Applied Nanotechnologies in Anticoagulant Therapy: From Anticoagulants to Coagulation Test Performance of Drug Delivery Systems
Abstract
:1. Introduction
2. Anticoagulant Therapy
2.1. Conventional Anticoagulant Agents
2.1.1. Unfractionated Heparin (UFH), Low-Molecular-Weight Heparin (LMWH), and Ultra-Low-Molecular-Weight Heparin (ULMWH)
Agents | Mw a (Da b) | Production Process | Trade Name (Pharma Company) | Anti-Factor Xa:IIa Ratio | References |
---|---|---|---|---|---|
LMWH | |||||
Ardeparin | 6000 | Peroxidative depolymerization | Normiflo© (Pfizer) | 1.9 | [15,22,36] |
Certoparin | 6000 | Deamine cleavage with isoamyl nitrate degradation | Sandoparin©, Mono-Embolex©, Sandoz© (Novartis) | 2.4 | [15,22,36] |
Dalteparin | 6000 | Nitrous acid depolymerization | Fragmin© (Pfizer) | 2.7 | [15,22,36] |
Enoxaparin | 4500 | Benzylation and alkaline depolymerization | Clexane©/Lovenox© (Sanofi-Aventis) | 3.8 | [15,22,37] |
Nadroparin | 5000 | Nitrous acid depolymerization | Fraxiparin© (Choay/Aspen) | 3.6 | [15,22] |
Parnaparin | 4500 | Hydrogen peroxide and cupric salt depolymerization | Fluxum© (Wasserman) | 3.0 | [22] |
Reviparin | 4000 | Nitrous acid depolymerization followed by chromatographic purification | Clivarine© (Abbott) | 3.5 | [15,22] |
Tinzaparin | 6000 | Heparinase digestion | Innohep© (Novo/Leo) | 1.5 | [15,22,24] |
ULMWH | |||||
Bemiparin | 3600 | β-eliminative cleavage through alkaline depolymerization | Hibor©, Ivor©, Zivor© (Sigma Tau) | 8.1 | [15,22,24] |
Semuloparin | 2400 | β-eliminative cleavage through selective and controlled depolymerization using a phosphazene base | (Sanofi-Aventis) | 80 | [22,28] |
Synthetic analogues | |||||
Fondaparinux | 1728 | Chemical synthesis | Arixtra© (GlaxoSmithKline) | ~850 UI anti-Xa/mg | [22,28] |
Idraparinux | 1728 | Chemical synthesis | (Sanofi-Aventis) | ~1600 UI anti-Xa/mg | [22] |
Idrabiotaparinux | 2052 | Chemical synthesis | (Sanofi-Aventis) | ~1600 UI anti-Xa/mg | [22] |
2.1.2. Vitamin K Antagonists (VKAs)
2.2. Novel Anticoagulant Drugs
3. Laboratory Assessment of Anticoagulant Therapy
3.1. Monitoring VKAs and UFH
3.2. Monitoring LMWH Therapy
3.3. Monitoring DOAC Therapy
4. Coagulation Test Performance of Drug Delivery Systems
4.1. Liposomes
4.2. Hydrogels
4.3. Polymeric Nanoparticles (PNPs)
4.4. Other Drug Delivery Systems
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CS | chitosan |
Chol | cholesterol |
CTAB | hexadecyltrimethyl ammonium bromide |
DSPE | 1,2-distearoyl-sn-glycero-3-phosphoethanolamine |
DSPE–PEG | 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethyleneglycol |
E80 | egg yolk lecithin |
Egg PC | phosphatidylcholine from egg yolk |
GMO | glyceryl monooleate |
HPMC | hydroxypropylmethylcellulose |
IPM | isopropyl myristate |
MBA | N,N-methylenebis (acrylamide) |
NA | not available |
PEI | polyethylenimine |
PC | phosphatidylcholine |
Plys | ε-polylysine |
PNP | polymeric nanoparticle |
SA | stearyl amine |
SEDDS | self-emulsifying drug delivery system |
SLN | solid lipid nanoparticles |
SNEDDS | self-nanoemulsifying drug delivery system |
TEA | triethylamine |
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Features | Factor IIa Inhibitor | Factor Xa Inhibitor | References | |||
---|---|---|---|---|---|---|
Dabigatran | Apixaban | Rivaroxaban | Edoxaban | Betrixaban | ||
Mw a (Da b) | 628 | 460 | 436 | 548 | 452 | [62] |
Bioavailability (%) | 6 | 50 | 80–100 | 62 | 34 | [62,63] |
Protein binding (%) | 35 | 87 | 92–95 | 55 | 60 | [61,63] |
Tmax c (h) | 1–3 | 1–4 | 2–4 | 1–2 | 3–4 | [61] |
Half-life (h) | 12–17 | 12 | 5–13 | 9–11 | 19–27 | [53,60] |
Reversal agents | Yes | No | No | No | No | [62] |
Renal clearance (%) | >80 | 25 | 66 | 35–50 | <7 | [61] |
Drug Delivery System | Active (Class) | Composition | Size Range | Major Outcomes | Ref |
---|---|---|---|---|---|
Liposomes | (LMWH) | Egg PC Tween® 20 Ethanol | 80–90 nm | LMWH-loaded flexosomes showed higher antifactor Xa (Anti-Xa) max than LMWH-loaded ethosome. | [96] |
Ardeparin (LMWH) | PC Chol DSPE DSPE-PEG-2000 and DSPE–PEG-5000 | 100–150 nm | Liposomal formulations showed sustained release and longer half-life compared to the plain solution or subcutaneous route. | [97] | |
