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Oral administration of peptide represents a promising delivery route, however, it is hindered by the harsh gastrointestinal environment, leading to low in vivo absorption. In this study, auto-adaptive protein corona-AT 1002-cationic liposomes (Pc-AT-CLs) are constructed with the characteristic of hydrophilic and electrically neutral surface properties for the encapsulation of liraglutide. BSA protein corona is used to coat AT-CLs reducing the adherence of mucus, and may fall off after penetrating the mucus layer. Transmucus transport experiment demonstrated that the mucus penetration amount of Pc-AT-CLs are 1.45 times that of AT-CLs. After penetrating the mucus layer, AT-CLs complete transmembrane transport by the dual action of AT and cationic surface properties. Transmembrane transport experiment demonstrated that the apparent permeability coefficient (Papp) of AT-CLs is 2.03 times that of CLs. In vivo tests demonstrated that Pc-AT-CLs exhibited a significant hypoglycemic effect and enhanced the relative bioavailability comparing to free liraglutide. Pc-AT-CLs protect liraglutide from degradation, facilitate its absorption, and ultimately improve its oral bioavailability.
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Sistemas de Liberación de Medicamentos , Hipoglucemiantes , Liposomas , Liraglutida , Moco , Animales , Liraglutida/administración & dosificación , Liraglutida/farmacocinética , Liraglutida/farmacología , Moco/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/química , Humanos , Disponibilidad Biológica , Administración Oral , Masculino , Ratas Sprague-Dawley , Ratas , Absorción Intestinal/efectos de los fármacosRESUMEN
Endometrial cancer is one of the three major malignant tumors of the reproductive system that threaten women's lives and health. The incidence of this disease is on the rise globally. Most cases of endometrial cancer comprise endometrioid adenocarcinomas, whose treatment is challenged by factors such as their high recurrence rate and the need to preserve fertility among young patients. Thus, oral endocrine therapy has become the main treatment modality. The main drugs used in oral endocrine therapy are progestins, selective estrogen receptor antagonists, and aromatase inhibitors. However, their clinical use is hindered by their low solubility and low oral utilization. The rapid development of nanotechnology allows the combination of these drugs with oral nano-formulations to create a good carrier. Such nanocarriers, including nanospheres, nanocapsules, and micelles can protect the drug against clearance and increase the site specificity of drug delivery. This paper reviews the pathogenesis of endometrioid endometrial cancer (EEC) and oral nano-formulations for endocrine therapy.
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Benign hyperplasia (BHP) is a common disorder that affects men over the age of 60 years. Transurethral resection of the prostate (TURP) is the gold standard for operative treatment, but a range of drugs are also available to improve quality of life and to reduce BHP-associated urinary tract infections and complications. Darifenacin, an anti-muscarinic agent, has been found effective for relieving symptoms of overactive bladder associated with BHP, but the drug has poor solubility and bioavailability, which are major challenges in product development. An inorganic/organic bio-composite with gastric pH-resistant property was synthesized for the targeted oral delivery of Darifenacin to the lower gastrointestinal tract (GIT). This development was accomplished through co-precipitation of calcium carbonate in quince seed-based mucilage. The FTIR, XRD, DSC, and TGA results showed good drug-polymer compatibility, and the SEM images showed calcite formation in the quince hydrogel system. After 72 h, the drug release of 34% and 75% were observed in acidic (0.1N HCl) and 6.8 pH phosphate buffer, respectively. A restricted/less drug was permeated through gastric membrane (21.8%) as compared to permeation through intestinal membrane (65%.) The developed composite showed significant reduction in testosterone-induced prostatic hyperplasia (2.39 ± 0.12***) as compared to untreated diseased animal group. No sign of organ toxicity was observed against all the developed composites. In this study, we developed an inorganic-organic composite system that is highly biocompatible and effective for targeting the lower GIT, thereby avoiding the first-pass metabolism of darifenacin.
