1. A multi-particulate pharmaceutical dosage form of a skeletal muscle relaxant providing a modified release profile comprising a population of extended release beads,
wherein said extended release beads comprise
an active-containing core particle comprising a skeletal muscle relaxant selected from the group consisting of cyclobenzaprine, pharmaceutically acceptable salts or derivatives thereof and mixtures thereof; and
an extended release coating comprising a water insoluble polymer membrane surrounding said core,
wherein said dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37\xb0 C. exhibits a drug release profile substantially corresponding to the following pattern:
after 2 hours, no more than about 40% of the total active is released;
after 4 hours, from about 40-65% of the total active is released
after 8 hours, from about 60-85% of the total active is released;
wherein said dosage form provides therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof; and
wherein said water insoluble polymer membrane comprises a water insoluble polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethylacrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof; and a plasticizer selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides and mixtures thereof.
2. The pharmaceutical dosage form of claim 1, wherein said skeletal muscle relaxant comprises cyclobenzaprine hydrochloride.
3. The pharmaceutical dosage form of claim 2 wherein said pharmaceutical dosage form provides a maximum blood plasma concentration (Cmax) within the range of about 80% to 125% of about 20 ngmL of cyclobenzapnine HCl and an AUC0-168 within the range of about 80% to 125% of about 740 ng\xb7hrmL and a Tmax within the range of 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzapnine HCl MR Capsule.
4. The pharmaceutical dosage form of claim 3 wherein the adjusted mean ratio of CMR 30 mgCMR 15 mg is greater than about 2 for each of AUC0-168 (p<0.001), AUC0-\u221e (p<0.001), and Cmax (p<0.001).
5. The pharmaceutical dosage form of claim 1, wherein said dosage form comprises only one extended release bead population.
6. The pharmaceutical dosage form of claim 1, wherein said water insoluble polymer membrane on the drug cores comprises from about 7% to 12% by weight of the extended release beads.
7. The pharmaceutical dosage form of claim 1, wherein said extended release coating further comprises a water soluble polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol polyvinylpyrrolidone and mixtures thereof.
8. The pharmaceutical dosage form of claim 1, wherein said skeletal muscle relaxant comprises cyclobeuzaprine.
9. The pharmaceutical dosage form of claim 1, wherein said drug release profile substantially corresponds to the following pattern:
after 2 hours, no more than about 40% of the total active is released;
after 4 hours, from about 40-65% of the total active is released;
after 8 hours, from about 60-85% of the total active is released; and
after 12 hours, from about 75-85% of the total active is released.
10. The pharmaceutical dosage form of claim 1, wherein said extended release coating further comprises a water soluble polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol polyvinylpyrrolidone and mixtures thereof.
11. The pharmaceutical dosage form of claim 1, wherein the water insoluble polymer membrane comprises ethyl cellulose.
12. The pharmaceutical dosage form of claim 11, wherein said plasticizer is diethyl phthalate.
13. The pharmaceutical dosage form of claim 11, wherein the extended release coating further comprises a water soluble polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol polyvinylpyrrolidone and mixtures thereof.
14. The pharmaceutical dosage form of claim 12, wherein the extended release coating further comprises a water soluble polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol polyvinylpyrrolidone and mixtures thereof.
15. The pharmaceutical dosage form of claim 14, wherein the water soluble polymer is hydroxypropyl methylcellulose.
16. The pharmaceutical dosage form of claim 15, wherein the skeletal muscle relaxant is cyclobenzaprine hydrochloride.
17. The pharmaceutical dosage form of claim 16, wherein the water insoluble polymer membrane comprises from about 7% to 12% by weight of the extended release beads.
18. The pharmaceutical dosage form of claim 17, wherein the drug release profile substantially corresponds to the following pattern:
after 2 hours, no more than about 40% of the total active is released;
after 4 hours, from about 40-65% of the total active is released;
after 8 hours, from about 60-85% of the total active is released; and
after 12 hours, from about 75-85% of the total active is released.
19. The pharmaceutical dosage form of claim 1, wherein said water insoluble polymer membrane comprises a water insoluble polymer selected from the group consisting of ethers of cellulose, esters of cellulose, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof.
20. The pharmaceutical dosage form of claim 19, wherein said extended release coating further comprises a water soluble polymer selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol polyvinylpyrrolidone and mixtures thereof.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
We claim:
1. An epitaxial article, comprising:
a substrate having a textured metal surface;
a single lanthanum metal oxide epitaxial buffer layer disposed on and in contact with said surface of said substrate, and
an electromagnetically active layer disposed on and in contact with said single epitaxial buffer layer.
2. The article according to claim 1, wherein said lanthanum metal oxide epitaxial buffer layer is selected from compounds having the general formula La1xAxMO3, wherein A and M are metals and 0x0.8.
3. The article according to claim 2, wherein A is at least one selected from the group consisting of Sr, Ba and Ca.
4. The article according to claim 2, wherein M is at least one selected from the group consisting of Mn and Co.
5. The article according to claim 1, wherein said lanthanum metal oxide epitaxial buffer layer has a resistivity at 300 K of less than 1 mOhm-cm.
