Erodible agent releasing device comprising poly(orthoesters) and poly(orthocarbonates)

• US 4,138,344 A
• Filed: 08/24/1977
• Issued: 02/06/1979
• Est. Priority Date: 01/28/1975
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Heller, Jorge, Choi, Nam S.
• Primary Examiner(s): Sebastian, Leland A.
• Application Number:
  US05/827,223
• Time in Patent Office: 531 Days
• Field of Search: 71/64 F, 71/64 G, 128/260, 252/1, 252/384, 252/522, 424/19, 424/20
• US Class Current: 252/1
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C08G 4/00 Condensation polymers of aldehydes or ketones with polyalcohols; Addition polymers of heterocyclic oxygen compounds containing in the ring at least once the grouping —O—C—O— of cyclic oligomers of aldehydes C08G2/00
• CPC Class Codes: C08G 65/34 from hydroxy compounds or their metallic derivatives C08G65/26 takes precedence
• CPC Class Codes: C08G 67/00 Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
• CPC Class Codes: Y10S 71/904 Carrier

Abstract

The invention concerns orthoester and orthocarbonate polymers having a repeating mer comprising a hydrocarbon radical and a symmetrical dioxycarbon unit of the general formula: ##STR1## WHEREIN R₁ is a multivalent hydrocarbon radical, R₂ and R₃ are hydrocarbon radicals with at least one of R₂ or R₃ bonded to the dioxycarbon through an oxygen linkage, and which polymers are synthesized by reacting a polyol with an orthoester or orthocarbonate. The polymers are useful for making articles of manufacture, including devices and coatings for delivering beneficial agents.

Claims

1. A device for the controlled release of an active agent to an environment of use, said device comprising:

a matrix of an erodible release rate controlling material, said material comprising a polymer of the formula;

##STR61## wherein R₁ is a member selected from the group of divalent, trivalent and tetravalent radicals consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and alkenyl of 2 to 7 carbons cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons, arylene, and arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkenyl of 2 to 7 carbons;

wherein R₂ and R₃ are selected from the group consisting of alkyl of 1 to 7carbons;

alkenyl of 2 to 7 carbons;

alkoxy of 1 to 7 carbons;

alkenyloxy of 2 to 7 carbons;

alkylene of 2 to 6 carbons;

alkenylene of 3 to 6 carbons;

alkyleneoxy of 2 to 6 carbons;

alkenyleneoxy of 3 to 6 carbons;

aryloxy;

aralkyleneoxy of 8 to 12 carbons;

aralkenyleneoxy of 8 to 12 carbons, oxa;

OR₁ O with R₁ as defined above;

a heterocyclic ring of 5 to 8 carbons and oxygen atoms formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a member selected from the group consisting of a heterocyclic and fused polycyclic rings when R₂ and R₃ are taken together, with at least one of said R₂ and R₃ a member selected from the group consisting of alkoxy, alkenyloxy and OR₁ O; and

n is greater than 10;

an active agent present in the matrix; and

wherein the device, when in the environment of use erodes at a controlled and continuous rate, thereby releasing the active agent at a controlled and continuous rate over a period of time.

2. A device according to claim 1, wherein R₁ is divalent when R₂ and R₃ are selected from the group consisting of alkyl, alkenyl, alkoxy and alkenyloxy with at least one of said R₂ and R₃ selected from the group consisting of alkoxy and alkenyloxy.

3. A device according to claim 1, wherein R₁ is divalent when R₂ and R₃ taken together is a member selected from the group consisting of heterocyclic and fused polycyclic rings.

4. A device according to claim 1, wherein R₂ and R₃ are a heterocyclic ring, R₂ is selected from the group consisting of alkyleneoxy and alkenyleneoxy and R₃ is a member selected from the group consisting of alkyleneoxy, alkenyleneoxy and alkylene.

5. A device according to claim 1, wherein R₂ and R₃ are a fused polycyclic ring, R₂ is selected from the group consisting of oxa, alkyleneoxy and alkenyleneoxy and R₃ is selected from the group consisting of aryloxy, aralkyleneoxy, aralkenyleneoxy and aralkylene.

6. A device according to claim 1, wherein R₁ is divalent when one of said R₂ and R₃ is a member selected from the group consisting of alkyl, alkenyl, alkoxy and alkenyloxy.

7. A device according to claim 1, wherein R₁ is trivalent when R₂ and R₃ taken together is a member selected from the group consisting of heterocyclic and fused polycyclic rings.

8. A device according to claim 1, wherein R₁ is tetravalent when R₂ and R₃ taken together is a member selected from the group consisting of heterocyclic and fused polycyclic rings.

9. A device according to claim 1, wherein R₂ and R₃ are bonded together with one of R₂ and R₃ selected from the group consisting of R₂ and R₃ selected from the group consisting of alkylenedioxy and alkenylenedioxy.

10. A device according to claim 1, wherein the matrix comprises a polymer of the following formula:

##STR62## wherein alkylene, cycloalkylene, a, b and n are as defined.

11. A device according to claim 1, wherein the matrix comprises a polymer of the following formula:

##STR63##

12. A device according to claim 11, wherein the polymer contains a member selected from the group consisting of trans isomers, cis isomers, and mixtures thereof.

13. A device for releasing an active agent, said device comprising:

a) a shaped matrix sized and adapted for placement in an environment of use and formed of the following formula;

##STR64## wherein R₁ is a member selected from the group consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons, alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with a member selected from the group consisting of an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

arylene, and arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and alkenyl of 2 to 7 carbons;

a is 0 to 1;

b is 2 to 6; and

n is greater than 10;

b) an active agent distributed in the matrix;

c) at least one surface defining at least a part of the device, and d) wherein when the device is in the environment of use the surface erodes at a controlled and continuous rate and concurrently therewith releasing the active agent at a controlled and continuous rate over a period of time.

14. A device according to claim 13, wherein the matrix is formed of a polymer containing a member selected from the group consisting of trans and cis isomers, and mixtures thereof.

15. A device for the release of an active agent to an environment of use, said device comprising a) an erodible release rate controlling material containing b) an active agent, the material comprising a copolymer of the following formula:

##STR65## wherein R₁ is a member selected from the group consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with a member selected from the group consisting of alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;

a is 0 to 1;

b is 2 to 6;

m is greater than 10;

n is greater than 10;

said copolymer comprising at least one of R₁, a, and b in mer I different than R₁, a, and b in mer II; and

wherein the material erodes when the device is in the environment of use at a controlled and continuous rate thereby releasing the active agent over time.

16. A device for the release of an active agent to an environment of use, said device comprising an erodible release rate controlling material containing an active agent, the material comprising a terpolymer of the following formula:

##STR66## wherein R₁ is a member selected from the group consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with a member selected from the group consisting of alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons; and

a is 0 to 1;

b is 2 to 6;

m, n, and p each are greater than 10;

said terpolymer comprising at least one of R₁, a, and b in mers I, II and III, that is different than R₁ a, and b in mers I, II and III; and

wherein the device, when in the environment of use, erodes at a controlled and continuous rate, thereby releasing agent at a controlled and continuous rate over time.