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Benzofuranos , Pirrolidinas , Solubilidad , Administración Oral , Animales , Benzofuranos/administración & dosificación , Benzofuranos/farmacocinética , Benzofuranos/química , Benzofuranos/farmacología , Masculino , Pirrolidinas/química , Pirrolidinas/administración & dosificación , Liberación de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Ratas , Hiperplasia Prostática/tratamiento farmacológico , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacocinética , Disponibilidad Biológica , Carbonato de Calcio/química , Concentración de Iones de Hidrógeno , Hidrogeles/química , Polímeros/químicaRESUMEN
Helicobacter pylori infects the gastric mucosa and induces chronic gastritis, peptic ulcers, and gastric cancer. Research has demonstrated that vaccination can induce a protective immune response and prevent H. pylori infection. Oral administration of the Lactococcus lactis live-carrier vaccine is safe and easily complied with by the public. In this study, two recombinant L. lactis strains were constructed that expressed antigens of H. pylori urease subunit alpha (UreA) and UreA fused with Escherichia coli heat-labile toxin B subunit (LTB-UreA), named LL-UreA and LL-LTB-UreA, respectively. The expression of antigen proteins was confirmed by Western blotting analysis. Survival assessment indicated that the engineered L. lactis could colonize in the digestive tract of BALB/c mice up to 10 days after the last oral administration with our immunization protocol. The ability to induce immune response and immune protective efficacy of the L. lactis were confirmed. These results indicated that oral administration with LL-UreA or LL-LTB-UreA could induce UreA-specific mucosal secretory IgA (sIgA) and cellular immune response, significantly increasing the cytokines levels of interferon-gamma (IFN-γ), interleukin (IL)-17A, and IL-10, together with the proportion of CD4+IFN-γ+ T cells and CD4+IL17A+ T cells. More importantly, oral administration of LL-UreA and LL-LTB-UreA brought about effective protection in mice to prevent H. pylori infection, especially LL-UreA, resulting in 70% of mice showing no H. pylori colonization and the remaining 30% showing only low levels of colonization. These findings underscore the potential of using orally administered engineered L. lactis vaccines to prevent H. pylori infection.
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Background: Chemotherapeutic drugs have some drawbacks in antineoplastic therapy, mainly containing seriously toxic side effects caused by injection and multi-drug resistance (MDR). Co-delivery with two or more drugs via nanomicelles is a promising strategy to solve these problems. Oral chemotherapy is increasingly preferred owing to its potential to enhance the life quality of patients. Methods and Results: The study intended to develop mixed micelles using D-α-Tocopherol poly(ethylene glycol) 1000 succinate (TPGS) and soluplus for the co-encapsulation of docetaxel (DTX) and curcumin (CUR), marked as (DTX+CUR)-loaded mixed micelles, treating drug-resistant breast cancer by oral administration. The (DTX+CUR)-loaded mixed micelles had a uniform particle size (~64 nm), high drug loading and encapsulation efficiency, in vitro sustained-release properties and good pH-dependent stability. In vitro cell study, the (DTX+CUR)-loaded mixed micelles displayed the highest cellular uptake, cytotoxicity, cell apoptosis-inducing rates and cell ROS-inducing levels on MCF-7/Adr cells. Notably, in vivo pharmacokinetic studies, (DTX+CUR)-loaded mixed micelles enhanced markedly the oral absorption of DTX compared to pure DTX, with a relative oral bioavailability of 574%. The (DTX+CUR)-loaded mixed micelles by oral administration had the same anticancer efficacy as taxotere by injection in resistant breast cancer bearing mice. Conclusion: (DTX+CUR)-loaded mixed micelles could provide a potential formulation for treating drug-resistant breast cancers by oral administration.
