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Semin Thromb Hemost 2022; 48(08): 949-954
DOI: 10.1055/s-0042-1749395
Review Article

Heparin: The Journey from Parenteral Agent to Nasal Delivery

Giovanni Carpenè   *
1   Section of Clinical Biochemistry and School of Medicine, University of Verona, Verona, Italy
,
Davide Negrini   *
1   Section of Clinical Biochemistry and School of Medicine, University of Verona, Verona, Italy
,
Giuseppe Lippi
1   Section of Clinical Biochemistry and School of Medicine, University of Verona, Verona, Italy
,
Emmanuel J. Favaloro 
2   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, New South Wales, Australia
3   Sydney Centres for Thrombosis and Haemostasis, Westmead, New South Wales, Australia
4   Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
,
Martina Montagnana
1   Section of Clinical Biochemistry and School of Medicine, University of Verona, Verona, Italy
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Abstract

Although the worldwide usage of direct oral anticoagulants has continuously increased over the past decade, heparin remains an important weapon in the current arsenal of anticoagulant drugs. Parenteral heparin administration (i.e., either intravenously or subcutaneously) has represented for decades the only possible route for generating a significant anticoagulant effect, although being notoriously associated with some important drawbacks such as discomfort and risk of low compliance, thus paving the way to searching for more amenable means of administration. We provide here an updated analysis of animal and human studies that have explored the feasibility, suitability, and efficiency of heparin administration through the unconventional nasal route, as a possible alternative to the more traditional parenteral injection. The major hurdles that contribute to impair intranasal absorption and systemic delivery of heparin are represented by its relatively high molecular weight and negative charge. Therefore, although pure drug administration would not be associated with efficient nasal adsorption, or by systemic biological activity (i.e., anticoagulant effect), the combination of low molecular weight heparins and absorption enhancers such as surfactants, mucoadhesive, cyclodextrins, polyethylenimines and encapsulation into (nano)carriers seems effective to at least partially improve drug transport through the nasal route and allow systemic delivery in animals. Besides generating anticoagulant effects, intranasal heparin administration can also produce local pleiotropic effects, mostly related to anti-inflammatory properties, such as attenuating airway allergic inflammation or inhibiting the binding of the spike protein of some coronaviruses (including severe acute respiratory syndrome coronavirus 2) to their host cell receptors. This preliminary evidence represents a valuable premise for planning future studies in humans aimed at establishing the pharmacokinetics and biological activity of locally and systemically delivered intranasal heparin formulations.

Keywords

heparin - low molecular weight heparin - nasal - anticoagulant

* Equally contributed to this work.




