Multi-arm poly(ethylene glycol) (PEG) amines have utility in the preparation of hydrogels for drug delivery, for conjugation to proteins to reduce toxicity and prolong the lifetime of the protein in the body, and for surface functionalization of medical devices and appliances. Of particular interest is the use of multi-arm PEG amines for the preparation of tissue adhesives formed by reacting the multi-arm PEG amine with an oxidized polysaccharide, as described by Kodokian et al. (copending and commonly owned U.S. Patent Application Publication No. 2006/0078536).
Methods for preparing multi-arm polyoxyalkylene amines are known. For example, Larkin et al. (U.S. Pat. No. 4,766,245) describe the conversion of three-arm and 8-arm poly(propylene glycols) to the corresponding polyamines by reaction with ammonia in the presence of hydrogen and a Raney nickel/aluminum catalyst. Nho et al. (U.S. Patent Application Publication No. U.S. 2004/0225097) describe the conversion of multi-arm PEG polyols to their corresponding multi-arm PEG amines by tosylation followed by reaction with aqueous ammonia for ten days. Additionally, Buckmann et al. (Makromol. Chem. 182:1379-1384 (1981)) describe the conversion of linear PEG to the corresponding diamine via a two step reaction comprising reacting the PEG with thionyl bromide to form the bromide derivative, followed by reaction with ethanolic ammonia.
All of the aforementioned methods suffer from various limitations, particularly when the multi-arm PEG amine is to be used in the preparation of hydrogels for use as a tissue adhesive or for drug delivery applications. Specifically, the conversion of the hydroxyl end groups to primary amines using these methods is generally less than 95%, which results in a low crosslink density when the multi-arm PEG amine is used to form a hydrogel tissue adhesive or drug delivery composition. Methods based on the use of the strong acid thionyl bromide result in acid-catalyzed depolymerization of the PEG polymer. Additionally, some methods result in the formation of salts or the contamination of the product with heavy metals or other toxic substances, all of which must be separated from the multi-arm PEG amine product.
Therefore, the problem to be solved is to provide a method for the preparation of multi-arm PEG amines from multi-arm PEG polyols that results in a high conversion of the hydroxyl end groups to primary amines. The method should also minimize acid-catalyzed depolymerization of the PEG, avoid the formation of salts, minimize the use of organic solvents, and avoid potential contamination with toxic byproducts.
Applicants have addressed the stated problem by discovering a two step method for preparing multi-arm PEG amines from multi-arm PEG polyols, wherein the multi-arm PEG polyol is reacted with thionyl chloride, and the resulting multi-arm PEG chloride is subsequently reacted with aqueous or anhydrous ammonia.
USPTO Backgrounds
USPTO Backgrounds