Gastric residence systems for sustained delivery of adamantane-class drugs

1. A gastric residence system comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof, wherein:

the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises:

a carrier polymer,

the adamantane-class drug or the pharmaceutically acceptable salt thereof, and

a release rate-modulating polymer film coated on the surface of the at least one elongate member, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour;

wherein the gastric residence system is configured to release the adamantane-class drug or the pharmaceutically acceptable salt thereof over a specified gastric residence period.

2. The gastric residence system of claim 1 , wherein the elongate members are affixed to the central elastomer via linkers, wherein the linkers are configured to weaken or degrade to allow passage of the gastric residence system through a pylorus after the specified gastric residence period.

3. The gastric residence system of claim 1 , wherein the adamantane-class drug or the pharmaceutically acceptable salt thereof is selected from the group consisting of memantine; amantadine; adapromine; nitromemantine; rimantadine; bromantane; tromantadine; neramexane; and a pharmaceutically acceptable salt of any one of memantine, amantadine, adapromine, nitromemantine, rimantadine, bromantane, tromantadine, and neramexane.

4. A gastric residence system comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof, wherein:

the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises:

a carrier polymer;

an adamantane-class drug or a salt thereof; and

a release rate-modulating polymer film, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C1-C12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour;

wherein over a seven-day incubation of the system in simulated gastric fluid, the amount of the adamantane-class drug or salt thereof released from the system during day 5 is at least about 40% of the amount of adamantane-class drug or salt thereof released during day 2; and

wherein at least about 7% of the total amount of adamantane-class drug or salt thereof in the system is released on day 2 and at least about 7% of the total amount of adamantane-class drug or salt thereof is released on day 5.

5. A gastric residence system comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof, wherein:

the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises:

a carrier polymer;

an adamantane-class drug or a salt thereof; and

a release rate-modulating polymer film, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour;

wherein over a seven-day incubation of the system in simulated gastric fluid, the amount of the adamantane-class drug or salt thereof released from the system during day 7 is at least about 20% of the amount of adamantane-class drug or salt thereof released during day 1; and wherein at least about 4% of the total amount of adamantane-class drug or salt thereof in the system is released on day 1 and at least about 4% of the total amount of adamantane-class drug or salt thereof is released on day 7.

6. A gastric residence system comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof, wherein:

the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises:

a carrier polymer,

an adamantane-class drug or a salt thereof, and

a release rate-modulating polymer film, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms;

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour.

7. A gastric residence system comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof, wherein:

the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises:

a carrier polymer,

an adamantane-class drug or a salt thereof; and

a release rate-modulating polymer film configured to control the release rate of the adamantane-class drug or salt thereof, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms,

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is at least about 40% lower than the release of adamantane-class drug or salt thereof from a second system in 40% ethanol/60% simulated gastric fluid over one hour, the second system comprising the same combination of carrier polymer and adamantane-class drug or salt thereof but lacking the release rate-modulating polymer film.

8. A gastric residence system comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof, wherein:

the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises:

a carrier polymer,

an adamantane-class drug or a salt thereof; and

a release rate-modulating polymer film configured to control the release rate of the adamantane-class drug or salt thereof, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour,

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in simulated gastric fluid over an initial 6 hour period is at least about 40% lower than the release of adamantane-class drug or salt thereof from a second system in simulated gastric fluid over an initial 6 hour period, the second system comprising the same combination of carrier polymer and adamantane-class drug or salt thereof but lacking the release rate-modulating polymer film; and

wherein the release of adamantane-class drug or salt thereof from the system in simulated gastric fluid over a seven-day period is at least about 60% of the total amount of adamantane-class drug or salt thereof originally present in the system.

9. A gastric residence system comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof, wherein:

the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises:

a carrier polymer;

an adamantane-class drug or a salt thereof; and

a release rate-modulating polymer film, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour,

wherein the polymer film is configured to control the release rate of the adamantane-class drug or salt thereof such that a best-fit linear regression model of the release rate of adamantane-class drug or salt thereof from the system in simulated gastric fluid has a coefficient of determination R 2 of at least about 0.8 over an initial period of seven days; and wherein the system releases about 40% to about 60% of the adamantane-class drug or salt thereof within a time of about 40% to about 60% of the seven-day period.