Publikationsverlauf

Artikel online veröffentlicht:
22. Juni 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 McLean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41: 250-257
    CrossrefPubMedGoogle Scholar
  • 2 Howell WH, Holt E. Two new factors in blood coagulation—heparin and pro-antithrombin. Am J Physiol 1918; 47: 328-341
    CrossrefPubMedGoogle Scholar
  • 3 Brinkhous KM, Smith HP, Warner ED, Seegers WH. The inhibition of blood clotting: an unidentified substance which acts in conjunction with heparin to prevent the conversion of prothrombin into thrombin. Am J Physiol 1939; 125: 683-687
    CrossrefPubMedGoogle Scholar
  • 4 Hirsh J, Anand SS, Halperin JL, Fuster V. American Heart Association. Guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Circulation 2001; 103 (24) 2994-3018
    Google Scholar
  • 5 Danielsson A, Raub E, Lindahl U, Björk I. Role of ternary complexes, in which heparin binds both antithrombin and proteinase, in the acceleration of the reactions between antithrombin and thrombin or factor Xa. J Biol Chem 1986; 261 (33) 15467-15473
    CrossrefPubMedGoogle Scholar
  • 6 Casu B, Oreste P, Torri G. et al. The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence. Chemical and 13C nuclear-magnetic-resonance studies. Biochem J 1981; 197 (03) 599-609
    CrossrefPubMedGoogle Scholar
  • 7 Hirsh J, Warkentin TE, Shaughnessy SG. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (1, Suppl): 64S-94S
    Google Scholar
  • 8 Holmer E, Kurachi K, Söderström G. The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin. Biochem J 1981; 193 (02) 395-400
    CrossrefPubMedGoogle Scholar
  • 9 de Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60 (06) 1251-1258
    CrossrefPubMedGoogle Scholar
  • 10 Favaloro EJ, Kershaw G, Mohammed S, Lippi G. How to optimize activated partial thromboplastin time (APTT) testing: solutions to establishing and verifying normal reference intervals and assessing APTT reagents for sensitivity to heparin, lupus anticoagulant, and clotting factors. Semin Thromb Hemost 2019; 45 (01) 22-35
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 11 Morabia A. Heparin doses and major bleedings. Lancet 1986; 1 (8492): 1278-1279
    CrossrefPubMedGoogle Scholar
  • 12 Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM. The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 1988; 28 (07) 609-618
    CrossrefPubMedGoogle Scholar
  • 13 Warkentin TE, Levine MN, Hirsh J. et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332 (20) 1330-1335
    CrossrefPubMedGoogle Scholar
  • 14 Shaughnessy SG, Young E, Deschamps P, Hirsh J. The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria. Blood 1995; 86 (04) 1368-1373
    CrossrefPubMedGoogle Scholar
  • 15 Palm M, Mattsson C. Pharmacokinetics of heparin and low molecular weight heparin fragment (Fragmin) in rabbits with impaired renal or metabolic clearance. Thromb Haemost 1987; 58 (03) 932-935
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 16 Mengiardi S, Tsakiris DA, Lampert ML, Hersberger KE. Drug use problems with self-injected low-molecular-weight heparins in primary care. Eur J Clin Pharmacol 2011; 67 (02) 109-120
    CrossrefPubMedGoogle Scholar
  • 17 Anselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strategies for biologics. Nat Rev Drug Discov 2019; 18 (01) 19-40
    CrossrefPubMedGoogle Scholar
  • 18 Laffleur F, Bauer B. Progress in nasal drug delivery systems. Int J Pharm 2021; 607: 120994
    CrossrefPubMedGoogle Scholar
  • 19 Sayani AP, Chien YW. Systemic delivery of peptides and proteins across absorptive mucosae. Crit Rev Ther Drug Carrier Syst 1996; 13 (1-2): 85-184
    PubMedGoogle Scholar
  • 20 Oreste P, Stella P, Zoppetti G. Detection of the low molecular weight heparin component of ITF 1300 in urines after intranasal administration to dogs. Semin Thromb Hemost 1994; 20 (03) 293-296
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 21 Monzani MV, Coltro G, Sala A. HPLC determination of ITF 188 and its metabolite ITF 1078 in urine after intranasal administration of new heparin salt ITF 1300 to dogs. Boll Chim Farm 1997; 136 (03) 272-274
    PubMedGoogle Scholar
  • 22 Arnold J, Ahsan F, Meezan E, Pillion DJ. Nasal administration of low molecular weight heparin. J Pharm Sci 2002; 91 (07) 1707-1714
    CrossrefPubMedGoogle Scholar
  • 23 Bianchini P, Bergonzini GL, Parma B, Osima B. Relationship between plasma antifactor Xa activity and the antithrombotic activity of heparins of different molecular mass. Haemostasis 1995; 25 (06) 288-298
    PubMedGoogle Scholar
  • 24 Mustafa F, Yang T, Khan MA, Ahsan F. Chain length-dependent effects of alkylmaltosides on nasal absorption of enoxaparin. J Pharm Sci 2004; 93 (03) 675-683
