Threo-DOPS controlled release formulation
The present invention relates to pharmaceutical formulations for the controlled delivery of threo-3-(3,4-dihydroxyphenyl)serine (threo-DOPS) and derivatives of it. Such formulations can contain an extended or slow release component that maintains therapeutic concentration of threo-DOPS in the blood plasma over a prolonged time period. They can be further combined with an immediate release formulation to produce a product that, when administered to a patient in need thereof, results in substantially steady levels of active drug, eliminating the sharp peaks and troughs in blood plasma drug levels experienced with the existing threo-DOPS formulations.
1. A pharmaceutical formulation comprising an effective amount of threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof in the form of particles or granules that are coated with or embedded in a slowly soluble polymeric membrane effective for dissolution controlled, extended release of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof over a period of time of at least 6 hours, the formulation being adapted for oral delivery.
2. The pharmaceutical formulation of claim 1 , wherein the slowly soluble polymeric membrane comprises one or more materials selected from the group consisting of ethylcellulose, cellulose acetate phthalate, acrylic resins, methacrylate hydrogels, methylmethacrylate, polymethacrylate, polylactic acid, polyvinyl chloride, hydroxypropylmethylcellulose, polyethylene glycols, carboxymethylcellulose, sodium carboxymethylcellulose, and mixtures thereof.
3. The pharmaceutical formulation of claim 1 , wherein the particles or granules of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof are non-pareil seeds having the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof applied to a surface thereof.
4. The pharmaceutical formulation of claim 1 , further comprising threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof in an immediate release form.
5. The pharmaceutical formulation of claim 4 , wherein the formulation provides for maximal release of the immediate release form within about 1 to about 3 hours after administration, and provides for maximal release of the extended release form between about 6 to about 24 hours after administration.
6. The pharmaceutical formulation of claim 4 , wherein one or both of the extended release form and immediate release form of the threo-3-(3,4-dihydroxyphenyl)serine, or a derivative or pharmaceutically-acceptable salt thereof, is released at a rate that is independent of the pH in the gastrointestinal tract.
7. The pharmaceutical formulation of claim 4 , wherein the formulation comprises 45-85% by weight of the threo-3-(3,4-dihydroxyphenyl) serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, in the extended release form and 15-55% by weight of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, in the immediate release form.
8. The pharmaceutical formulation of claim 4 , wherein the extended release form further comprises an osmotically active salt.
9. The pharmaceutical formulation of claim 1 , further comprising an excipient selected from the group consisting of lubricants, channeling agents, surfactants, fillers, coating materials, and combinations thereof.
10. The pharmaceutical formulation of claim 9 , wherein the excipient is selected from the group consisting of silicon dioxide, magnesium stearate, sodium lauryl sulfate, sodium taurocholate, polysorbate, lactose, hydroxypropylmethylcellulose, ethylcellulose, triethyl citrate, microcrystalline cellulose, polyvinyl alcohol, sodium chloride, dibasic calcium phosphate, polyvinylpyrrolidone, and mixtures thereof.
11. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is suitable for once-daily administration.
12. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is suitable for twice- or three-times daily administration.
13. A pharmaceutical formulation comprising an effective amount of threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof surrounded by a water-insoluble polymeric material effective for diffusion controlled, extended release of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof over a period of time of at least 6 hours, wherein the formulation is in the form of a reservoir device or a matrix device, and wherein the formulation is adapted for oral delivery.
14. The pharmaceutical formulation of claim 13 , further comprising threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof in an immediate release form.
15. The pharmaceutical formulation of claim 14 , wherein the formulation provides for maximal release of the immediate release form within about 1 to about 3 hours after administration, and provides for maximal release of the extended release form between about 6 to about 24 hours after administration.
16. The pharmaceutical formulation of claim 14 , wherein one or both of the extended release form and immediate release form of the threo-3-(3,4-dihydroxyphenyl)serine, or a derivative or pharmaceutically-acceptable salt thereof, is released at a rate that is independent of the pH in the gastrointestinal tract.
17. The pharmaceutical formulation of claim 14 , wherein the formulation comprises 45-85% by weight of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, in the extended release form and 15-55% by weight of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, in the immediate release form.
18. The pharmaceutical formulation of claim 13 , wherein the extended release form further comprises an osmotically active salt.
19. The pharmaceutical formulation of claim 13 , further comprising an excipient selected from the group consisting of lubricants, channeling agents, surfactants, fillers, and combinations thereof.
20. The pharmaceutical formulation of claim 19 , wherein the excipient is selected from the group consisting of silicon dioxide, magnesium stearate, sodium lauryl sulfate, sodium taurocholate, polysorbate, lactose, hydroxypropylmethylcellulose, ethylcellulose, triethyl citrate, microcrystalline cellulose, polyvinyl alcohol, sodium chloride, dibasic calcium phosphate, polyvinylpyrrolidone, and mixtures thereof.
