Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product

• US 4,764,364 A
• Filed: 02/25/1986
• Issued: 08/16/1988
• Est. Priority Date: 02/25/1986
• Status: Expired due to Fees

• Current Assignee: SRI International, Inc.
• Original Assignee: SRI International
• Inventors: Heller, Jorge, Ng, Steve Y., Penhale, Donald W. H.
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US06/833,215
• Time in Patent Office: 903 Days
• Field of Search: 528/392, 424/19, 424/22, 424/78, 424/426, 514/866, 514/950, 514/964, 523/105, 128/260
• US Class Current: 514/772.7
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C08G 2650/42 containing orthoester groups
• CPC Class Codes: C08G 65/002 from unsaturated compounds unsaturated oxiranes C08G65/14
• CPC Class Codes: C08G 65/34 from hydroxy compounds or their metallic derivatives C08G65/26 takes precedence

Abstract

Biodegradible polymers are provided which may contain a biologically active substance, e.g. a drug such as insulin, which is released over a period of time as the polymer erodes when in contact with a body fluid. The polymer contains an amine functionality whereby it erodes faster at low acid pH'"'"'s than at higher acid pH'"'"'s. As an example, the polymer may contain insulin and may contain or may have an encapsulating hydrogel containing glucose oxidase. As the blood sugar level of a diabetic person rises, e.g., afte a meal, glucose diffuses into the polymer or hydrogel and is converted to gluconic acid which lowers the pH, and accelerates erosion and the release of insulin.

Claims

1. Bioerodible polymers capable of functioning as carriers of biologically active substances and release thereof by erosion of the polymer when brought into contact with an aqueous environment, said polymers containing in at least a substantial proportion of the polymer molecules an amine functionality such that the rate of erosion of the polymer in an acidic aqueous environment will increase as the pH of the environment diminishes.

2. The polymers of claim 1 which are poly(ortho esters) resulting from polymerization of a ketene acetal having a functionality of two or more with a polyol.

3. The polymers of claim 2 wherein the polymers are cross linked.

4. The polymers of claim 2 wherein the polymers are linear.

5. Polymers of claim 2 wherein the amine functionality is incorporated (1) in a group linking two molecules of a diketene acetal to produce a prepolymer diketene acetal, or (2) in the polyol or (3) in both the linking group and the polyol.

6. The polymers of claim 5 wherein the amine functionality is embodied in a secondary or tertiary amine group which is part of an open chain or a cyclic group or in a pendent primary, secondary or tertiary amine group.

7. Polymers having the repeating mer unit:

##STR10## wherein n is an integer substantially greater than 10;

wherein R₁ and R₂ are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group;

○

R is a quadrivalent organic grouping;

R₃ and R₄ are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group;

R₅ is an essentially hydrocarbon group which is the residue of a polyol R₅ (OH)_a wherein a is an integer equal to two or more, such polyol being a single molecular species or a mixture of molecular species; and

wherein such linear chain may be crosslinked with other such chains, at least a substantial portion of the polymers having an amine functionality incorporated in the ○

R or in R₅ or in both, whereby the rate of erosion of the polymer in contact with an acidic aqueous medium is substantially greater at lower acidic pH'"'"'s than at higher acidic pH'"'"'s.

8. Polymers of claim 7 wherein the amine functionality is incorporated in ○

R .

9. Polymers of claim 7 wherein the amine functionality is incorporated in R₅.

10. Polymers of claim 7 wherein the amine functionality is incorporated in both ○

R and R₅.

11. Polymers of claim 7 wherein ○

R is the group ##STR11## wherein R is a linking group and ○

R is a quadrivalent organic grouping.

12. Polymers of claim 11 wherein an amine functionality is incorporated in R.

13. Polymers of claim 11 wherein an amine functionality is incorporated in R₅.

14. Polymers of claim 11 wherein an amine functionality is incorporated in both R and R5.

15. Compounds having the structure ##STR12## wherein R₁ and R₂ are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group;

○

R is a quadrivalent organic grouping;

R₃ and R₄ are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; and

R is a linking group.

16. Compounds of claim 15 wherein R contains an amine group.

17. A method of producing biodegradible polymers which undergo faster erosion in an aqueous medium at lower acid pH'"'"'s than at higher acid pH'"'"'s, said method comprising copolymerizing at least two different monomeric species selected to produce a biodegradible polymer, at least one of such species containing an amine functionality.

18. The method of claim 17 wherein both species contain an amine functionality.

19. The method of claim 17 wherein one species is a ketene acetal having at least two ketene groups and the other species is a polyol.

20. The method of claim 19 wherein both the ketene acetal and the polyol contain an amine functionality.

21. The method of claim 19 wherein said ketene acetal has the structure ##STR13## wherein R₁ and R₂ are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group;

○

R is a quadrivalent organic grouping;

R₃ and R₄ are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; and

R is a linking group and the biologically active substance is premixed with said ketene acetal.

22. The method of claim 17 wherein the species are selected to cross link and the resulting product is a cross linked polymer.

23. The method of claim 22 wherein a biologically active substance is incorporated in one or the other or both species or in the mixture of the two prior to cross linking.