    CrossrefPubMedGoogle Scholar
  • 25 Yang T, Mustafa F, Ahsan F. Alkanoylsucroses in nasal delivery of low molecular weight heparins: in-vivo absorption and reversibility studies in rats. J Pharm Pharmacol 2004; 56 (01) 53-60
    CrossrefPubMedGoogle Scholar
  • 26 Yang T, Hussain A, Paulson J, Abbruscato TJ, Ahsan F. Cyclodextrins in nasal delivery of low-molecular-weight heparins: in vivo and in vitro studies. Pharm Res 2004; 21 (07) 1127-1136
    CrossrefPubMedGoogle Scholar
  • 27 Yildiz A, Okyar A, Baktir G, Araman A, Özsoy Y. Nasal administration of heparin-loaded microspheres based on poly(lactic acid). Farmaco 2005; 60 (11-12): 919-924
    CrossrefPubMedGoogle Scholar
  • 28 Yang T, Hussain A, Bai S, Khalil IA, Harashima H, Ahsan F. Positively charged polyethylenimines enhance nasal absorption of the negatively charged drug, low molecular weight heparin. J Control Release 2006; 115 (03) 289-297
    CrossrefPubMedGoogle Scholar
  • 29 Lider O, Mekori YA, Miller T. et al. Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity. Eur J Immunol 1990; 20 (03) 493-499
    CrossrefPubMedGoogle Scholar
  • 30 Matzner Y, Marx G, Drexler R, Eldor A. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis. Thromb Haemost 1984; 52 (02) 134-137
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 31 Ekre HPT, Fjellner B, Hägermark O. Inhibition of complement dependent experimental inflammation in human skin by different heparin fractions. Int J Immunopharmacol 1986; 8 (03) 277-286
    CrossrefPubMedGoogle Scholar
  • 32 Bowler SD, Smith SM, Lavercombe PS. Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects. Am Rev Respir Dis 1993; 147 (01) 160-163
    CrossrefPubMedGoogle Scholar
  • 33 Ahmed T, Garrigo J, Danta I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 1993; 329 (02) 90-95
    CrossrefPubMedGoogle Scholar
  • 34 Vancheri C, Mastruzzo C, Armato F. et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol 2001; 108 (05) 703-708
    CrossrefPubMedGoogle Scholar
  • 35 Ogawa T, Shimizu S, Tojima I, Kouzaki H, Shimizu T. Heparin inhibits mucus hypersecretion in airway epithelial cells. Am J Rhinol Allergy 2011; 25 (02) 69-74
    CrossrefPubMedGoogle Scholar
  • 36 Ogawa T, Shimizu S, Shimizu T. The effect of heparin on antigen-induced mucus hypersecretion in the nasal epithelium of sensitized rats. Allergol Int 2013; 62 (01) 77-83
    CrossrefPubMedGoogle Scholar
  • 37 Fu LS, Tsai JJ, Chen YJ, Lin HK, Tsai MC, Chang MDT. Heparin protects BALB/c mice from mite-induced airway allergic inflammation. Int J Immunopathol Pharmacol 2013; 26 (02) 349-359
    CrossrefPubMedGoogle Scholar
  • 38 Huang JN, Tsai MC, Fang SL. et al. Low-molecular-weight heparin and unfractionated heparin decrease Th-1, 2, and 17 expressions. PLoS One 2014; 9 (11) e109996
    CrossrefPubMedGoogle Scholar
  • 39 Lippi G, Sanchis-Gomar F, Henry BM. Coronavirus disease 2019 (COVID-19): the portrait of a perfect storm. Ann Transl Med 2020; 8 (07) 497
    CrossrefPubMedGoogle Scholar
  • 40 Kielian M. Enhancing host cell infection by SARS-CoV-2. Science 2020; 370 (6518): 765-766
    CrossrefPubMedGoogle Scholar
  • 41 Evans JP, Liu SL. Role of host factors in SARS-CoV-2 entry. J Biol Chem 2021; 297 (01) 100847
    CrossrefPubMedGoogle Scholar
  • 42 Kim SY, Jin W, Sood A. et al. Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions. Antiviral Res 2020; 181: 104873
    CrossrefPubMedGoogle Scholar
  • 43 Mycroft-West CJ, Su D, Pagani I. et al. Heparin inhibits cellular invasion by sars-cov-2: structural dependence of the interaction of the spike s1 receptor-binding domain with heparin. Thromb Haemost 2020; 120 (12) 1700-1715
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 44 Tandon R, Sharp JS, Zhang F. et al. Effective inhibition of sars-cov-2 entry by heparin and enoxaparin derivatives. J Virol 2021; 95 (03) e01987 -20
    CrossrefPubMedGoogle Scholar
  • 45 Harris HM, Boyet KL, Liu H. et al. Safety and pharmacokinetics of intranasally administered heparin. Pharm Res 2022; 39 (03) 541-551
    CrossrefPubMedGoogle Scholar
  • 46 Lippi G, Gosselin R, Favaloro EJ. Current and emerging direct oral anticoagulants: state-of-the-art. Semin Thromb Hemost 2019; 45 (05) 490-501
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 47 Kurmi BD, Tekchandani P, Paliwal R, Paliwal SR. Nanocarriers in improved heparin delivery: recent updates. Curr Pharm Des 2015; 21 (30) 4509-4518
    CrossrefPubMedGoogle Scholar
  • 48 Lippi G, Henry BM, Favaloro EJ. The benefits of heparin use in COVID-19: pleiotropic antiviral activity beyond anticoagulant and anti-inflammatory properties. . Semin Thromb Hemost 2022 (e-Pub ahead of print). DOI: 10.1055/s-0042-1742740.
    Artikel in Thieme ConnectPubMedGoogle Scholar