Toward Effective Long-Term Prevention of Thromboembolism: Novel Oral Anticoagulant Delivery Systems

ABSTRACT

Despite intensive research in the field of oral anticoagulants over the last decade, simple and effective long-term prevention of thromboembolism is still an unmet need. In addition to drug discovery approaches, the development of novel oral drug delivery systems (DDSs) of clinically well-established anticoagulants presents an intriguing mean of improvement of anticoagulant therapy. The latter topic is therefore the focus of the present review. All relevant clinical trials with anticoagulants formulated in the oral DDS are reviewed, and selected preclinical examples of promising novel anticoagulant DDSs are also described. For greater understanding, a background on DDS and drug absorption from the gastrointestinal tract is also provided. Three leading approaches for the oral anticoagulant DDS are currently being investigated in clinical settings, all relying on coadministration of anticoagulants with specific carriers. In contrast to the clinical setting, a diverse range of possibilities for oral delivery of anticoagulant are being investigated in preclinical trials (e.g., nanotechnology), and it would be therefore interesting to examine their performance in clinical trials.

KEYWORDS

Drug delivery systems - anticoagulants - oral delivery - absorption - gastrointestinal tract

REFERENCES

• 1 Norman P. Antithrombotics: Will generics temper the strong sales trend? SPECTRUM therapy markets and emerging technologies antithrombotics.  , Decision Resources 2006; 
• 2 Hirsh J, Bauer K A, Donati M B, Gould M, Samama M M, Weitz J I. American College of Chest Physicians . Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, suppl) 141S-159S
• 3 Greinacher A, Warkentin T E. The direct thrombin inhibitor hirudin.  Thromb Haemost. 2008;  99(5) 819-829
• 4 Walenga J M, Bounameaux H, Ikeda Y. Landmarks in anti-thrombin drug development: the argatroban story.  Semin Thromb Hemost. 2007;  34 1-2
• 5 Ieko M. Dabigatran etexilate, a thrombin inhibitor for the prevention of venous thromboembolism and stroke.  Curr Opin Investig Drugs. 2007;  8(9) 758-768
• 6 Laux V, Perzborn E, Kubitza D, Misselwitz F. Preclinical and clinical characteristics of rivaroxaban: a novel, oral, direct factor Xa inhibitor.  Semin Thromb Hemost. 2007;  33(5) 515-523
• 7 Agnelli G, Eriksson B I, Cohen A T EXTEND Study Group et al. Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.  Thromb Res. 2009;  123(3) 488-497
• 8 Kimmel S E. Warfarin therapy: in need of improvement after all these years.  Expert Opin Pharmacother. 2008;  9(5) 677-686
• 9 Sobieraj-Teague M, O’Donnell M, Eikelboom J. New anticoagulants for atrial fibrillation.  Semin Thromb Hemost. 2009;  35(5) 515-524
• 10 Levi M, Hobbs F D, Jacobson A K et al.. Improving antithrombotic management in patients with atrial fibrillation: current status and perspectives.  Semin Thromb Hemost. 2009;  35(6) 527-542
• 11 Harenberg J. New anticoagulants in atrial fibrillation.  Semin Thromb Hemost. 2009;  35(6) 574-585
• 12 Harenberg J. Development of new anticoagulants: present and future.  Semin Thromb Hemost. 2008;  34(8) 779-793
• 13 Fareed J, Hoppensteadt D A, Fareed D et al.. Survival of heparins, oral anticoagulants, and aspirin after the year 2010.  Semin Thromb Hemost. 2008;  34(1) 58-73
• 14 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa.  Semin Thromb Hemost. 2008;  34(1) 39-57
• 15 Mousa S A. Heparin, low molecular weight heparin, and derivatives in thrombosis, angiogenesis, and inflammation: emerging links.  Semin Thromb Hemost. 2007;  33(5) 524-533
• 16 Laux V, Perzborn E, Kubitza D, Misselwitz F. Preclinical and clinical characteristics of rivaroxaban: a novel, oral, direct factor Xa inhibitor.  Semin Thromb Hemost. 2007;  33(5) 515-523
• 17 Thomas V H, Bhattachar S, Hitchingham L et al.. The road map to oral bioavailability: an industrial perspective.  Expert Opin Drug Metab Toxicol. 2006;  2(4) 591-608