Enoxaparin (LMWH) | Soybean PC Chol SA Eudragit® S 100 | 100–200 nm | Eudragit-coated liposomes showed higher permeation and oral bioavailability when compared to uncoated liposomes. | [113] | |
Hydrogels | Bemiparin (LMWH) Nadroparin (LMWH) Tinzaparin (LMWH) | Eudragit® RS 30D | 130 nm | Gel formulations were able to deliver LMWHs across the skin barrier, and after 24 h, the drug was not detected in plasma. | [11] |
Heparin (UFH) | CS hydrochloride Lutrol® F127 Lutrol® F68 HPMC | 150–400 nm | The dual system enabled the lowest absorption rate of heparin into systemic circulation and provided heparin concentrations above the prophylaxis threshold for 5 days. | [101] | |
Enoxaparin (LMWH) | CS Pluronic® F127 PEI Plys | 100–1000 nm | Thermo-sensitive hydrogels were able to prolong the enoxaparin release. | [114] | |
Heparin (UFH) | Gelatin MBA TEA | NA | Heparin-loaded hydrogels showed sustained release for 60 h and platelet adhesion was significantly reduced. | [115] | |
PNP | Enoxaparin (LMWH) | CS GMO Pluronic® F127 | 290–320 nm | The optimized formulation showed higher oral bioavailability compared with the drug solution. | [7] |
Fondaparinux (Synthetic analogues) | Labrafac® WL 1349 Lipoïd® S75-3 Lipoïd® GMBH Solutol® HS 15 CTAB SA | 40–65 nm | Cationic lipid nanocapsules showed increased oral bioavailability and longer half-life when compared to fondaparinux control solutions (oral and intravenous). | [106] | |
Enoxaparin (LMWH) | Pluronic® F-68 CTAB Dextran sulfate PLGA Precirol ATO 5 E80 Tween 80 Poloxamer 407 | 180–195 nm | Enoxaparin/CTAB nanoparticles showed three-fold improved gastrointestinal permeation when compared with the drug solution. | [116] | |
Enoxaparin (LMWH) | 145–160 nm | LPHNs improved the drug’s intestinal permeation, enhanced the oral bioavailability, and showed therapeutic efficacy. | [117] | ||
SLN | (LMWH) | Compritol 888 ATO Stearic, palmitic and myristic acid PC | 280–380 nm | The SLNs were able to improve the LMWH bioavailability in comparison to the free drug solution. | [109] |
SNEDDDS | Enoxaparin (LMWH) | Capmul MCM EP, Capmul PG-8 EP/NF Captex 8000, Peceol Labrafil M 1944 CS, Labrasol Maisine 35-1, Transcutol HP Myglyol 840, Cremophor EL PEG, triacetin, olive and sesame oil | 30–245 nm | SEDDS formulations showed sustained enoxaparin release and two-fold bioavailability. | [118] |
Rivaroxaban (Factor Xa inhibitor) | IPM Ethyl oleate, Tween20, and Tween80 Cremophor, Cremophor HEL, and Transutol | 50–105 nm | SNEDDS showed higher dissolution than the commercial formulation. The SNEDDS technology used in rivaroxaban successfully enhanced drug bioavailability in fasting conditions, and no food effects were observed in the rivaroxaban–SNEDDS formulation. | [119] | |
Rivaroxaban (Factor Xa inhibitor) | Transcutol HP Capryol TM 90 Maisine TM 35-1 Castor oil, oleic acid, triacetin, IPM Cremophore EL PEG 300 and PEG 400 Tween 20, Tween 80, and Span 80 | 10–115 nm | Safe SNEDDS formulations enhanced oral and intravenous bioavailability in comparison to the drug suspension. Moreover, SNEDDS exhibited anticoagulant efficacy in a rat thrombosis model. | [120] |
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Patriota, Y.B.G.; Chaves, L.L.; Gocke, E.H.; Severino, P.; Soares, M.F.R.; Soares-Sobrinho, J.L.; Souto, E.B. Applied Nanotechnologies in Anticoagulant Therapy: From Anticoagulants to Coagulation Test Performance of Drug Delivery Systems. Appl. Nano 2021, 2, 98-117. https://doi.org/10.3390/applnano2020009
Patriota YBG, Chaves LL, Gocke EH, Severino P, Soares MFR, Soares-Sobrinho JL, Souto EB. Applied Nanotechnologies in Anticoagulant Therapy: From Anticoagulants to Coagulation Test Performance of Drug Delivery Systems. Applied Nano. 2021; 2(2):98-117. https://doi.org/10.3390/applnano2020009
Chicago/Turabian StylePatriota, Yuri B. G., Luíse L. Chaves, Evren H. Gocke, Patricia Severino, Mônica F. R. Soares, José L. Soares-Sobrinho, and Eliana B. Souto. 2021. "Applied Nanotechnologies in Anticoagulant Therapy: From Anticoagulants to Coagulation Test Performance of Drug Delivery Systems" Applied Nano 2, no. 2: 98-117. https://doi.org/10.3390/applnano2020009