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

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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 R.sub.1 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; R.sub.2 and R.sub.3 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; OR.sub.1 O with R.sub.1 as defined above; a heterocyclic ring of 5 to 8 carbon and oxygen atoms formed when R.sub.2 and R.sub.3 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 R.sub.2 and R.sub.3 are taken together; a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R.sub.2 and R.sub.3 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 R.sub.2 and R.sub.3 is a member selected from the group consisting of alkoxy, alkenyloxy and OR.sub.1 O; R.sub.2 and R.sub.3 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 17.alpha.-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-17.alpha.-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 R.sub.1 is divalent, R.sub.2 and R.sub.3 are taken together to form a heterocyclic ring with R.sub.2 a member selected from the group consisting of alkyleneoxy and alkenyleneoxy, and R.sub.3 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.

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 R.sub.1 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.

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.
Other info:

Inventors: Choi, Nam Sok (Seoul, KS, US)
Heller, Jorge (Palo Alto, CA, US)

Application Number: 544808
Filing Date: 1975-01-28
Publication_date: 1978-06-06
Assignee: Alza Corporation (Palo Alto, CA)
Primary Class(es): 424/424 424/426, 424/427, 424/433, 424/436, 424/484, 424/486
Other Classes:
US Patent Ref:

3887699	Jun, 1975	Yolles	128/260.
3960150	Jun, 1977	Hussain	424/19.
4001388	Jan, 1977	Shell	424/19.
4014987	Mar, 1977	Heller	424/19.

Other Refs:
Primary Examiner: Jiles, Henry R.
Assistant Examiner: Owens, Cary
Attorney: Sabatine; Paul L., Ciotti; Thomas E., Mandell; Edward L.