Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation

Sang Kyoon Kim, Bagalkot Vaishali, Eunhye Lee, Seulki Lee, Yong Kyu Lee, Tadiparthi Suresh Kumar, Hyun Tae Moon, Youngro Byun

Research output: Contribution to journalArticle

Abstract

Introduction: Heparin, one of the most potent anticoagulants widely used for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE), is currently available to patients only by parental administration. In this study, we propose a new oral delivery system of heparin by conjugating it with deoxycholic acid which reformulated by adding dimethyl sulfoxide to increase its bioavailability. Materials and methods: The chemical conjugates (LMWH-DOCA) of low molecular weight heparin (4.5 kDa) with deoxycholic acid (DOCA) were synthesized by controlling the conjugation ratio. The absorption of LMWH-DOCA after its oral administration was measured by anti-FXa assay according to the conjugation ratio of DOCA, concentration of DMSO solution and dose of LMWH-DOCA, respectively. Furthermore, the incidences of mucosal damage by LMWH-DOCA in 10% DMSO solution were evaluated using H&E staining and SEM. Results: Three kinds of LMWH-DOCA were synthesized according to the DOCA conjugation ratios of LD1, LD2 and LD3, whose anticoagulant activities were 89, 86 and 85 IU/mg, respectively, and the activity of LMWH was 97 IU/mg. LMWH-DOCA was completely dissolved in 10% DMSO solution, and its bioavailability in the oral dose was significantly increased (17.6% for LD2 in 10% DMSO solution) without causing any damages in intestinal tissues. Conclusions: The chemical conjugate of heparin and DOCA in the soluble state could be efficiently absorbed in the intestine. Therefore, we propose this system as a new strategy of oral heparin delivery for the treatment of patients who are at high risk to DVT and PE.

Original languageEnglish (US)
Pages (from-to)419-427
Number of pages9
JournalThrombosis Research
Volume117
Issue number4
DOIs
StatePublished - 2006
Externally publishedYes

Fingerprint

Deoxycholic Acid
Heparin
Low Molecular Weight Heparin
Dimethyl Sulfoxide
Pulmonary Embolism
Venous Thrombosis
Anticoagulants
Biological Availability
Intestines
Oral Administration
Staining and Labeling

Keywords

  • Conjugate
  • Deoxycholic acid
  • DMSO
  • Low molecular weight heparin
  • Oral delivery

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Hematology

Cite this

Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation. / Kim, Sang Kyoon; Vaishali, Bagalkot; Lee, Eunhye; Lee, Seulki; Lee, Yong Kyu; Kumar, Tadiparthi Suresh; Moon, Hyun Tae; Byun, Youngro.

In: Thrombosis Research, Vol. 117, No. 4, 2006, p. 419-427.

Research output: Contribution to journalArticle

Kim, SK, Vaishali, B, Lee, E, Lee, S, Lee, YK, Kumar, TS, Moon, HT & Byun, Y 2006, 'Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation', Thrombosis Research, vol. 117, no. 4, pp. 419-427. https://doi.org/10.1016/j.thromres.2005.03.027
Kim, Sang Kyoon ; Vaishali, Bagalkot ; Lee, Eunhye ; Lee, Seulki ; Lee, Yong Kyu ; Kumar, Tadiparthi Suresh ; Moon, Hyun Tae ; Byun, Youngro. / Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation. In: Thrombosis Research. 2006 ; Vol. 117, No. 4. pp. 419-427.
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abstract = "Introduction: Heparin, one of the most potent anticoagulants widely used for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE), is currently available to patients only by parental administration. In this study, we propose a new oral delivery system of heparin by conjugating it with deoxycholic acid which reformulated by adding dimethyl sulfoxide to increase its bioavailability. Materials and methods: The chemical conjugates (LMWH-DOCA) of low molecular weight heparin (4.5 kDa) with deoxycholic acid (DOCA) were synthesized by controlling the conjugation ratio. The absorption of LMWH-DOCA after its oral administration was measured by anti-FXa assay according to the conjugation ratio of DOCA, concentration of DMSO solution and dose of LMWH-DOCA, respectively. Furthermore, the incidences of mucosal damage by LMWH-DOCA in 10{\%} DMSO solution were evaluated using H&E staining and SEM. Results: Three kinds of LMWH-DOCA were synthesized according to the DOCA conjugation ratios of LD1, LD2 and LD3, whose anticoagulant activities were 89, 86 and 85 IU/mg, respectively, and the activity of LMWH was 97 IU/mg. LMWH-DOCA was completely dissolved in 10{\%} DMSO solution, and its bioavailability in the oral dose was significantly increased (17.6{\%} for LD2 in 10{\%} DMSO solution) without causing any damages in intestinal tissues. Conclusions: The chemical conjugate of heparin and DOCA in the soluble state could be efficiently absorbed in the intestine. Therefore, we propose this system as a new strategy of oral heparin delivery for the treatment of patients who are at high risk to DVT and PE.",
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T1 - Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation

AU - Kim, Sang Kyoon

AU - Vaishali, Bagalkot

AU - Lee, Eunhye

AU - Lee, Seulki

AU - Lee, Yong Kyu

AU - Kumar, Tadiparthi Suresh

AU - Moon, Hyun Tae

AU - Byun, Youngro

PY - 2006

Y1 - 2006

N2 - Introduction: Heparin, one of the most potent anticoagulants widely used for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE), is currently available to patients only by parental administration. In this study, we propose a new oral delivery system of heparin by conjugating it with deoxycholic acid which reformulated by adding dimethyl sulfoxide to increase its bioavailability. Materials and methods: The chemical conjugates (LMWH-DOCA) of low molecular weight heparin (4.5 kDa) with deoxycholic acid (DOCA) were synthesized by controlling the conjugation ratio. The absorption of LMWH-DOCA after its oral administration was measured by anti-FXa assay according to the conjugation ratio of DOCA, concentration of DMSO solution and dose of LMWH-DOCA, respectively. Furthermore, the incidences of mucosal damage by LMWH-DOCA in 10% DMSO solution were evaluated using H&E staining and SEM. Results: Three kinds of LMWH-DOCA were synthesized according to the DOCA conjugation ratios of LD1, LD2 and LD3, whose anticoagulant activities were 89, 86 and 85 IU/mg, respectively, and the activity of LMWH was 97 IU/mg. LMWH-DOCA was completely dissolved in 10% DMSO solution, and its bioavailability in the oral dose was significantly increased (17.6% for LD2 in 10% DMSO solution) without causing any damages in intestinal tissues. Conclusions: The chemical conjugate of heparin and DOCA in the soluble state could be efficiently absorbed in the intestine. Therefore, we propose this system as a new strategy of oral heparin delivery for the treatment of patients who are at high risk to DVT and PE.

AB - Introduction: Heparin, one of the most potent anticoagulants widely used for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE), is currently available to patients only by parental administration. In this study, we propose a new oral delivery system of heparin by conjugating it with deoxycholic acid which reformulated by adding dimethyl sulfoxide to increase its bioavailability. Materials and methods: The chemical conjugates (LMWH-DOCA) of low molecular weight heparin (4.5 kDa) with deoxycholic acid (DOCA) were synthesized by controlling the conjugation ratio. The absorption of LMWH-DOCA after its oral administration was measured by anti-FXa assay according to the conjugation ratio of DOCA, concentration of DMSO solution and dose of LMWH-DOCA, respectively. Furthermore, the incidences of mucosal damage by LMWH-DOCA in 10% DMSO solution were evaluated using H&E staining and SEM. Results: Three kinds of LMWH-DOCA were synthesized according to the DOCA conjugation ratios of LD1, LD2 and LD3, whose anticoagulant activities were 89, 86 and 85 IU/mg, respectively, and the activity of LMWH was 97 IU/mg. LMWH-DOCA was completely dissolved in 10% DMSO solution, and its bioavailability in the oral dose was significantly increased (17.6% for LD2 in 10% DMSO solution) without causing any damages in intestinal tissues. Conclusions: The chemical conjugate of heparin and DOCA in the soluble state could be efficiently absorbed in the intestine. Therefore, we propose this system as a new strategy of oral heparin delivery for the treatment of patients who are at high risk to DVT and PE.

KW - Conjugate

KW - Deoxycholic acid

KW - DMSO

KW - Low molecular weight heparin

KW - Oral delivery

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