Controlled drug delivery high molecular weight polyanhydrides

• US 4,888,176 A
• Filed: 06/12/1987
• Issued: 12/19/1989
• Est. Priority Date: 05/21/1984
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Langer, Robert S., Laurencin, Cato T., Domb, Abraham J.
• Primary Examiner(s): Schofer, Joseph L.
• Assistant Examiner(s): Kulkosky, Peter F.
• Application Number:
  US07/061,294
• Time in Patent Office: 921 Days
• Field of Search: 528/176, 424/426, 424/78
• US Class Current: 514/772.3
• CPC Class Codes: A61L 17/10 containing macromolecular materials
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: C08G 67/04 Polyanhydrides
• CPC Class Codes: C08L 73/02 Polyanhydrides

Abstract

A bioerodible controlled drug release device is produced as a homogeneous polymeric matrix from a high molecular weight polyanhydride and a suitable biologically active substance. The high molecular weight polyanhydride is defined by a molecular weight greater than 20,000 and an intrinsic viscosity greater than 0.3 dl/g. The controlled drug release device is preferrably formed by solvent casting with the biologically active substance and exhibits zero order release, improved correlation between the rate of release and polymer degradation, and an induction period between introduction to the eroding environment and the initial release of the biologically active substance. The controlled drug release devices are stable for extended periods of time, flexible and durable and not subject to fracture and disintegration.

Claims

1. A bioerodible controlled drug release device comprising a homogeneous polymeric matrix of:

(a) an effective amount of at least one biologically active substance, and;

(b) a high molecular weight hydrophobic polyanhydride copolymer having a weight average molecular weight greater than 20,000 and an intrinsic viscosity greater than 0.3 dl/in chloroform at 23°

C., said polyanhydride produced from at least one dicarboxylic acid selected from the group consisting of;

aliphatic dicarboxylic acids having the formula;

space="preserve" listing-type="equation">HOOC--H.sub.2 --C--R--CH.sub.2 --COOH;

aromatic dicarboxylic acids having the formula;

##STR1## aromatic dicarboxylic acids having the formula;

##STR2## aliphatic-aromatic dicarboxylic acids having the formula;

##STR3## aromatic and aliphatic heterocyclic dicarboxylic acids having the formula;

##STR4## wherein X is selected from the group consisting of oxygen, nitrogen, and sulfur, and

n is an integer between 1 and 3; and

aromatic and aliphatic heterocyclic dicarboxylic acids of the above formula in combination with at least one dicarboxylic acid selected from the group consisting of aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids having more than one phenyl group;

wherein the R groups are divalent organic radical groups.

2. The bioerodible controlled drug release device of claim 1 wherein said hydrophobic polyanhydride copolymer is synthesized by the steps of

(a) selecting at least one essentially pure prepolymer from at least one essentially pure dicarboxylic acid reacted with acetic anhydride

(b) polymerizing said prepolymer under a predetermined temperature, vacuum and for a length of time whereby the resulting polyanhydride has a molecular weight in excess of 20,000 and an intrinsic viscosity greater than 0.3 dl/g in an inorganic solvent at room temperature.

3. The bioerodible controlled drug release device of claim 2 wherein said predetermined vacuum of said polymerization step is at least 10^-2 mm Hg.

4. The bioerodible controlled drug release device of claim 3 wherein said polymerization step is carried out in the presence of a catalyst.

5. The bioerodible controlled drug release device of claim 4 wherein said catalyst is selected from the group comprising alkaline earth metal oxides, calcium carbonate, coordination complexes of diethylzinc and hydroxylated compounds or Cd(CH₃ COO)₂.

6. The bioerodible controlled drug release device of claim 1 wherein said high molecular weight hydrophobic polyanhydride has a molecular weight between 20,000 and 240,000 and has an intrinsic viscosity between 0.3 dl/g and 1.18 dl/g in chloroform at 23°

C.

7. The bioerodible controlled drug release device of claim 1 wherein said high molecular weight hydrophobic polyanhydride is synthesized from a dicarboxylic acid selected from the group consisting of sebacic acid, bis(p-carboxyphenoxy) alkanes, isophthalic acid, dodecanedioic acid, hydroquinone-O,O'"'"'-diacetic acid, 1,4-bis(carboxymethyl) benzene, 2,2-bis(4-carboxyphenyl) propane, terephthalic acid, 1,4 phenylene dipropionic acid, bis(4-carboxyphenyl) alkanes and cyclohexane dicarboxylic acids.

8. The bioerodible controlled drug release device of claim 1 wherein said homogeneous matrix is prepared by the steps of

(a) dissolving said hydrophobic polyanhydride in a suitable solvent to form a solution;

(b) combining to the solution said biologically active substance; and

,

(c) evaporating the solvent.

9. The bioerodible controlled drug release device of claim 1 wherein said biologically active substance is a peptide.

10. The bioerodible controlled drug release device of claim 1 wherein said biologically active substance is a protein.

11. The bioerodible controlled drug release device of claim 1 wherein said biologically active substance is a steroid.

12. The bioerodible controlled drug release device of claim 1 wherein said biologically active substance is an antibiotic.

13. The bioerodible controlled drug release device of claim 1 wherein said device is adapted for subcutaneous implantation in an animal.

14. The bioerodible controlled drug release device of claim 1 wherein said device is adapted for transdermal administration of said biologically active substance.

15. A bioerodible controlled release device adapted for dispensing at least one biologically active substance at a controlled rate comprising a homogeneous polymeric matrix of:

(a) an effective amount of at least one biologically active substance; and

(b) a hydrophobic polyanhydride copolymer having a weight average molecular weight greater than 20,000 and an intrinsic viscosity greater than 0.3 dl/g in chloroform at 23°

C., said polyanhydride produced from at least one dicarboxylic acid selected from the group consisting of;

aliphatic dicarboxylic acids having the formula;

space="preserve" listing-type="equation">HOC--H.sub.2 --C--R--CH.sub.2 --COOH;

aromatic dicarboxylic acids having the formula;

##STR5## aromatic dicarboxylic acids having the formula;

##STR6## aliphatic-aromatic dicarboxylic acids having the formula;

##STR7## aromatic and aliphatic heterocyclic dicarboxylic acids having the formula;

##STR8## nitrogen and sulfur, and wherein

X is selected from the group consisting of oxygen,

n is an integer between 1 and 3; and

aromatic and aliphatic heterocyclic dicarboxylic acids of the above formula in combination with at least one dicarboxylic acid selected from the group consisting of aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and aromatic dicarboxylic acids having more than one phenyl group;

wherein the R groups are divalent organic radical groups, wherein said polyanhydride includes at least 5% aromatic repeating units.

16. The bioerodible controlled release device of claim 15 wherein said polyanhydride copolymer includes at least 20% aromatic repeating units.

17. A bioerodible composition comprising at least one biologically active substance and a high molecular weight polyanhydride having a molecular weight greater than 20,000, an intrinsic viscosity greater than 0.3 dl/g in chloroform at 23°

C., said polyanhydride having at least 20% aromatic repeating units.

18. The bioerodible composition of claim 17 wherein said bioerodible composition and biologically active substance is a homogeneous polymeric matrix.