Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)

• US 4,093,709 A
• Filed: 01/28/1975
• Issued: 06/06/1978
• 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 Sok
• Primary Examiner(s): Jiles, Henry R.
• Assistant Examiner(s): Owens, Cary
• Application Number:
  US05/544,808
• Time in Patent Office: 1,225 Days
• Field of Search: 424/19, 424/20, 128/260, 128/268
• US Class Current: 424/424
• 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 drug delivery device for the controlled and continuous administration of drug, wherein the device comprises:

(a) a shaped matrix sized and adapted for administering drug to an animal and formed of a bioerodible drug release rate controlling pharmaceutically acceptable material, which material comprises 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 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, 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, and an alkenyl of 2 to 7 carbons;

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

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 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons 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 fused polycyclic ring of 8 to 12 carbon and oxygen atoms 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

wherein at least one of said R₂ and R₃ is a member selected from the group consisting of alkoxy, alkenyloxy and OR₁ O;

R₂ and R₃ when taken together are a member selected from the group of heterocyclic and fused polycyclic rings having at least one oxygen atom in the ring; and

wherein n is greater than 10;

(b) a drug selected from the group consisting of locally and systemically acting pharmaceutically acceptable drugs present in the matrix; and

, (c) wherein the device when in operation bioerodes at a controlled and continuous rate over a prolonged period of time, thereby administering a therapeutically effective amount of drug to the animal at a controlled and continuous rate over a prolonged period of time.

2. The drug delivery device for the administration of drug according to claim 1 wherein a layer formed of a drug impervious material is suitably fixed to the matrix.

3. The drug delivery device for the administration of drug according to claim 1 wherein the matrix has a passageway for increasing the surface releasing drug from the device over a prolonged period of time.

4. The drug delivery device for the administration of drug according to claim 1 wherein the matrix comprises intertwisted fibers thereby providing means for influencing the rate of drug release throughout the drug release period.

5. The drug delivery device for the administration of drug according to claim 1 wherein the device comprises a continuous matrix having drug dispersed therethrough and wherein the matrix has a geometric shape sized and adapted for placement on the animal and implantation and insertion in the animal.

6. The drug delivery device for the administration of drug according to claim 1 wherein the matrix is a wall forming a tube-shaped body containing drug therein which drug is released by controlled bioerosion over a prolonged period of time.

7. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug in the vagina.

8. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for use as an implant.

9. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug in the gastrointestinal tract.

10. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug in the anus.

11. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug in the uterus.

12. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug intramuscularly.

13. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug subcutaneously.

14. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug in the eye.

15. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is manufactured as an ocular insert sized, shaped and adapted for placement in the eye, with the insert formed of drug release rate controlling material containing drug, and which material has a drug impervious layer on a surface thereof.

16. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized, shaped and adapted for releasing drug to the skin.

17. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the drug is a member selected from the group consisting of androgenic, estrogenic, and progestational steroids.

18. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the drug is a member selected from the group consisting of 17α

-hydroxyprogesterone, 19-nor-progesterone, progesterone and norethindrone.

19. The drug delivery device for administering an effective amount of drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized and shaped as an implant formed of poly(2,2-dioxo-cis/trans-1,4-cyclohexane dimethylene tetrahydrofuran) containing norethindrone.

20. The drug delivery device for administering drug at a controlled rate over a prolonged period of time according to claim 1 wherein the device is sized and shaped as an implant adapted for administering drug to a human, and wherein the implant is formed of poly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran) and the drug is hormonal 17-hydroxy-19-nor-17α

-pregn-4-en-20-yn-3-one useful as a fertility inhibitor.

21. The drug delivery device for the administration of drug according to claim 1 wherein R₁ is divalent, R₂ and R₃ are taken together to form a heterocyclic ring with R₂ a member selected from the group consisting of alkyleneoxy and alkenyleneoxy, and R₃ is a member selected from the group consisting of alkyleneoxy, alkenyleneoxy and alkylene.

22. The drug delivery device for administering drug at a controlled rate over a prolonged period of time wherein the locally and systemically acting drug according to claim 1 is a member selected from the group consisting of physiologically and pharmacologically effective central nervous system drugs, hypnotic, sedative, psychic energizer, tranquilizer, anticonvulsant, antiparkinson, muscle relaxant, analgesic, antipyretic, anti-inflammatory, anesthetic, antispasmodic, antimicrobial, antiviral, antiulcer, hormonal, sympathomimetic, diuretic, hypoglycemic, vitamin and opthalmic drug which drug is released in a therapeutically effective amount as the device bioerodes over a prolonged period of time.

23. The drug delivery device for the administration of an antimicrobial drug according to claim 1 wherein the device is formed of poly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran) and wherein the device is adapted for application to the skin by inunction.

24. The drug delivery device for administering drug according to claim 1 wherein the matrix and drug form an ointment for topical application to skin, mucosa and wounds, and wherein the polymer is viscous poly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran) and the drug is sulfonamide.

25. The drug delivery device for administering drug according to claim 1 wherein the device is adapted for application to skin, mucosa and wounds, and wherein the device comprises an ointment and a support layer with the layer made of a non-toxic material, and wherein the ointment is formed of matrix and drug, which matrix is viscous poly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran) and which drug is sulfonamide.

27. A drug delivery device for the controlled and continuous administration of drug according to claim 1, wherein the matrix is poly(2,2-dioxo-cis/trans-1,4-cyclohexane dimethylene tetrahydrofuran).

28. A drug delivery device for the controlled and continuous administration of drug according to claim 1, wherein the matrix is poly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran).

29. A method for the controlled administration of a drug to an animal which method comprises administering the drug delivery device according to claim 1 to the animal.

30. A method for the controlled administration of a drug to an animal which method comprises administering the drug delivery device according to claim 1, wherein the animal is a mammal, the device is sized, shaped and adapted for implantation in the mammal, and the drug in the device is a member selected from the group consisting of estrogenic and progestational steroids.

31. The method for the controlled administration of drug according to claim 29, wherein the animal is a human.

26. A drug delivery device for the controlled administration of drug, wherein the device comprises:

(a) a shaped matrix sized and adapted for administering drug to a human and formed of a hydrophobic, bioerodible drug release rate controlling material, which material comprises a polymer of the formula;

##STR62## 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;

cycloakylene 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, 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

wherein a is 0 or 1, b is 2 to 6, and n is greater than 10;

(b) a drug selected from the group consisting of physiologically and pharmacologically active drugs present in the matrix; and

(c) wherein the device when in operation bioerodes and releases drug at a rate preselected from (1) a zero order rate, (2) a continuous rate and (c) a variable rate, which rate is produced by preselecting the polymer, the drug and the geometric shape of the device.