• 18 Hurst S, Loi C M, Brodfuehrer J, El-Kattan A. Impact of physiological, physicochemical and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans.  Expert Opin Drug Metab Toxicol. 2007;  3(4) 469-489
• 19 Custodio J M, Wu C Y, Benet L Z. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption.  Adv Drug Deliv Rev. 2008;  60(6) 717-733
• 20 Martinez M N, Amidon G L. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals.  J Clin Pharmacol. 2002;  42(6) 620-643
• 21 Löbenberg R, Amidon G L. Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards.  Eur J Pharm Biopharm. 2000;  50(1) 3-12
• 22 Salama N N, Eddington N D, Fasano A. Tight junction modulation and its relationship to drug delivery.  Adv Drug Deliv Rev. 2006;  58(1) 15-28
• 23 Wright E M. The passive permeability of the small intestine.  Biomembranes. 1974;  4A 159-198
• 24 Oostendorp R L, Beijnen J H, Schellens J H. The biological and clinical role of drug transporters at the intestinal barrier.  Cancer Treat Rev. 2009;  35(2) 137-147
• 25 Murakami T, Takano M. Intestinal efflux transporters and drug absorption.  Expert Opin Drug Metab Toxicol. 2008;  4(7) 923-939
• 26 Heyman M, Crain-Denoyelle A M, Desjeux J F. Endocytosis and processing of protein by isolated villus and crypt cells of the mouse small intestine.  J Pediatr Gastroenterol Nutr. 1989;  9(2) 238-245
• 27 Jain K K. Drug delivery systems—an overview.  Methods Mol Biol. 2008;  437 1-50
• 28 Gomez-Orellana I. Strategies to improve oral drug bioavailability.  Expert Opin Drug Deliv. 2005;  2(3) 419-433
• 29 Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules.  Nat Rev Drug Discov. 2003;  2(4) 289-295
• 30 Aungst B J. Intestinal permeation enhancers.  J Pharm Sci. 2000;  89(4) 429-442
• 31 Malkov D, Wang H Z, Dinh S, Gomez-Orellana I. Pathway of oral absorption of heparin with sodium N-[8-(2-hydroxybenzoyl)amino] caprylate.  Pharm Res. 2002;  19(8) 1180-1184
• 32 Rivera T M, Leone-Bay A, Paton D R, Leipold H R, Baughman R A. Oral delivery of heparin in combination with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate: pharmacological considerations.  Pharm Res. 1997;  14(12) 1830-1834
• 33 Hauel N H, Nar H, Priepke H, Ries U, Stassen J M, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors.  J Med Chem. 2002;  45(9) 1757-1766
• 34 Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.  Drug Metab Dispos. 2008;  36(2) 386-399
• 35 des Rieux A, Fievez V, Garinot M, Schneider Y J, Préat V. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach.  J Control Release. 2006;  116(1) 1-27
• 36 Vauthier C, Couvreur P. Nanomedicines: a new approach for the treatment of serious diseases.  J Biomed Nanotechnol. 2007;  3 223-224
• 37 de la Fuente M, Csaba N, Garcia-Fuentes M, Alonso M J. Nanoparticles as protein and gene carriers to mucosal surfaces.  Nanomed. 2008;  3(6) 845-857
• 38 Florence A T. Nanoparticle uptake by the oral route: fulfilling its potential?.  Drug Discov Today. 2005;  2 75-81
• 39 Hyers T M, Hull R D, Weg J G. Antithrombotic therapy for venous thromboembolic disease.  Chest. 1995;  108 335S-351S
• 40 Arbit E, Goldberg M, Gomez-Orellana I, Majuru S. Oral heparin: status review.  Thromb J. 2006;  4 6
• 41 Agarwal R, Klein G F, Chaudhary K. Liquid heparin formulation.  International patent application. , WO00134114
• 42 Mousa S A, Zhang F, Aljada A et al.. Pharmacokinetics and pharmacodynamics of oral heparin solid dosage form in healthy human subjects.  J Clin Pharmacol. 2007;  47(12) 1508-1520
• 43 Berkowitz S D, Marder V J, Kosutic G, Baughman R A. Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty.  J Thromb Haemost. 2003;  1(9) 1914-1919
• 44 Baughman R A, Kapoor S C, Agarwal R K, Kisicki J, Catella-Lawson F, FitzGerald G A. Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans.  Circulation. 1998;  98(16) 1610-1615
