Low molecular weight heparin triethanolamine salt usable as local delivery antithrombotic treating agent, preparing process and use thereof

A low-molecular-weight heparin, ethanolamine salt technology, applied in the direction of organic active ingredients, medical preparations containing active ingredients, blood diseases, etc., can solve problems such as restricting the use of antithrombotic agents

Active Publication Date: 2009-12-02
SYNTEX SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The strong ionic character of low-molecular-weight heparins (and even the original heparins, due to their relatively high molecular weight) has severely limited the use of this substance as a topically administered antithrombotic agent, and indeed, no topical formulations containing Pharmaceutical preparations of low molecular weight heparins for the relief or prevention of varicose veins, hemorrhoids, traumatic edema, or postoperative hematoma (plastic or cosmetic surgery)

Method used

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  • Low molecular weight heparin triethanolamine salt usable as local delivery antithrombotic treating agent, preparing process and use thereof
  • Low molecular weight heparin triethanolamine salt usable as local delivery antithrombotic treating agent, preparing process and use thereof
  • Low molecular weight heparin triethanolamine salt usable as local delivery antithrombotic treating agent, preparing process and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Depolymerization of heparin

[0037] 100 g of USP / EP grade heparin for injection was dissolved in sufficient distilled water to obtain 500 ml of a 20% solution.

[0038] The solution was placed in a 4-necked spherical bottle equipped with a stirrer, pH meter electrode, heating and reflux cooling device. The aqueous solution was heated to 94-96°C, followed by the addition of 1M hypochlorous acid solution (prepared by adjusting the pH of a pre-cooled 80 g / l sodium hypochlorite solution to 6 with hydrochloric acid) at 0 / 5°C. 290 mL of 1 M HClO solution was added over a 60 minute reaction time, while HCl or NaOH was added to the aqueous solution as needed to keep the pH stable at 5.0-6.0.

[0039] After the 60-minute reaction was over, 3% sodium chloride was added and 2 times the volume of ethanol was added with vigorous stirring to cause rapid precipitation of the reaction product, resulting in immediate termination of the depolymerization reaction.

[0040] Salt for...

Embodiment 2

[0058] Depolymerization of heparin

[0059] 100 grams of USP / EP grade heparin for injection was dissolved in sufficient distilled water to obtain 500 ml of a 20% (w / v) solution and transferred to a balloon provided with heating, stirring and reflux cooling.

[0060] will consist of 20 ml of 30% H 2 o 2 and 1 ml of 1.5% FeSO 4 ·7H 2 Reagents of composition O were heated to 80°C and added with stirring.

[0061] After heating and stirring for 40 minutes, the reaction was stopped immediately by adding 2% NaCl and precipitating the depolymerized polysaccharide by adding 2 volumes of ethanol.

[0062] The obtained precipitate was dissolved in a sufficient amount of distilled water to obtain a 10% solution, and the solution was applied to a 1 liter column capacity (φ5.2 cm × 50 cm height) containing ion exchange resin ( IR-120 (Rohm Haas) (phase H + ) column, flow rate 0.42 cm 3 / cm 2 × minutes. The acidic eluate was collected in an ice bath and its pH was adjusted to 5....

Embodiment 3

[0079] Lyophilization in the presence of mannitol: addressing the inherent hygroscopicity of LMWH-TEA

[0080] 18.6 g of LMWH-TEA obtained in Example 2 was dissolved in sufficient distilled water to obtain 125 ml of a 15% (weight to volume) solution. While stirring, 12.40 grams of USP grade mannitol was added, as in this example, mannitol is very soluble at room temperature when the initial solution concentration is not higher than 15%.

[0081] The solution was lyophilized to obtain a dry powder of the crystals with greatly reduced hygroscopicity, which was ready for grinding. The ground powder is fluid and does not agglomerate.

[0082] The following analysis table is provided for comparison:

[0083] LMWH-TEA LMWH-TEA / Mannitol

[0084] Anti-Xa activity 50 IU / mg 30 IU / mg

[0085] Anti-IIa activity 24 IU / mg 14 IU / mg

[0086] Sulfur (S) 6.8% 4.2%

[0087] S / COO - Ratio 2.1 2.1

[0088] Triethanolamine 50% 30%

[0089] Sodium (Na) 280ppm 170ppm

[0090...

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Abstract

The present invention discloses low molecular weight heparin triethanolamine salts useful as antithrombotic therapeutic agents for topical administration, wherein at least 60% of the total amount thereof has a molecular weight below 8000 Da and an average molecular weight between 4000-6000 Da, said salt It also contains 6.1-7.5% by weight (theoretical value is 6.8%) of organic sulfur and 42.6-52.1% by weight (theoretical value is 47.4%) of triethanolamine. The invention also discloses the method of preparing said heparin salt and eliminating the hygroscopicity of said salt, as well as the pharmaceutical composition used in local antithrombotic treatment and its application.

Description

technical field [0001] The present invention relates to a new chemical substance obtained by the salt formation of depolymerized acidic polysaccharide, especially low molecular weight heparin, and organic base triethanolamine. Furthermore, the present invention describes a pharmaceutical dosage form comprising said low molecular weight heparin (LMWH) triethanolamine (TEA) salt for therapeutic administration by topical route. Furthermore, the present invention relates to a new process for the preparation of said low molecular weight heparin triethanolamine salt. Also described are methods of eliminating the hygroscopicity of heparin salts, as well as pharmaceutical compositions for topical application and their use in antithrombotic therapy. Background technique [0002] In general, acidic polysaccharides, especially heparin, can be depolymerized by methods well reported in US Patent 4977250 / EP 268885. [0003] Said document describes a process for the chemical depolymeriza...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08B37/10A61K31/727A61P9/14A61K9/06A61K9/107A61P7/02C08B37/00
CPCC08B37/0078A61K31/727C08B37/0075A61P7/02A61P9/14
Inventor V·B·迪阿兹O·E·马提耐兹
Owner SYNTEX SA
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