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Antineoplásicos , Neoplasias de la Mama , Curcumina , Docetaxel , Resistencia a Antineoplásicos , Micelas , Polietilenglicoles , Curcumina/farmacocinética , Curcumina/química , Curcumina/administración & dosificación , Curcumina/farmacología , Docetaxel/farmacocinética , Docetaxel/administración & dosificación , Docetaxel/química , Docetaxel/farmacología , Humanos , Femenino , Animales , Neoplasias de la Mama/tratamiento farmacológico , Administración Oral , Resistencia a Antineoplásicos/efectos de los fármacos , Células MCF-7 , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Vitamina E/química , Vitamina E/administración & dosificación , Vitamina E/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Polivinilos/química , Polivinilos/farmacocinética , Polivinilos/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula , Taxoides/farmacocinética , Taxoides/administración & dosificación , Taxoides/química , Taxoides/farmacología , Liberación de Fármacos , Ratas Sprague-DawleyRESUMEN
Purpose: Conventional oral formulations for inflammatory bowel disease (IBD) treatment are less than satisfactory, due to the poor controllability of drug release and lack of specificity to the inflammation sites in the gastrointestinal (GI) tract. To overcome these limitations, we developed a multiple carbohydrate-based nanosystem with pH/ROS dual responsibility and charge-mediated targeting ability for IBD-specific drug delivery. Methods: In view of the overproduction of ROS and overexpression of cationic proteins in the inflammatory colon, the designed nanosystem was composed of oxidation-sensitive cyclodextrin (OX-CD), chitosan (CS) and pectin (AHP). OX-CD was utilized to load dexamethasone (DM) by the solvent evaporation method. CS and AHP with opposite charges were sequentially coated onto OX-CD to generate the nanosystems by the electrostatic self-assembly method. The physicochemical properties, stability, dual-sensitive drug release behavior, cytotoxicity, cellular uptake and anti-inflammatory activity were investigated in vitro. In vivo bio-distribution and therapeutic efficacy of the nanosystem were further evaluated in the ulcerative colitis (UC) mice. Results: The obtained AHP/CS/OX-CD-DM nanosystem (ACOC-DM) could maintain stability under the GI pH environments, and release drug in the inflammatory colon with pH/ROS sensitivity. Dual polysaccharide-coated ACOC-DM exhibited higher cellular uptake and anti-inflammatory efficacy in macrophages than single polysaccharide-coated CS/OX-CD-DM nanosystem (COC-DM). Orally administrated ACOC-DM could enhance inflammation targeting ability and therapeutic efficacy of DM in the UC mice. Conclusion: This carbohydrate-based nanosystem with pH/ROS dual sensitivity and inflammation targeting capacity may serve as a safe and versatile nanoplatform for IBD therapy.
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Antiinflamatorios , Quitosano , Colitis Ulcerosa , Dexametasona , Pectinas , Animales , Colitis Ulcerosa/tratamiento farmacológico , Ratones , Quitosano/química , Dexametasona/química , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Dexametasona/farmacología , Pectinas/química , Antiinflamatorios/química , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antiinflamatorios/farmacocinética , Ciclodextrinas/química , Ciclodextrinas/farmacología , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Células RAW 264.7 , Concentración de Iones de Hidrógeno , Humanos , Especies Reactivas de Oxígeno/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Portadores de Fármacos/química , Masculino , Nanopartículas/químicaRESUMEN
Purpose: Docetaxel (DTX) is a valuable anti-tumor chemotherapy drug with limited oral bioavailability. This study aims to develop an effective oral delivery system for DTX using natural nanoparticles (Nnps) derived from Coptidis Rhizoma extract. Methods: DTX-loaded self-assembled nanoparticles (Nnps-DTX) were created using an optimized heat-induction strategy. Nnps-DTX's shape, size, Zeta potential, and in vitro stability were all carefully examined. Additionally, the study investigated the encapsulation efficiency, loading capacity, crystal form, and intermolecular interactions of DTX in Nnps-DTX. Subsequently, the solubility, release, cellular uptake, metabolic stability, and preclinical pharmacokinetics of DTX in Nnps-DTX were systematically evaluated. Finally, the cytotoxicity of Nnps-DTX was assessed in three tumor cell lines. Results: Nnps-DTX was spherical in shape, 138.6 ± 8.2 nm in size, with a Zeta potential of -20.8 ± 0.6 mV, a DTX encapsulation efficiency of 77.6 ± 8.5%, and a DTX loading capacity of 6.8 ± 1.9%. Hydrogen bonds, hydrophobic interactions, and electrostatic interactions were involved in the formation of Nnps-DTX. DTX within Nnps-DTX was in an amorphous form, resulting in enhanced solubility (23.3 times) and release compared to free DTX. Following oral treatment, the mice in the Nnps-DTX group had DTX peak concentrations 8.8, 23.4, 44.6, and 5.7 times higher in their portal vein, systemic circulation, liver, and lungs than the mice in the DTX group. Experiments performed in Caco-2 cells demonstrated a significant increase in DTX uptake by Nnps-DTX compared to free DTX, which was significantly inhibited by indomethacin, an inhibitor of caveolae-mediated endocytosis. Furthermore, compared to DTX, DTX in Nnps-DTX demonstrated better metabolic stability in liver microsomes. Notably, Nnps-DTX significantly reduced the viability of MCF-7, HCT116, and HepG2 cells. Conclusion: The novel self-assembled nanoparticles considerably enhanced the cellular absorption, solubility, release, metabolic stability, and pharmacokinetics of oral DTX and demonstrated strong cytotoxicity against tumor cell lines.