21. The pharmaceutical formulation of claim 13 , wherein the pharmaceutical formulation is suitable for once-daily administration.
22. The pharmaceutical formulation of claim 13 , wherein the pharmaceutical formulation is suitable for twice- or three-times daily administration.
23. The pharmaceutical formulation of claim 13 , wherein the formulation is in the form of a reservoir device wherein the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof is in a core surrounded by the water insoluble polymeric material.
24. The pharmaceutical formulation of claim 23 , wherein the water insoluble polymeric material is selected from the group consisting of hydroxypropylcellulose/polyvinyl acetate combinations, polyethylene glycol/ethylcellulose combinations, ethylcellulose, poly(hydroxymethacrylate), and combinations thereof.
25. The pharmaceutical formulation of claim 13 , wherein the formulation is in the form of a matrix device wherein the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof is dispersed in the water insoluble polymeric material.
26. The pharmaceutical formulation of claim 25 , wherein the water insoluble polymeric material is selected from the group consisting of hydrated methylcellulose, carnauba wax and stearyl alcohol combinations, carbopol, glyceryl tristearate, methyl acrylate/methyl methacrylate combinations, polyvinyl chloride, polyethylene, and combinations thereof.
27. The pharmaceutical formulation of claim 13 , wherein the water insoluble polymeric material further comprises an amount of a water soluble material that is adapted to solubilize in the presence of water such that the water insoluble polymeric material surrounding the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof exhibits a porosity.
28. The pharmaceutical formulation of claim 27 , wherein the water soluble material comprises a combination of ethylcellulose and methylcellulose.
29. A pharmaceutical formulation in an extended release form comprising: an effective amount of threo-3-(3,4-dihydroxyphenyl)serine, or a derivative or pharmaceutically-acceptable salt thereof, a coating/matrix material, a channeling agent, and a filler, wherein the formulation provides continuous release of threo-3-(3,4-dihydroxyphenyl)serine, or a derivative or pharmaceutically-acceptable salt thereof, over a period of at least 6 hours, and wherein the formulation is adapted for oral delivery.
30. The pharmaceutical formulation of claim 29 , wherein the threo-3-(3,4-dihydroxyphenyl)serine, or a derivative or pharmaceutically-acceptable salt thereof, is provided in a core surrounded by a water-insoluble polymeric material.
31. The pharmaceutical formulation of claim 29 , wherein the coating/matrix material is selected from the group consisting of shellacs, beeswax, glyceryl monostearate, glyceryl palmostearate, stearyl alcohol, ethylcellulose, cellulose acetate phthalate, acrylic resins, methacrylate hydrogels, methylmethacrylate, polymethacrylate, polylactic acid, polyvinyl chloride, hydroxypropylmethylcellulose, polyethylene glycols, carboxymethylcellulose, sodium carboxymethylcellulose, and mixtures thereof.
32. The pharmaceutical formulation of claim 29 , wherein the channeling agent is silicon dioxide.
33. The pharmaceutical formulation of claim 29 , wherein the filler is selected from the group consisting of lactose, sodium chloride, triethyl citrate, and combinations thereof.
34. The pharmaceutical formulation of claim 29 , further comprising an excipient selected from the group consisting of surfactants, lubricants, granulating agents, and combinations thereof.
35. The pharmaceutical formulation of claim 34 , comprising a surfactant selected from the group consisting of sodium lauryl sulfate, sodium taurocholate, polysorbates, and combinations thereof.
36. The pharmaceutical formulation of claim 34 , comprising the lubricant magnesium stearate.
37. The pharmaceutical formulation of claim 29 , further comprising an effective amount of threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, in an immediate release form.
38. The pharmaceutical formulation of claim 37 , wherein one or both of the extended release form and the immediate release form of the threo-3-(3,4-dihydroxyphenyl)serine, or a derivative or pharmaceutically-acceptable salt thereof, is released at a rate that is independent of the pH in the gastrointestinal tract.
39. The pharmaceutical formulation of claim 37 , wherein the formulation provides for maximal release of the immediate release form within about 1 to about 3 hours after administration, and provides for maximal release of the extended release form between about 6 to about 24 hours after administration.
40. The pharmaceutical formulation of claim 37 , wherein the formulation comprises 45-85% by weight of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, in the extended release form and 15-55% by weight of the threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or a pharmaceutically-acceptable salt thereof, in the immediate release form.
41. The pharmaceutical formulation of claim 29 , wherein the formulation is suitable for once daily administration.
42. The pharmaceutical formulation of claim 29 , wherein the formulation is suitable for twice a day or three times a day administration.