Studies on the intestinal absorption of low molecular weight heparin using saturated fatty acids and their derivatives as an absorption enhancer in rats.
Intestinal absorption of low molecular weight heparin (LMWH) as well as unfractionated heparin (UFH) is limited due to its large molecular size and extensive negative charge. Development of its oral formulations would allow outpatient treatment with LMWH and UFH, and contribute a reduction in hospital expenses. The present study was aimed at evaluating the absorption enhancers Labrasol and Gelucire 44/14, which mainly consist of glycerides and fatty acids esters, to improve the intestinal absorption of LMWH. The absorption effects of saturated fatty acids with several carbon chain lengths (C6-C14) were also investigated. LMWH formulated with or without absorption enhancer was administered to the duodenum of fasted rats. The doses of LMWH and absorption enhancer were 20 mg/kg and 30 mg/kg, respectively. Plasma anti-Xa activity was measured as a marker of the LMWH absorption. By administration of the LMWH formulation with Labrasol but not with Gelucire 44/14, the plasma anti-Xa activity was increased to a level above 0.2 IU/ml which is the critical level for elucidation of its anticoagulant activity. Saturated fatty acids also enhanced the intestinal absorption of LMWH, and the order of absorption-enhancing effect was C10=C12>C14>C16>C8> or =C6. These results suggest that the intestinal absorption of LMWH varies with carbon chain lengths of the saturated fatty acids.
Mori
Saori
S
Shimizu Research Center, Shimizu Pharmaceutical Co., Ltd., Shimizu Miyakami, Shizuoka, Japan. saori_mori@ajinomoto.com
Matsuura
Akihiro
A
Rama Prasad
Yarasani Venkata
YV
Takada
Kanji
K
D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics*; D004386:Duodenum / Q000378:metabolism; D004655:Emulsions / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005227:Fatty Acids / Q000494:pharmacology*; D005989:Glycerides; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D009930:Organic Chemicals; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000277:Adjuvants, Pharmaceutic; D000925:Anticoagulants; D004655:Emulsions; D065427:Factor Xa Inhibitors; D005227:Fatty Acids; D005989:Glycerides; D006495:Heparin, Low-Molecular-Weight; D009930:Organic Chemicals; C440220:Labrasol; C104509:gelucire 44-14; D011092:Polyethylene Glycols; C080945:parnaparin