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Docetaxel , Nanopartículas , Animales , Docetaxel/farmacocinética , Docetaxel/química , Docetaxel/farmacología , Docetaxel/administración & dosificación , Humanos , Administración Oral , Nanopartículas/química , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Ratones , Línea Celular Tumoral , Coptis chinensis , Tamaño de la Partícula , Masculino , Liberación de Fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Supervivencia Celular/efectos de los fármacos , Disponibilidad Biológica , Solubilidad , Ratas Sprague-Dawley , Ratones Endogámicos BALB CRESUMEN
Peptide glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective drugs for treating type 2 diabetes (T2DM) and have been proven to benefit the heart and kidney. Apart from oral semaglutide, which does not require injection, other peptide GLP-1RAs need to be subcutaneously administered. However, oral semaglutide also faces significant challenges, such as low bioavailability and frequent gastrointestinal discomfort. Thus, it is imperative that advanced oral strategies for peptide GLP-1RAs need to be explored. This review mainly compares the current advantages and disadvantages of various oral delivery strategies for peptide GLP-1RAs in the developmental stage and discusses the latest research progress of peptide GLP-1RAs, providing a useful guide for the development of new oral peptide GLP-1RA drugs.
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Aortic dissection (AD) is a severe cardiovascular disease necessitating active therapeutic strategies for early intervention and prevention. Nucleic acid drugs, known for their potent molecule-targeting therapeutic properties, offer potential for genetic suppression of AD. Piwi-interacting RNAs, a class of small RNAs, hold promise for managing cardiovascular diseases. Limited research on these RNAs and AD exists. This study demonstrates that an antagomir targeting heart-apoptosis-associated piRNA (HAAPIR) effectively regulates vascular remodeling, mitigating AD occurrence and progression through the myocyte enhancer factor 2D (Mef2D) and matrix metallopeptidase 9 (MMP9) pathways. Green tea-derived plant exosome-like nanovesicles (PELNs) are used for oral administration of antagomir. The antagomir-HAAPIR-nanovesicle complex, after purification and optimization, exhibits a high packing rate, while the antagomir is resistant to enzyme digestion. Administered to mice, the complex targets the aortic lesion, reducing AD incidence and improving survival. Moreover, MMP9 and Mef2D expression decrease significantly, inhibiting the phenotypic conversion of human aortic smooth muscle cells. PELNs encapsulate the antagomir-HAAPIR complex, maintaining stability, mediating transport into the bloodstream, and delivering Piwi-interacting RNAs to AD sites. Thus, HAAPIR is a potential target for persistent clinical AD prevention and treatment, and nanovesicle-encapsulated nucleic acids offer a promising cardiovascular disease treatment, providing insights for other therapeutic targets.
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3D-printed dosage forms comprised of Carbopol and Eudragit were fabricated through semi-solid extrusion, combining Enoxaparin (Enox) and the permeation enhancer SNAC in a single-step process without subsequent post-processing. Inks were characterized using rheology and Fourier-transform infrared (FTIR) spectroscopy. The stability of Enox in the fabricated dosage forms was assessed by means of Nuclear Magnetic Resonance (NMR) and Circular Dichroism (CD) analysis. In vitro release studies revealed the release of Enox in a sustained manner, whereas ex vivo experiments demonstrated the mucoadhesive properties of the 3D-printed dosage forms and their ability to enhance Enox permeability across intestinal mucosa. Cellular assays (CCK-8 assay) revealed a dose- and time-dependent response following incubation with the 3D-printed dosage forms. The encapsulation of SNAC in the 3D-printed dosage forms demonstrated their capacity to increase the transcellularly transport of macromolecule across Caco-2 monolayer in a reversible manner, as confirmed by Transepithelial Resistance (TEER) measurements.