• 45 Hull R D, Kakkar A K, Marder V J et al.. Oral SNAC–heparin vs. enoxaparin for preventing venous thromboembolism following total hip replacement.  Blood. 2002;  100 148a , Abstract 558
• 46 Pineo G, Hull R, Marder V. Oral delivery of heparin: SNAC and related formulations.  Best Pract Res Clin Haematol. 2004;  17(1) 153-160
• 47 Majuru S. Advances in the oral delivery of heparin from solid dosage forms using Emisphere's Eligenm^® Oral Drug Delivery Technology.  Drug Deliv Technol. 2004;  4 84-89
• 48 Riley M G, Castelli M C, Paehler E A. Subchronic oral toxicity of salcaprozate sodium (SNAC) in Sprague-Dawley and Wistar rats.  Int J Toxicol. 2009;  28(4) 278-293
• 49 Riley M G, York R G. Peri- and postnatal developmental toxicity of salcaprozate sodium (SNAC) in Sprague-Dawley rats.  Int J Toxicol. 2009;  28(4) 266-277
• 50 Maher S, Leonard T W, Jacobsen J, Brayden D J. Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic.  Adv Drug Del Rev. 2009;  61(15) 1427-1449
• 51 Leonard T W, Lynch J, McKenna M J, Brayden D J. Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET.  Expert Opin Drug Deliv. 2006;  3(5) 685-692
• 52 Squier C A, Kremer M J. Biology of oral mucosa and esophagus.  J Natl Cancer Inst Monogr. 2001;  29(29) 7-15
• 53 Modi P. Development of the RapidMist drug delivery system for the treatment of diabetes, cardiovascular diseases and breakthrough cancer pain.  Drugs Fut. 2005;  30(3) 271-276
• 54 Panka J M inventor. Micellar pharmaceutical compositions for buccal and pulmonary application.  European patent. , EP1261320
• 55 Bernstein G. Delivery of insulin to the buccal mucosa utilizing the RapidMist system.  Expert Opin Drug Deliv. 2008;  5(9) 1047-1055
• 56 Motlekar N A, Youan B B. The quest for non-invasive delivery of bioactive macromolecules: a focus on heparins.  J Control Release. 2006;  113(2) 91-101
• 57 Siekmeier R, Scheuch G. Systemic treatment by inhalation of macromolecules—principles, problems, and examples.  J Physiol Pharmacol. 2008;  59(suppl 6) 53-79
• 58 Rao R, Nanda S. Sonophoresis: recent advancements and future trends.  J Pharm Pharmacol. 2009;  61(6) 689-705
• 59 Yang T, Mustafa F, Bai S, Ahsan F. Pulmonary delivery of low molecular weight heparins.  Pharm Res. 2004;  21(11) 2009-2016
• 60 Zhang Y J, Ma C H, Lu W L et al.. Permeation-enhancing effects of chitosan formulations on recombinant hirudin-2 by nasal delivery in vitro and in vivo.  Acta Pharmacol Sin. 2005;  26(11) 1402-1408
• 61 Pacini S, Punzi T, Gulisano M, Cecchi F, Vannucchi S, Ruggiero M. Transdermal delivery of heparin using pulsed current iontophoresis.  Pharm Res. 2006;  23(1) 114-120
• 62 Maggio E T. Compositions for drug administration. US patent application US2009047347A1
• 63 Yang T, Arnold J J, Ahsan F. Tetradecylmaltoside (TDM) enhances in vitro and in vivo intestinal absorption of enoxaparin, a low molecular weight heparin.  J Drug Target. 2005;  13(1) 29-38
• 64 Arnold J, Ahsan F, Meezan E, Pillion D J. Nasal administration of low molecular weight heparin.  J Pharm Sci. 2002;  91(7) 1707-1714
• 65 Clausen A E, Kast C E, Bernkop-Schnürch A. The role of glutathione in the permeation enhancing effect of thiolated polymers.  Pharm Res. 2002;  19(5) 602-608
• 66 Kast C E, Guggi D, Langoth N, Bernkop-Schnürch A. Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil.  Pharm Res. 2003;  20(6) 931-936
• 67 Kim S K, Lee D Y, Lee E et al.. Absorption study of deoxycholic acid-heparin conjugate as a new form of oral anti-coagulant.  J Control Release. 2007;  120(1-2) 4-10
• 68 Hoffart V, Lamprecht A, Maincent P et al.. Oral bioavailability of low molecular weight heparin using polymeric delivery system.  J Control Release. 2006;  113 38-42
• 69 Jiao Y, Ubrich N, Marchand-Arvier M et al.. In vitro and in vivo evaluation of oral heparin-loaded polymeric nanoparticles in rabbits.  Circulation. 2002;  105(2) 230-235
