Bioerodible sustained release drug delivery systems
View Patent ↗The present invention relates to sustained release drug delivery systems, medical devices incorporating said systems, and methods of use and manufacture thereof. The inventive systems feature bioerodible drug delivery devices that include biocompatible solid and biocompatible fluid compositions to achieve desired sustained release drug delivery.
1. A drug delivery system comprising:
an inner core, comprising
(i) a biocompatible fluid component,
(ii) a biocompatible solid component, wherein said biocompatible solid component comprises a bioerodible polymer, and said biocompatible solid component is dissolved, suspended, or dispersed in the biocompatible fluid component, and
(iii) at least one agent dispersed, suspended, or dissolved within the inner core, wherein the at least one agent comprises a peptide or protein and has the structure
A(-L-) m S n
wherein A is a residue of the peptide or protein, m and n are independently integers in the range of 1-4; L is a covalent bond or a linker moiety, and S is a polyoxyethylene ether group having the formula —(OCH 2 CH 2 ) p OR, where p is in the range of 2-12 and R is a C 1 -C 4 alkyl group;
wherein the inner core is a viscous paste or a gel;
a first polymer layer, impermeable to the passage of the at least one agent, that covers at least part of but less than 100% of said inner core; and
a second polymer layer, permeable to the passage of the at least one agent, wherein the permeability of the second polymer layer to the passage of the at least one agent permits the at least one agent to diffuse from the inner core when the drug delivery system is surrounded by a physiological fluid.
2. The drug delivery system of claim 1 , wherein the biocompatible fluid component is polyethylene glycol.
3. The drug delivery system of claim 1 , wherein the biocompatible solid component is poly(dl-lactide-co-glycolide).
4. The drug delivery system of claim 1 , wherein the first polymer layer covers at least about 50% of the inner core.
5. The drug delivery system of claim 1 , wherein the first polymer layer is formed of a material selected from polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate copolymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasticized ethylene vinylacetate copolymer, polyvinyl alcohol, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, cross-linked polyvinylpyrrolidone, polytrifluorochloroethylene chlorinated polyethylene, poly(1,4-isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl-chloride-diethyl fumarate copolymer, silicone rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, and vinylidene chloride-acrylonitrile copolymer.
6. The drug delivery system of claim 1 , wherein the first polymer layer is formed of a material selected from cross-linked polyvinyl alcohol, plasticized ethylene vinylacetate copolymer, polyvinyl alcohol, polymethylmethacrylate, plasticized nylon, plasticized soft nylon, silicone rubbers, and silicone-carbonate copolymers.
7. The drug delivery system of claim 1 , wherein the at least one agent has a permeability coefficient in the second layer at least about 1×10 −5 cm/s but less than about 1×10 −2 cm/s.
8. The drug delivery system of claim 1 , wherein the at least one agent has a release rate from the drug delivery system that is limited primarily by the permeability of the at least one agent in the inner core.
9. The drug delivery system according to claim 1 , wherein the system is water-permeable.
10. A drug delivery device, comprising:
the drug delivery system according to claim 1 ; and
a pharmaceutically acceptable carrier capable of delivering the at least one agent to a site within the body.
11. A method of administering an agent to a patient in need thereof, comprising:
providing the drug delivery system according to claim 1 , said system containing an effective amount of an agent suitable for treating the patient; and administering the drug delivery system to the patient.
12. A medical device, comprising the drug delivery system according to claim 1 adapted to provide a therapeutically effective amount of a drug to a patient in need thereof.
13. A method of manufacturing a drug delivery system, comprising:
providing an inner core, said inner core comprising
(i) a biocompatible fluid component;
(ii) a biocompatible solid component, wherein said biocompatible solid component comprises a bioerodible polymer, and said biocompatible solid component is dissolved, suspended, or dispersed in the biocompatible fluid component,
(iii) at least one agent dispersed within said inner core, wherein the at least one agent comprises a peptide or protein and has the structure
A(-L-) m S n
wherein A is a residue of the peptide or protein, m and n are independently integers in the range of 1-4; L is a covalent bond or a linker moiety, and S is a polyoxyethylene ether group having the formula —(OCH 2 CH 2 ) p OR, where p is in the range of 2-12 and R is a C 1 -C 4 alkyl group;
wherein the inner core is a viscous paste or a gel;
combining said inner core with a first polymer layer that is impermeable to the at least one agent and covers at least part of but less than 100% of said inner core; and
adding a second polymer layer that is permeable to the passage of the at least one agent, wherein the permeability of the second polymer layer to the passage of the at least one agent permits the at least one agent to diffuse from the inner core when the drug delivery system is surrounded by a physiological fluid.
14. The method of claim 13 , wherein the inner core and first polymer layer are combined by co-extrusion.
15. The method of claim 13 , wherein the biocompatible fluid component is polyethylene glycol.
16. The method of claim 13 , wherein the biocompatible solid component is poly(dl-lactide-co-glycolide).
17. A method of claim 13 , wherein the first polymer layer is formed of a material selected from polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate copolymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasticized ethylene vinylacetate copolymer, polyvinyl alcohol, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, cross-linked polyvinylpyrrolidone, polytrifluorochloroethylene chlorinated polyethylene, poly(1,4-isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl-chloride-diethyl fumarate copolymer, silicone rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, and vinylidene chloride-acrylonitrile copolymer.
18. A method of claim 17 , wherein the first polymer layer is formed of a material selected from cross-linked polyvinyl alcohol, plasticized ethylene vinylacetate copolymer, polyvinyl alcohol, polymethylmethacrylate, plasticized nylon, plasticized soft nylon, silicone rubbers, and silicone-carbonate copolymers.
19. The drug delivery system of claim 1 , wherein the first polymer layer comprises a synthetic polymer.
20. The drug delivery system of claim 1 , wherein the system delivers the at least one agent over a period of at least 1 week when implanted in the patient.
21. The drug delivery system of claim 1 , wherein the system delivers the at least one agent over a period of at least 2 days when implanted in a patient.
22. The drug delivery system of claim 1 , wherein the biocompatible solid component is more soluble in the biocompatible fluid component than in physiological fluid.
23. The drug delivery system of claim 1 , wherein the second polymer layer covers at least part of the first polymer layer.
24. The method of claim 11 , wherein administering comprises injecting the system into the patient.
25. The drug delivery system of claim 1 , wherein the inner core is a viscous paste.
26. The drug delivery system of claim 1 , wherein the inner core is a gel.
27. The method of claim 13 , wherein the inner core is a viscous paste.
28. The method of claim 13 , wherein the inner core is a gel.