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Liberación de Fármacos , Enoxaparina , Impresión Tridimensional , Comprimidos , Células CACO-2 , Humanos , Administración Oral , Enoxaparina/administración & dosificación , Enoxaparina/farmacocinética , Enoxaparina/química , Resinas Acrílicas/química , Animales , Ácidos Polimetacrílicos/química , Mucosa Intestinal/metabolismo , Masculino , Sistemas de Liberación de Medicamentos/métodos , Adhesividad , Permeabilidad , Polivinilos/química , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Anticoagulantes/químicaRESUMEN
A general platform for the safe and effective oral delivery of biologics would revolutionize the administration of protein-based drugs, improving access for patients and lowering the financial burden on the health-care industry. Because of their dimensions and physiochemical properties, nanomaterials stand as promising vehicles for navigating the complex and challenging environment in the gastrointestinal (GI) tract. Recent developments have led to materials that protect protein drugs from degradation and enable controlled release in the small intestine, the site of absorption for most proteins. Yet, once present in the small intestine, the protein must transit through the secreted mucus and epithelial cells of the intestinal mucosa into systemic circulation, a process that remains a bottleneck for nanomaterial-based delivery. One attractive pathway through the intestinal mucosa is the paracellular route, which avoids cell trafficking and other degradative processes in the interior of cells. Direct flux between cells is regulated by epithelial tight junctions (TJs) that seal the paracellular space and prevent protein flux. Here, we describe a smart nanoparticle system that directly and transiently disrupts TJs for improved protein delivery, an unrealized goal to-date. We take inspiration from enteropathogenic bacteria that adhere to intestinal epithelia and secrete inhibitors that block TJ interactions in the local environment. To mimic these natural mechanisms, we engineer nanoparticles (EnteroPatho NPs) that attach to the epithelial glycocalyx and release TJ modulators in response to the intestinal pH. We show that EnteroPatho NPs lead to TJ disruption and paracellular protein delivery, giving rise to a general platform for oral delivery.
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Nanopartículas , Uniones Estrechas , Humanos , Nanopartículas/química , Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Proteínas/química , Proteínas/metabolismo , Mucosa Intestinal/metabolismo , Portadores de Fármacos/química , Células CACO-2 , AnimalesRESUMEN
The incidence of ulcerative colitis (UC) is rapidly rising worldwide. Oral drug delivery system is a promising approach for treating UC, but it often fails to accumulate to the inflammatory lesions, thus, it is impressive to develop a colon-targeted oral delivery system for preventing systemic toxicity and maintaining UC therapeutics. Here, a negative-charged PLGA nanoparticle system was designed to encapsulate celastrol (Cel), and then chitosan and mannose were coated on the surface of the nanoparticles (MC@Cel-NPs) to endow these nanoparticles with the mucosal adsorption and macrophage targeting abilities. MC@Cel-NPs demonstrate excellent resist decomposition ability against the strong acidic gastrointestinal environment, and accumulates in the specific inflammatory sites through the affinity of electrostatic reaction. After releasing the payload, MC@Cel-NPs could remarkably alleviate the colon inflammation, which was evidenced by the decrease in pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 in both blood and colon sections, and scavenging reactive oxygen species (ROS) in colon cells, including macrophage, neutrophil, T cell, and B cell. This nanoparticle system provided a new approach for treating UC through a Chinese herbal ingredient-related oral delivery manner.
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Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable â¼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a 'gut neutral' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota - an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.