• 70 Chen M C, Wong H S, Lin K J et al.. The characteristics, biodistribution and bioavailability of a chitosan-based nanoparticulate system for the oral delivery of heparin.  Biomaterials. 2009;  30(34) 6629-6637
• 71 Scala-Bertola J, Rabiskova M, Lecompte T, Bonneaux F, Maincent P. Granules in the improvement of oral heparin bioavailability.  Int J Pharm. 2009;  374(1-2) 12-16
• 72 Motlekar N A, Srivenugopal K S, Wachtel M S, Youan B B. Evaluation of the oral bioavailability of low molecular weight heparin formulated with glycyrrhetinic acid as permeation enhancer.  Drug Dev Res. 2006;  67(2) 166-174
• 73 Hoffart V, Lamprecht A, Maincent P, Lecompte T, Vigneron C, Ubrich N. Oral bioavailability of a low molecular weight heparin using a polymeric delivery system.  J Control Release. 2006;  113(1) 38-42
• 74 Lanke S S, Gayakwad S G, Strom J G, D’souza M J. Oral delivery of low molecular weight heparin microspheres prepared using biodegradable polymer matrix system.  J Microencapsul. 2009;  26(6) 493-500
• 75 Grabovac V, Schmitz T, Föger F, Bernkop-Schnürch A. Papain: an effective permeation enhancer for orally administered low molecular weight heparin.  Pharm Res. 2007;  24(5) 1001-1006
• 76 Motlekar N A, Fasano A, Wachtel M S, Youan B B. Zonula occludens toxin synthetic peptide derivative AT1002 enhances in vitro and in vivo intestinal absorption of low molecular weight heparin.  J Drug Target. 2006;  14(5) 321-329
• 77 Motlekar N A, Srivenugopal K S, Wachtel M S, Youan B B. Modulation of gastrointestinal permeability of low-molecular-weight heparin by L-arginine: in-vivo and in-vitro evaluation.  J Pharm Pharmacol. 2006;  58(5) 591-598
• 78 Ito Y, Kusawake T, Prasad Y V, Sugioka N, Shibata N, Takada K. Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies.  Int J Pharm. 2006;  317(2) 114-119
• 79 Lee Y K, Kim S K, Lee D Y et al.. Efficacy of orally active chemical conjugate of low molecular weight heparin and deoxycholic acid in rats, mice and monkeys.  J Control Release. 2006;  111(3) 290-298
• 80 Motlekar N A, Srivenugopal K S, Wachtel M S, Youan B B. Oral delivery of low-molecular-weight heparin using sodium caprate as absorption enhancer reaches therapeutic levels.  J Drug Target. 2005;  13(10) 573-583
• 81 Kim S K, Lee E H, Vaishali B et al.. Tricaprylin microemulsion for oral delivery of low molecular weight heparin conjugates.  J Control Release. 2005;  105(1-2) 32-42
• 82 Kim S K, Vaishali B, Lee E et al.. Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation.  Thromb Res. 2006;  117(4) 419-427
• 83 Yang T, Arnold J J, Ahsan F. Tetradecylmaltoside (TDM) enhances in vitro and in vivo intestinal absorption of enoxaparin, a low molecular weight heparin.  J Drug Target. 2005;  13(1) 29-38
• 84 Schmitz T, Leitner V M, Bernkop-Schnürch A. Oral heparin delivery: design and in vivo evaluation of a stomach-targeted mucoadhesive delivery system.  J Pharm Sci. 2005;  94(5) 966-973
• 85 Kast C E, Guggi D, Langoth N, Bernkop-Schnürch A. Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil.  Pharm Res. 2003;  20(6) 931-936
• 86 Lee Y, Nam J H, Shin H C, Byun Y. Conjugation of low-molecular-weight heparin and deoxycholic acid for the development of a new oral anticoagulant agent.  Circulation. 2001;  104(25) 3116-3120
• 87 Lamprecht A, Ubrich N, Maincent P. Oral low molecular weight heparin delivery by microparticles from complex coacervation.  Eur J Pharm Biopharm. 2007;  67(3) 632-638
• 88 Kim S K, Lee D Y, Lee E et al.. Absorption study of deoxycholic acid-heparin conjugate as a new form of oral anti-coagulant.  J Control Release. 2007;  120(1-2) 4-10
• 89 Jiao Y, Ubrich N, Marchand-Arvier M et al.. In vitro and in vivo evaluation of oral heparin-loaded polymeric nanoparticles in rabbits.  Circulation. 2002;  105(2) 230-235
• 90 Lee Y, Kim S H, Byun Y. Oral delivery of new heparin derivatives in rats.  Pharm Res. 2000;  17(10) 1259-1264
• 91 Cen X, Ni J, Tan T et al.. Investigation on recombinant hirudin via oral route.  Peptides. 2006;  27(4) 836-840