Tricaprylin microemulsion for oral delivery of low molecular weight heparin conjugates.
Heparin is available to patients only by parenteral administrations due to its low oral bioavailability. For the oral delivery of low molecular weight heparin (LMWH), LMWH-DOCA was synthesized by chemical conjugation of LMWH and deoxycholic acid (DOCA) and this conjugate was formulated in a microemulsion system. The coupling ratios of DOCA to LMWH for LD1 and LD2 were 1.33 and 2.37, respectively. The microemulsion was composed of tricaprylin, surfactant mixture (Tween 80 and Span 20) and LMWH-DOCA in water, and their volume ratio was 5:3:1:1. Pharmacokinetic parameters of LMWH were not significantly changed by conjugation with DOCA; however, when LMWH-DOCA in tricaprylin microemulsion was orally administered in mice, its bioavailability was increased up to 1.5%. Furthermore, the enhancing effect of the conjugated DOCA in the tricaprylin microemulsion on the absorption of LMWH in the intestine was more significantly increased in monkey than in mice. Since the tricaprylin microemulsion could dissolve LMWH-DOCA, this formulation could maximize the enhancing effect of the conjugated DOCA on the absorption of LMWH in the intestine. Finally, it was expected that 20 mg/kg of LMWH-DOCA in the tricaprylin microemulsion was enough to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).
Kim
Sang Kyoon
SK
Center for Cell and Macromolecular Therapy, Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, South Korea.
Lee
Eun Hye
EH
Vaishali
Bagalkot
B
Lee
Seulki
S
Lee
Yong-kyu
YK
Kim
Choong-Yong
CY
Moon
Hyun Tae
HT
Byun
Youngro
Y
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D002210:Caprylates / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003900:Desoxycorticosterone; D004655:Emulsions; D005079:Excipients; D006207:Half-Life; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects; D008252:Macaca fascicularis; D051379:Mice; D008813:Mice, Inbred ICR; D008970:Molecular Weight; D009821:Oils / Q000737:chemistry / Q000494:pharmacology; D011136:Polysorbates; D012995:Solubility; D013012:Sorbitol; D014280:Triglycerides / Q000737:chemistry*
D000925:Anticoagulants; D002210:Caprylates; D004655:Emulsions; D005079:Excipients; D006495:Heparin, Low-Molecular-Weight; D009821:Oils; D011136:Polysorbates; D014280:Triglycerides; D003900:Desoxycorticosterone; D013012:Sorbitol; C003637:tricaprylin