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Antipsicóticos , Disponibilidad Biológica , Emulsiones , Microbioma Gastrointestinal , Lípidos , Clorhidrato de Lurasidona , Nanopartículas , Solubilidad , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Ratas , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Antipsicóticos/química , Masculino , Clorhidrato de Lurasidona/administración & dosificación , Clorhidrato de Lurasidona/farmacocinética , Clorhidrato de Lurasidona/química , Administración Oral , Nanopartículas/química , Lípidos/química , Ratas Sprague-Dawley , Agua/química , Excipientes/química , Química Farmacéutica/métodosRESUMEN
Insulin is commonly administered to diabetic patients subcutaneously and has shown poor patient compliance. Due to this, research has been carried out extensively to find molecules that could deliver insulin orally. In this context, a new type of pH-responsive hydrogel, composed of microcrystalline cellulose and methacrylic acid-based hydrogels, has been developed and studied for the oral delivery of insulin. These hydrogels were prepared by free radical polymerization using potassium persulphate as initiator and N, N'-methylenebisacrylamide as a cross-linker. These pH-sensitive hydrogels showed swelling in distilled water as high as 5800 %. The hydrogels were investigated for swelling in saline and glucose solutions, and pH sensitivity was confirmed by swelling in solutions of different pH. The morphological shape was established by SEM, and the structure was analyzed by FTIR. Thermal degradation was investigated by TGA. In vitro release studies have confirmed pH sensitivity, showing lower insulin release at pH 1.2 than at pH 6.8. The encapsulation efficiency was determined to be 56.00 ± 0.04 %. It was further validated by in-vivo investigations for which insulin was loaded into hydrogels and administered orally to healthy and diabetic Wistar rats at 40 IU/kg, showing maximum hypoglycemic effect at 6 h, which was sustained for 24 h. In the stomach's acidic environment, the gels remained unaffected due to the formation of intermolecular polymer complexes. Insulin remained in the gel and was protected from proteolytic degradation. Thus, pH-responsive methacrylic acid-based hydrogels are promising for biomedical applications, especially oral drug delivery.
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Celulosa , Liberación de Fármacos , Hidrogeles , Hipoglucemiantes , Insulina , Metacrilatos , Hidrogeles/química , Animales , Concentración de Iones de Hidrógeno , Insulina/administración & dosificación , Insulina/química , Administración Oral , Celulosa/química , Celulosa/análogos & derivados , Metacrilatos/química , Masculino , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Ratas Wistar , Sistemas de Liberación de Medicamentos , Ratas , Portadores de Fármacos/químicaRESUMEN
Successful oral insulin administration can considerably enhance the quality of life (QOL) of diabetes patients who must frequently take insulin injections. However, Oral insulin administration is seriously hampered by gastrointestinal enzymes, wide pH range, mucus and mucosal layers, which limit insulin oral bioavailability to ≤2 %. Herein, we developed a simple, inexpensive and safe dual ß-cyclodextrin/dialdehyde glucan-coated keratin nanoparticle (ß-CD-K-IN-DG). The resulted ß-CD-K-IN-DG not only gave the ultra-high insulin loading (encapsulation efficiency (98.52 %)), but also protected insulin from acid and enzymatic degradation. This ß-CD-K-IN-DG had a notable hypoglycemic effect, there was almost 80 % insulin release after 4 h of incubation under hyperglycemic conditions. Ex vivo results confirmed that ß-CD-K-IN-DG possessed high mucus-penetration ability. Transepithelial transport and uptake mechanism studies revealed that bypass transport pathway and endocytosis promoted ß-CD-K-IN-DG entered intestinal epithelial cells, thus increased the bioavailability of insulin (12.27 %). The improved stability of insulin during in vivo transport implied that ß-CD-K-IN-DG might be a potential tool for the effective oral insulin administration.
