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Oral delivery of macromolecules

A macromolecular, selected technology, applied in the direction of medical preparations with non-active ingredients, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of non-transportation

Inactive Publication Date: 2004-08-04
(株)美大富历寿
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As another example, P.W.Swaan et al. reported in "Enhanced Transepithelial Transport of Peptides by Conjugation to Cholic Acid" (Enhanced Transepithelial Transport of Peptides by Conjugation to Cholic Acid)-8 Bioconjugate Chemistry, 520-525 (1997) Bile acid conjugates of up to 6 amino acids (i.e., about 900 Da) showed affinity for intestinal bile acid transporters, but bile acid conjugates of only 6 amino acids tested were not transported by bile acid carriers

Method used

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Examples

Experimental program
Comparison scheme
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Embodiment 1

[0076] Synthesis of Heparin-DOCA Conjugate

[0077]A dimethylformamide (DMF) solution of 5 ml of N-hydroxysuccinimide (HOSu, 92 mg / 5 ml) was mixed with a DMF solution of 5 ml of dicyclohexylcarbodiimide (DCC) (165 mg / 5 ml), Then 5ml of DOCA (196mg / 5ml) in DMF was added. The molar ratio of DOCA, HOSu and DCC is 1:1.6:1.6. The concentrations of HOSu and DCC were slightly higher than that of DOCA to fully activate DOCA. The resulting solution was reacted at room temperature under vacuum for 5 hours, and then dicyclohexylurea (DCU), a by-product precipitated during the reaction, was removed. Unreacted DCC was removed by dropwise addition of distilled water and filtration. The remaining HOSu was then removed by adding 15 ml of distilled water. Activated DOCA was precipitated and then lyophilized. The activated DOCA was then dissolved in DMF and reacted with heparin at room temperature for 4 hours. The amount of heparin used in these reactions was 40-400 mg. After the reactio...

Embodiment 2

[0081] Preparation of heparin-cholesterol conjugates

[0082] The hydroxyl groups of cholesterol are activated by reaction with chloroacetic acid to generate free carboxyl groups. This modified cholesterol was then reacted with a solution of HOSu and DCC in 10 ml of DMF following the procedure of Example 1. The molar ratio of cholesterol, HOSu and DCC was 1:1.6:1.6, and the reaction was carried out at room temperature for 5 hours. To remove unreacted DCC and HOSu, water was added and the solution was filtered through a 0.45 μm membrane. Next, the activated cholesterol was reacted with the heparin solution for 4 hours. Two products are obtained from this reaction: a water-soluble product and a water-insoluble product. These products were worked up according to the procedure in Example 1 above.

Embodiment 3

[0084] Synthesis of heparin-alkanoic acid conjugates

[0085] The procedure of Example 1 was followed to couple lauric and palmitic acids to heparin. The carboxyl group of the alkanoic acid is coupled with the amine group of heparin to form an amide bond. Coupling reagents include HOSu and DCC.

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Abstract

Polysaccharides, which are widely used as an anticoagulation drugs, especially heparin, are clinically administered only by intravenous or subcutaneous injection because of their strong hydrophilicity and high negative charge. Amphiphilic heparin derivatives were synthesized by conjugation to bile acids, sterols, and alkanoic acids, respectively. These heparin derivatives were slightly hydrophobic, exhibited good solubility in water, and have high anticoagulation activity. These slightly hydrophobic heparin derivatives are efficiently absorbed in the gastrointestinal tract and can be used in oral dosage forms. Methods of using these amphiphilic heparin derivatives and similarly modified macromolecules for oral administration are also disclosed.

Description

field of invention [0001] The present invention relates to derivatives of macromolecules, including polysaccharide derivatives, having increased hydrophobicity compared to unmodified macromolecules or polysaccharides. More specifically, the present invention relates to the oral delivery and absorption of hydrophobic macromolecules such as amphiphilic heparin derivatives and amphiphilic polysaccharide derivatives, wherein the biological activity of the macromolecule or polysaccharide is preserved. In a preferred embodiment of the invention, the hydrophobic macromolecules and amphiphilic polysaccharide derivatives have a molecular weight greater than 1000 and can be absorbed after oral administration. Background of the invention [0002] Heparin is a polysaccharide composed of sulfated D-glucosamine and D-glucuronic acid residues. Heparin is strongly negatively charged due to its large ionizable sulfate moiety. It is a relatively strong acid that readily forms water-soluble ...

Claims

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Application Information

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IPC IPC(8): A61K31/727A61K38/00A61K38/23A61K38/28A61K47/12A61K47/28A61K47/48A61P3/10A61P7/12A61P19/10C08B37/00
CPCA61K31/727C08B37/0075C08B37/00A61K47/4823A61K47/48038A61K47/48123A61K47/542A61K47/554A61K47/61A61P3/10A61P7/02A61P7/12A61P19/10A61K47/50
Inventor 边荣鲁李容圭
Owner (株)美大富历寿
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