summarize the recent progress in those biomaterial-based cGAS-STING agonism strategies to generate robust antitumor immunity, categorized by the chemical nature of those cGAS-STING stimulants and carrier substrates. Finally, a perspective is provided to discuss the existing challenges and potential opportunities in cGAS-STING modulation for tumor therapy.
Topics: Biocompatible Materials; Excipients; Immunity, Innate; Immunization; Nucleotidyltransferases; Signal Transduction; Neoplasms; Antineoplastic Agents
PubMed: 37002605
DOI: 10.1016/j.ymthe.2023.03.026 -
Pharmaceutics May 2024Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can...
Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the pharmacokinetic effect of PEG400 on baicalin in hepatocytes and its mechanism, the present study first started with the effect of PEG400 on the metabolic disposition of baicalin at the hepatocyte level, and then the effect of PEG400 on the protein expression of baicalin-related transporters (BCRP, MRP2, and MRP3) was investigated by using western blot; the effect of MDCKII-BCRP, MDCKII-BCRP, MRP2, and MRP3 was investigated by using MDCKII-BCRP, MDCKII-MRP2, and MDCKII-MRP3 cell monolayer models, and membrane vesicles overexpressing specific transporter proteins (BCRP, MRP2, and MRP3), combined with the exocytosis of transporter-specific inhibitors, were used to study the effects of PEG400 on the transporters in order to explore the possible mechanisms of its action. The results demonstrated that PEG400 significantly influenced the concentration of baicalin in hepatocytes, and the AUC of baicalin increased from 75.96 ± 2.57 μg·h/mL to 106.94 ± 2.22 μg·h/mL, 111.97 ± 3.98 μg·h/mL, and 130.42 ± 5.26 μg·h/mL ( ˂ 0.05). Furthermore, the efflux rate of baicalin was significantly reduced in the vesicular transport assay and the MDCKII cell model transport assay, which indicated that PEG400 had a significant inhibitory effect on the corresponding transporters. In conclusion, PEG400 can improve the bioavailability of baicalin to some extent by affecting the efflux transporters and thus the metabolic disposition of baicalin in the liver.
PubMed: 38931853
DOI: 10.3390/pharmaceutics16060731 -
Nutrients Aug 2023Gestational diabetes mellitus (GDM), defined as abnormal glucose tolerance that presents during the second and third trimesters of pregnancy, is a growing issue in the... (Randomized Controlled Trial)
Randomized Controlled Trial
Gestational diabetes mellitus (GDM), defined as abnormal glucose tolerance that presents during the second and third trimesters of pregnancy, is a growing issue in the United States and worldwide. If left untreated or poorly controlled, GDM can result in numerous consequences for both the mother and the fetus; thus, it is imperative that different avenues of management for GDM be explored. There is a paucity of studies that examine how lifestyle changes, including dietary and physical activity, affect management of GDM. We examined how counseling on lifestyle changes can affect cardiometabolic risks in women with GDM. We conducted a 12-week randomized controlled trial based on behavioral counseling in which women with GDM (N = 38) were randomized into either a nutrition education (control) (N = 18) group or nutrition intervention (N = 20) group. The nutrition education group were given dietary counseling regarding healthy dietary choices based on USDA guidelines, while the nutrition intervention group were instructed to consume a total of one cup of whole berries and one cup of leafy vegetables daily along with performing postprandial exercise (walking). Blood samples, anthropometric measures, and dietary and physical activity data, recorded in daily food and activity logs, were collected at baseline and at the end of the study and compared between the two groups. Dietary counseling on supplementation with whole berries and leafy vegetables resulted in increased fiber intake, increased antioxidant intake and total serum antioxidant capacity, improved random blood glucose, decreased serum IL-6, and improved HDL cholesterol versus the control group (all < 0.05). These results highlight that whole berry and leafy vegetable supplementation-based dietary counseling can improve the metabolic pathways involved in gestational diabetes pathogenesis and prognosis. These functional foods must be recommended in the management of pregnancies affected by GDM.
Topics: Pregnancy; Female; Humans; Fruit; Vegetables; Diabetes, Gestational; Antioxidants; Nutritional Status; Excipients
PubMed: 37630814
DOI: 10.3390/nu15163624 -
Current Pharmaceutical Design 2024
Topics: Artificial Intelligence; Excipients; Humans; Pharmaceutical Preparations
PubMed: 38288798
DOI: 10.2174/0113816128285827240119095013 -
Food Chemistry Oct 2023In this study, tomato sauces were prepared by adding different levels of emulsified oil (0, 5, 10, or 20 wt%) to tomato pomace. The effects of adding these excipient...
In this study, tomato sauces were prepared by adding different levels of emulsified oil (0, 5, 10, or 20 wt%) to tomato pomace. The effects of adding these excipient emulsions on the concentration, bioaccessibility, and bioactivity of the carotenoids and phenolics in the tomato sauces were then determined. The carotenoid and phenolic profiles were analyzed by HPLC and LC-MS/MS, respectively. The bioaccessibility values of the lycopene, lutein, and β-carotene were around 36-82%, 73-112%, and 67-94% for tomato sauces with excipient emulsions, respectively. In contrast, they were considerably lower for tomato sauces without excipient emulsions, being around 24-31%, 69-71%, and 45-62%, respectively. The TPC and TAC values of the tomato sauces with the excipient emulsions were significantly higher than those without. Considerably higher concentrations of carotenoids and phenolic compounds were detected in the tomato sauce samples containing the excipient emulsions. These results suggest that the presence of the oil droplets increased the extractability, stability, and bioaccessibility of the nutraceuticals in the tomato sauce.
Topics: Antioxidants; Emulsions; Excipients; Solanum lycopersicum; Chromatography, Liquid; Biological Availability; Tandem Mass Spectrometry; Carotenoids; Phenols
PubMed: 37263092
DOI: 10.1016/j.foodchem.2023.136395