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Portadores de Fármacos , Insulina , Queratinas , Nanopartículas , beta-Ciclodextrinas , Nanopartículas/química , Insulina/administración & dosificación , Insulina/farmacocinética , Insulina/química , beta-Ciclodextrinas/química , Administración Oral , Humanos , Animales , Queratinas/química , Portadores de Fármacos/química , Glucanos/química , Disponibilidad Biológica , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratones , Masculino , Células CACO-2 , Liberación de FármacosRESUMEN
Benznidazole (BNZ) serves as the primary drug for treating Chagas Disease and is listed in the WHO Model List of Essential Medicines for Children. Herein, a new child-friendly oral BNZ delivery platform is developed in the form of supramolecular eutectogels (EGs). EGs address BNZ's poor oral bioavailability and provide a flexible twice-daily dose in stick-pack format. This green and sustainable formulation strategy relies on the gelation of drug-loaded Natural Deep Eutectic Solvents (NaDES) with xanthan gum (XG) and water. Specifically, choline chloride-based NaDES form stable and biocompatible 5 mg/mL BNZ-loaded EGs. Rheological and Low-field NMR investigations indicate that EGs are viscoelastic materials comprised of two co-existing regions in the XG network generated by different crosslink distributions between the biopolymer, NaDES and water. Remarkably, the shear modulus and relaxation spectrum of EGs remain unaffected by temperature variations. Upon dilution with simulated gastrointestinal fluids, EGs results in BNZ supersaturation, serving as the primary driving force for its absorption. Interestingly, after oral administration of EGs to rats, drug bioavailability increases by 2.6-fold, with a similar increase detected in their cerebrospinal fluid. The noteworthy correlation between in vivo results and in vitro release profiles confirms the efficacy of EGs in enhancing both peripheral and central BNZ oral bioavailability.
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Disponibilidad Biológica , Nitroimidazoles , Polisacáridos Bacterianos , Animales , Administración Oral , Nitroimidazoles/administración & dosificación , Nitroimidazoles/farmacocinética , Nitroimidazoles/química , Polisacáridos Bacterianos/química , Masculino , Sistemas de Liberación de Medicamentos/métodos , Ratas , Tripanocidas/administración & dosificación , Tripanocidas/farmacocinética , Tripanocidas/química , Geles , Solventes/química , Ratas Sprague-Dawley , Reología , Liberación de Fármacos , Colina/química , Colina/administración & dosificación , Colina/farmacocinéticaRESUMEN
Among the various pharmaceutical forms, tablets offer numerous advantages, like ease of administration, cost-effectiveness in production, and better stability of biomolecules. Beyond these benefits, the tablet form opens up possibilities for alternative routes for the local delivery of biopharmaceuticals such as oral or vaginal administration, thereby expanding the therapeutic applications of these biomolecules and overcoming the inconvenients associated with parenteral administration. However, to date there is limited information on the feasibility of developing biomolecules in the tablet form. In this study, we have evaluated the feasibility of developing monoclonal antibodies in the tablet form while preserving their biological properties. Different excipients and process parameters were studied to assess their impact on the antibody's integrity during tableting. ELISA results show that applying compression pressure up to 100 MPa is not detrimental to the antibody's binding properties when formulated from a lyophilized powder containing trehalose or sucrose as the major excipient. This observation was confirmed with SPR and ultracentrifugation experiments, which demonstrated that neither the binding affinity for both Fc and Fab antibody fragments nor its aggregation rate are affected by the tableting process. After compression, the tablets containing the antibodies have been shown to be stable for 6 months at room temperature.
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Anticuerpos Monoclonales , Excipientes , Comprimidos , Excipientes/química , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/administración & dosificación , Estabilidad de Medicamentos , Trehalosa/química , Sacarosa/química , Química Farmacéutica/métodos , Polvos , Sistemas de Liberación de Medicamentos/métodos , Composición de Medicamentos/métodos , LiofilizaciónRESUMEN
Amifostine (AMF) as the first-line radiation protection drug, usually suffered from low compliance and short half-life upon clinical applications. The development of oral drug delivery system (DDS) for AMF is a promising solution. However, the inherent shortages of AMF present significant challenges in the design of suitable oral DDS. Here in this study, we utilized the ability of calcium ions to bind with AMF and prepared AMF loaded calcium carbonate (CC) core, CC/AMF, using phase transferred coprecipitation method. We further modified the CC/AMF using phospholipids to prepare AMF loaded lipid-calcium carbonate (LCC) hybrid nanoparticles (LCC/AMF) via a thin-film dispersion method. LCC/AMF combines the oral advantages of lipid nanoparticles with the drug-loading capabilities of CC, which was shown as uniform nano-sized formulation with decent stability in aqueous solution. With favorable intestinal transport and absorption effects, it effectively enhances the in vivo radiation protection efficacy of AMF through oral administration. More importantly, we further investigated the cellular accumulation profile and intracellular transport mechanism of LCC/AMF using MDCK and Caco-2 cell lines as models. This research not only alters the current administration method of AMF to enhance its convenience and compliance, but also provides insights and guidance for the development of more suitable oral DDS for AMF in the future.