10. A gastric residence system providing an extended release drug dosage form, comprising:

a plurality of elongate members comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof and a carrier polymer, wherein the gastric residence system has a compacted configuration and an uncompacted configuration,

wherein the adamantane-class drug or a pharmaceutically acceptable salt thereof is blended with the carrier polymer such that the drug or salt thereof is distributed throughout the elongate member, and

a release rate-modulating polymer film coating at least one elongate member, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour;

wherein the plurality of elongate members are attached to a central elastomer; and

wherein said gastric residence system provides extended release of the adamantane-class drug or pharmaceutically acceptable salt thereof.

11. A gastric residence system providing an extended release drug dosage form, comprising a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof and a component adapted to provide extended release of the adamantane-class drug or a pharmaceutically acceptable salt thereof in an aqueous environment,

wherein the gastric residence system has a compacted configuration and an uncompacted configuration,

the gastric residence system comprises a plurality of elongate members affixed to a central elastomer,

wherein at least one elongate member comprises a carrier polymer and the adamantane-class drug or the pharmaceutically acceptable salt thereof;

wherein the gastric residence system comprises a release rate-modulating polymer film, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour;

wherein the system has a dissolution profile characterized by about 10% to 20% dissolution of the initial amount of adamantane-class drug or pharmaceutically acceptable salt thereof present in the system during an initial 24 hour period in the aqueous environment.

12. A gastric residence system providing an extended release drug dosage form, comprising:

a plurality of elongate members, wherein at least one elongate member comprises a therapeutically effective amount of an adamantane-class drug or a pharmaceutically acceptable salt thereof and a carrier polymer,

wherein the gastric residence system has a compacted configuration and an uncompacted configuration,

wherein the adamantane-class drug or a pharmaceutically acceptable salt thereof is blended with the carrier polymer such that the drug or salt thereof is distributed throughout the at least one elongate member, and

a release rate-modulating polymer film coating the at least one elongate member, wherein the release rate-modulating polymer film comprises one or more polyester materials with a repeating unit of the form —R 1 —O—C(═O)—, wherein R 1 is selected from the group consisting of C 1 -C 12 alkylene groups, ethers containing between two and twelve carbon atoms, and polyethers containing between three and twelve carbon atoms, and

wherein the release rate-modulating polymer film is configured such that the release of adamantane-class drug or salt thereof from the system in 40% ethanol/60% simulated gastric fluid over one hour is no more than about 40% higher compared to release of adamantane-class drug or salt thereof from an equivalent system in 100% simulated gastric fluid over one hour;

wherein the adamantane-class drug or a pharmaceutically acceptable salt thereof comprises about 40% to about 60% by weight of the at least one elongate member;

wherein the plurality of elongate members are attached to a central elastomer; and

wherein said gastric residence system provides extended release of the adamantane-class drug or pharmaceutically acceptable salt thereof.

13. The gastric residence system of claim 1 , wherein the adamantane-class drug or the pharmaceutically acceptable salt thereof is memantine or a pharmaceutically acceptable salt of memantine.

14. The gastric residence system of claim 1 , wherein the release rate-modulating polymer film comprises polycaprolactone.

15. The gastric residence system of claim 1 , wherein the release rate-modulating polymer film further comprises a porogen.

16. The gastric residence system of claim 1 , wherein the release rate-modulating polymer film further comprises a plasticizer.

17. The gastric residence system of claim 1 , wherein the polymer film further comprises an anti-tack agent.

18. The gastric residence system of claim 1 , wherein the elongate members further comprise at least one excipient.

19. The gastric residence system of claim 1 , wherein the elongate members further comprise an anti-oxidant.

20. The gastric residence system of claim 1 , wherein the elongate members further comprise silica.

21. The gastric residence system of claim 1 , wherein the central elastomer comprises silicone rubber.

22. The gastric residence system of claim 1 , wherein the gastric residence system comprises about 140 mg to about 420 mg of memantine or a pharmaceutically acceptable salt thereof.