Figures Abstract A platform capable of specifically delivering an antiviral drug to the liver infected with hepatitis B is a major concern in hepatology. Vaccination has had a major effect on decreasing the emerging numbers of new cases of infection.
However, the total elimination of the hepatitis B virus from the coated option requires prolonged therapy. In this work, we aimed to target the liver macrophages with lipid polymer hybrid nanoparticles LPHcombining the merit of polymeric nanoparticles and lipid vesicles. The hydrophilic antiviral drug, entecavir Eloaded LPH coated option were optimized and physicochemically characterized.
A modulated lipidic corona, as well as, an additional coat with vitamin E were used to extend the drug release enhance the macrophage uptake.
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The selected vitamin E coated LPH nanoparticles enriched with lecithin-glyceryl monostearate lipid shell exhibited high entrapment for E Upon macrophage uptake in vitro assessment, the presented formulation displayed promising traits, enhancing the cellular retention in J macrophages cells. In vivo and antiviral activity futuristic studies would help in the potential application of the ELPH in hepatitis B control.
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This is an open access article distributed under the terms of the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files.
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Funding: The author s received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Introduction Lately an increased alertness about the role of hepatic macrophages in viral hepatitis has been recognized [ 12 ].
Being members of the reticuloendothelial system, they have been acknowledged as key participants in the prevention of the disease progression [ 2 ]. Delivery strategies using nanotherapeutics to target the macrophages had been well specified [ 3 ]. The nanocarriers should possess a defined size, with a targeted coated option coated option surface to facilitate both passive and active cellular targeting liver targeting [ 4 ].
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Hepatitis B virus HBV infection accounts for increased deaths worldwide, due to the risk of cirrhosis, hepatocellular cancer, portal hypertension and liver failure [ 5 ].
To date, the antiviral therapies, have failed to realize complete removal of the virus from the body and treatment prolonged duration, without the possible emergence of drug resistance [ 67 ]. Due to its high lethality, researchers advanced that in the future, good therapy of HBV should be coated option composite treatment build up from nucleot s ide analogs, immunostimulants and possibly curative vaccines.
Among the antiviral nucleot s ide analogues, entecavir Ehas been highly recommended due to various merits: i potency, ii low resistance, and iii low systemic toxicity [ 8 — 10 ]. In a very recent multicenter cohort study conducted by Chinese researchers, E monotherapy offered evidence of lowered virological breakthrough and heightened HBV-DNA suppression compared to combination therapy of antiviral agents; lamivudine and adefovir [ 9 ].
Zoutendijk and coworkers suggested E monotherapy for 48 weeks [ 11 ]. However, the oral administration of Coated option is associated with poor patient compliance and adverse reactions, resulting from intake of E on empty stomach, necessitating the fabrication of sustained release formulation [ 6 ].
In this context, long-acting parenteral formulations of E have been well-investigated by various research groups, including liquid coated option [ 12 ], lipidic prodrug [ 13 ], albumin nanoparticles [ 8 ] and PLGA microspheres [ 6 ].
Highly optimized carriers with sub-cellular targeting moieties coated option been opted to enhance hepatic Kupffer cells and hepatocytes targeting efficiency for competent antiviral delivery [ 5 ].
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Fabrication of polymeric nanoparticles and lipid nanocarriers is considered as the most noticeable tool to fulfill such purpose. Polymeric nanoparticles have been employed to provide good hydrophobic drug loading, biodegradability, structural integrity and stability characteristics [ 1415 ].
On the other hand, the use of lipid nanocarriers such as liposomes is coated option, due to their good biocompatibility as well as the ease of modification by different targeting moieties [ 16 ], Besides, up till now, they are the only nanocarriers being approved in clinical applications and scaled-up for industrial production [ 17 ]. However, both nanocarriers, when utilized separately, have some limitations due to poor loading of hydrophilic bioactive compounds and uncontrolled drug release from polymeric nanoparticles and drug leakage and instability during storage from lipid nanocarriers [ 1819 ].
Home Blog Among the vast array of industrial metal finishing options are two comparable processes known as electrophoretic deposition colloquially known as electrocoating or e-coating and powder coating.
Hence, lipid-polymer coated option nanoparticles LPH was designed, combining the advantages of both polymer- and lipid-based nanoparticles. LPH are archetype of nanocarriers composed of an internal polymeric core enclosed by an outer lipid bioactive shell composed of one or more layers or components [ 2021 ].
By virtue of their unique structure, LPH have versatile competence to encapsulate different types of payloads such as hydrophilic, hydrophobic drugs or nucleic acids, highlighting promising in vivo therapeutic outcomes [ 22 — 25 ]. The concomitance of both polymer and lipid imparts the LPH structural integrity, serum stability, sustained drug release from the polymer core and high biocompatibility from the lipid shell [ 21 ].
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Finally, rapid opsonization induced by the lipidic shell resulting in rapid uptake of the particles by the mononuclear phagocyte system MPS in the coated option and spleen has been previously proven [ 2627 ]. Different polymers and lipids have been exploited for the fabrication of LPH.
Lecithin LEC is a type of phospholipids coated option are vital components of the cell membrane to conserve membrane fluidity [ 29 ]. Generally, phospholipids play a crucial role in solubilization, sustainment of drug release, improvement of therapeutic efficacy and biocompatibility [ 3031 ]. In light, the aim of this study is to formulate and evaluate a new long-acting macrophage-directed platform for the antiviral agent E.
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The optimized formulae, obtained from Box-Behnken BBD statistical design, were subjected to different modulations to prolong the drug release to the maximum. CH is well-reputed neutral lipid commonly used in liposomes, heightening the packing of phospholipid molecules, rigidity and stabilization of liposomes [ 34 ]. GMS is a single-chained biocompatible self-assembly amphiphilic monoglyceryl ester, showing significant applications in drug delivery as self-nanoemulsifying drug delivery systems, solid lipid nanoparticles, polymer lipid nanoparticles [ 35 — 37 ] Vitamin E, is a lipid soluble vitamin coated option antioxidant [ 38 ] and immunomodulatory activities [ 39 ].
It has been reported to improve the phagocytic potential of macrophage in broilers [ 40 ]. It is worth mentioning that this investigation assesses for the first time macrophage targeting of vitamin E coated E loaded nanopharmaceuticals, as an indicator of the efficient hepatic therapeutic system, an issue that has not been attempted yet coated option previously reported E carriers. In this regard, confocal laser scanning microscopy CLSM and flow cytometry was performed to evaluate the qualitative and quantitative macrophage retention of ELPH respectively.
Materials and methods 2.
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Potassium dihydrogen orthophosphate, sodium hydroxide, sodium chloride, potassium chloride, sodium dibasic hydrogen orthophosphate, hydrochloric acid and Tween 80 polysorbate 80 : obtained from Fluka Chemika-BioChemika, Switzerland.
Determination of entecavir solubility in different lipids. The solubility of entecavir E in different single lipids or different mixtures of LEC with CH or GMS was determined as described in supplementary information [ 4344 ].
Preparation of E LPH. Different formulations ELPH were prepared using modified single-step nanoprecipitation self-assembly method as described elsewhere [ 14 ].
Slow dripping of the organic phase into the aqueous phase was done while stirring at room temperature for 2 h. After soaking, the dispersions was re-centrifuged under the same conditions to remove excess vitamin E.