One step preparation of poly(amide-anhydride)

• US 4,933,431 A
• Filed: 11/09/1988
• Issued: 06/12/1990
• Est. Priority Date: 07/31/1987
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Kothari, Rohit, Giannos, Steven, Langer, Robert S., Domb, Abraham J., Ron, Eyal, Mathiowitz, Edith
• Primary Examiner(s): Anderson, Harold D.
• Application Number:
  US07/269,448
• Time in Patent Office: 580 Days
• Field of Search: 528/328, 528/310, 528/312, 528/314, 528/315, 528/271
• US Class Current: 528/328
• CPC Class Codes: C08G 67/04 Polyanhydrides
• CPC Class Codes: C08G 69/08 derived from amino-carboxylic acids
• CPC Class Codes: C08G 69/10 Alpha-amino-carboxylic acids polysuccinimides C08G73/1092

Abstract

A method for synthetizing polyanhydrides in solution using coupling agents and a removable acid acceptor to effect a one-step polymerization of dicarboxylic acids. As used in the method, these coupling agents include phosgene, diphosgene, and acid chlorides. Insoluble acid acceptors include insoluble polyamines and crosslinked polyamines such as polyethyleneimine and polyvinylpyridine and inorganic bases such as K₂ CO₃, Na₂ CO₃, NaHCO₃, and CaCO₃. The only byproduct formed is a removable hydrochloric acid-acid acceptor.

Examples are provided of the polymerization of highly pure polyanhydrides using phosgene, diphosgene or an acid chloride as the coupling agent, in combination with either an insoluble acid acceptor or a soluble acid acceptor in a solvent wherein the polymerizaiton byproduct or polymer is insoluble.

A particularly important application of these polyanhydrides is in the formation of drug delivery devices containing bioactive compounds. The method is also useful in the polymerization of dicarboxylic acids including heat liable dipeptides of glutamic or aspartic acid.

Claims

1. A highly pure poly(amide-anhydride) produced by reacting in solution under dehydrative coupling conditions a coupling agent and an insoluble acid acceptor with at least one dipeptide selected from the group consisting of dipeptides of aspartic acid, dipeptides of glutamic acid, and combinations thereof.

2. The highly pure poly(amide-anhydride) of claim 1 wherein the coupling agent is selected from the group consisting of phosgene, diphosgene, and acid chlorides.

3. The highly pure poly(amide-anhydride) of claim 1 wherein the insoluble acid acceptor is selected from the group consisting of insoluble polyamines, crosslinked polyamines, and inorganic bases.

4. A highly pure poly(amide-anhydride) produced by reacting in solution a coupling agent with a dipeptide selected from the group consisting of dipeptides of aspartic acid, dipeptides of glutamic acid, and combinations thereof, wherein the polyanhydride is soluble in solution, substantially unhydrolized, and free of coupling agent and reaction byproducts.

5. A method for polymerizing highly pure poly(amide-anhydride)s comprising reacting in a non-aqueous solution under dehydrative conditions a coupling agent and an acid acceptor with at least one dipeptide of amino acids selected from the group consisting of glutamic acid, aspartic acid, and combinations thereof, wherein the acid acceptor is insoluble in a solvent in which the poly(amide-anhydride) is soluble.

6. The method of claim 5 wherein the coupling agent is selected from the group consisting of phosgene, diphosgene, and acid chlorides.

7. The method of claim 5 wherein the insoluble acid acceptor is selected from the group consisting of insoluble polyamines, crosslinked polyamines, and inorganic bases.