Asunto(s)
Amifostina , Carbonato de Calcio , Nanopartículas , Protectores contra Radiación , Carbonato de Calcio/química , Administración Oral , Animales , Humanos , Células CACO-2 , Protectores contra Radiación/administración & dosificación , Protectores contra Radiación/química , Protectores contra Radiación/farmacología , Protectores contra Radiación/farmacocinética , Nanopartículas/química , Amifostina/administración & dosificación , Amifostina/farmacología , Perros , Lípidos/química , Células de Riñón Canino Madin Darby , Sistemas de Liberación de Medicamentos/métodos , Protección Radiológica/métodos , Portadores de Fármacos/químicaRESUMEN
Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract (GIT). Glucagon-like peptide-2 (GLP-2) analogs possess high potential in the treatment of IBD by enhancing intestinal repair and attenuating inflammation. Due to the enzymatic degradation and poor intestinal absorption, GLP-2 analogs are administered parenterally, which leads to poor patient compliance. This work aims to develop IBD-targeted nanoparticles (NPs) for the oral delivery of the GLP-2 analog, Teduglutide (TED). Leveraging the overproduction of Reactive Oxygen Species (ROS) in the IBD environment, ROS-sensitive NPs are developed to target the intestinal epithelium, bypassing the mucus barrier. PEGylation of NPs facilitates mucus transposition, but subsequent PEG removal is crucial for cellular internalization. This de-PEGylation is possible by including a ROS-sensitive thioketal linker within the system. ROS-sensitive NPs are established, with the ability to fully de-PEGylate via ROS-mediated cleavage. Encapsulation of TED into NPs resulted in the absence of absorption in 3D in vitro models, potentially promoting a localized action, and avoiding adverse effects due to systemic absorption. Upon oral administration to colitis-induced mice, ROS-sensitive NPs are located in the colon, displaying healing capacity and reducing inflammation. Cleavable PEGylated NPs demonstrate effective potential in managing IBD symptoms and modulating the disease's progression.
RESUMEN
The potential of camel milk-derived exosomes (CMDE) to enhance the bioavailability of Cannabidiol (CBD) was investigated. CBD-CMDE formulation was prepared using an established procedure and its particle size was 138.4 ± 4.37 nm, and CBD entrapment efficiency of 56.56 ± 4.26 %. In-vitro release studies showed release of 78.27 ± 5.37 % and 46.42 ± 4.75 % CBD from CMDE and control CBD formulation respectively in pH 6.8 at 24 hr. The apparent permeability (Papp) of CBD-CMDE was found to be enhanced by 3.95-fold with Papp of 22.9*10-6 ± 0.34 cm/sec as compared to control CBD formulation with Papp of 5.8*10-6 ± 0.65 cm/sec in MDCK cells. CBD-CMDE was found to be more potent than CBD in 2D cytotoxicity assay with IC50 values of 3.6 ± 0.54 µM, 3.88 ± 0.54 µM and 7.53 ± 0.59 µM, 7.53 ± 0.59 µM against Doxorubicin (DOX) resistant MDA-MB-231 and Rapamycin (RM) resistant MDA-MB-468 breast cancer cells respectively. Moreover, 3D spheroids assay results demonstrated CBD-CMDE with IC50 values of 14 ± 0.85 µM, 15 ± 0.07 µM as compared to CBD alone with IC50 values of 25 ± 0.93 µM, 34.7 ± 0.08 µM in MDA-MB-231 DOX RT cells and MDA-MB-468 RM RT cells respectively. In-vivo PK studies showed enhanced bioavailability of CBD from CBD-exosomes with AUC(0-24h) of 1350.56 ± 187.50 h.ng/mL as compared to CBD control formulation with AUC(0-24h) of 351.95 ± 39.10 h.ng/mL with a single oral dose of 12 mg/kg. The data indicate that CMDE significantly improved the oral bioavailability of CBD. Overall, CMDE can be used to enhance the oral absorption of poorly bioavailable APIs.