Polyanhydrides with improved hydrolytic degradation properties

• US 4,857,311 A
• Filed: 07/31/1987
• Issued: 08/15/1989
• Est. Priority Date: 07/31/1987
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Langer, Robert S., Domb, Abraham J.
• Primary Examiner(s): Schoffer, Joseph L.
• Assistant Examiner(s): Kulkosky, Peter F.
• Application Number:
  US07/080,631
• Time in Patent Office: 746 Days
• Field of Search: 424/78, 528/271
• US Class Current: 514/772.3
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08G 67/04 Polyanhydrides

Abstract

Polyanhydrides with uniform distribution of alkyl and aromatic residues are prepared by melt polycondensation or solution polymerization of p-carboxyphenoxyalkanoic acids or p-carboxyphenylalkanoic acids. These polymers are soluble in common organic solvents and have low melting points, generally in the range of 40°-100° C.

The polyanhydrides are especially well suited for forming bioerodible matrices in controlled bioactive compound delivery devices. A polymeric matrix formed according to the method described here degrades uniformly during drug release, preventing the wholescale channeling of the bioactive compound into the environment, and eliminating the problem of the presence of the polymer matrix at the site long after drug release. The polymer displays zero-order kinetic degradation profiles over various periods of time (days to months), at a rate useful for controlled drug delivery. Furthermore, a desired degradation rate may be obtained by choosing the appropriate length of the aliphatic moiety.

Claims

1. A polyanhydride having the general formula ##STR4## wherein X is selected from the group consisting of O and CH₂, n is an integer between 2 and 25, and y is at least 2, and

wherein the polyanhydride is soluble in organic solvents and has a melting point of approximately 100°

C. or less.

2. The polymer of claim 1 further comprising a bioactive compound for use in a controlled bioactive compound delivery device.

3. The polymers of claim 1 which have a melting point between 40°

C. and 100°

C.

4. The polymers of claim 1 which display zero order kinetic degradation profiles past 60% degradation.

5. The polymers of claim 1 formed by the polymerization of monomers selected from the group consisting of p-carboxyphenoxyvaleric acid, and p-carboxyphenoxyoctanoic acid.

6. The polymers of claim 5 further comprising a bioactive compound for use in a controlled drug delivery device.

7. The polymers of claim 5 which have a melting point between 40°

C. and 100°

C.

8. The polymers of claim 5 which display zero order kinetic degradation profiles past 60% degradation.

9. A method of preparing a controlled bioactive compound delivery device comprising

selecting monomers having both aromatic and aliphatic moieties which may be polymerized into a polyanhydride with a uniform distribution of aliphatic and aromatic residues in the polymer chain, having the general formula ##STR5## wherein X is selected from the group consisting of O and CH₂, n is an integer between 2 and 25, and y is at least 2, and

wherein the polyanhydride is soluble in organic solvents and has a melting point of approximately 100°

C. or less.

10. The method of claim 15 further comprising

polymerizing the monomers to form a polymer having the formula ##STR6## wherein X is selected from the group consisting of O and CH₂, n is an integer between 2 and 25, and y is at least 2.

11. The method of claim 10 further comprising:

providing a bioactive compound selected from the group consisting of proteins, drugs, saccharides, nucleic acid sequences, and combinations thereof.

12. The method of claim 9 further comprising polymerizing monomers selected from the group consisting of p-carboxyphenoxyalkanoic acids.

13. The method of claim 12 wherein the monomers are selected from the group consisting of p-carboxyphenoxyvaleric acid, and p-carboxyphenoxyoctanoic acid.

14. The method of claim 9 further comprising polymerizing the monomers to form a polymeric matrix, providing a bioactive compound, and embedding the bioactive compound in the polymeric matrix.

15. The method of claim 14 further comprising implanting the bioactive compound delivery device.

16. The method of claim 11 further comprising polymerizing the monomers with a bioactive compound.

17. The method of claim 16 further comprising implanting the controlled bioactive compound delivery device.

18. A polyanhydride with the general formula ##STR7## wherein X is selected from the group consisting of O and CH₂, Y is an aromatic, Z is an aliphatic having between 2 and 25 carbon molecules in the backbone, and y is at least 2, and

wherein the polyanhydride is soluble in organic solvents and has a melting point of approximately 1000°

C. or less.