6. The article according to claim 1, wherein said lanthanum metal oxide epitaxial buffer layer has a resistivity at 300 K of less than 0.1 mOhm-cm.
7. The article according to claim 1, wherein said electromagnetically active layer includes a superconducting layer.
8. The article according to claim 7, wherein said superconductor layer comprises an oxide superconductor.
9. The article according to claim 7, wherein said oxide superconductor comprises at least one oxide superconductor selected from the group consisting of REBa2Cu3O7 where RE is a rare earth element, Tl1Ba2Can1CunO2n3, where n is an integer between 1 and 4, Tl2Ba2Can1CunO2n4 wherein is an integer between 1 and 4, and Hg1Ba2Can1CunO22n2, where n is an integer between 1 and 4.
10. The article according to claim 1, wherein said substrate is a rolled and annealed biaxially-textured metal substrate.
11. The article according to claim 1, wherein said textured metal surface comprises at least one metal selected from the group consisting of Cu, Cu-based alloys, Co, Mo, Cd, Pd, Pt, Ag, Al, Ni, and Ni-based alloys.
12. The article according to claim 1, wherein said textured metal surface comprises at least one metal selected from the group consisting of Ni and Ni-based alloys with at least one alloying agent selected from the group consisting of Co, Cr, V, Mo, W, and rare earth elements.
13. An epitaxial article, comprising:
a substrate having a textured metal surface;
a lanthanum metal oxide epitaxial buffer layer disposed on and in contact with said surface of said substrate;
at least one epitaxial capping layer disposed on and in contact with said lanthanum metal oxide epitaxial buffer layer, said epitaxial capping layer being of a different composition than said lanthanum metal oxide epitaxial buffer layer, and
an electromagnetically active layer disposed on and in contact with said epitaxial capping layer.
14. The article according to claim 13, wherein said epitaxial buffer layer is selected from compounds having the general formula La1xAxMO3, wherein A and M are metals and 0x0.8.
15. The article according to claim 14, wherein A is at least one selected from the group consisting of Sr, Ba and Ca.
16. The article according to claim 14, wherein M is at least one selected from the group consisting of Mn and Co.
17. The article according to claim 15, wherein said electromagnetically active layer includes a superconducting layer.
18. The article according to claim 17, wherein said superconductor layer comprises an oxide superconductor.
19. The article according to claim 17, wherein said oxide superconductor comprises at least one oxide superconductor selected from the group consisting of REBa2CU3O7, where RE is a rare earth element Tl1Ba2Can1CunO2n3, where n is an integer between 1 and 4, Tl2Ba2Can1CunO2n4, where n is an integer between 1 and 4, and Hg1Ba2Can1CunO2n2, where n is an integer between 1 and 4.
20. The article according to claim 13, wherein said substrate is a rolled and annealed biaxially-textured metal substrate.
21. The article according to claim 13, wherein said metal textured surface comprises at least one metal selected from the group consisting of Cu, Cu-based alloys, Co, Mo, Cd, Pd, Pt, Ag, Al, Ni, and Ni-based alloys.
22. The article according to claim 13, wherein said textured metal surface comprises at least one metal selected from the group consisting of Ni and Ni-based alloys with at least one alloying agent selected from the group consisting of Co, Cr, V, Mo, W, and rare earth elements.
23. The article according to claim 13, wherein said epitaxial capping layer comprises at least one material which is a rare earth oxide.
24. The article according to claim 13, wherein said epitaxial capping layer is at least one material selected from the group consisting of SRO, LNO, YSZ, CeO2 and Y2O3.
25. A method for preparing an epitaxial article, comprising the steps of:
providing a substrate with a textured metal surface;
depositing a single lanthanum metal oxide epitaxial buffer layer on and in contact with said surface of said substrate, and
depositing an electromagnetically active layer on and in contact with said single lanthanum metal oxide epitaxial buffer layer.
26. The method according to claim 25, further comprising the step of providing a biaxially-textured metal surface.
27. The method according to claim 26, further comprising the step of rolling and annealing a metal material to form said biaxially-textured substrate surface.
28. The method according to claim 25, further comprising the step of rolling and annealing a metal substrate, said metal substrate comprising at least one metal selected from the group consisting of Cu, Cu-based alloy, Co, Mo, Cd, Pd, Pt, Ag, Al, Ni, and Ni-based alloys.
29. The method according to claim 25, further comprising the step of rolling and annealing a metal substrate, said metal substrate comprising at least one metal selected from the group consisting of Ni and Ni-based alloy with at least one alloying agent selected from the group consisting of Co, Cr, V, Mo, W, and rare earth elements.
30. The method according to claim 25, wherein said lanthanum metal oxide epitaxial buffer layer is selected from compounds having the general formula La1xAxMO3, wherein A and M are metals and 0x0.8.
31. The method according to claim 30, wherein A is at least one selected from the group consisting of Sr, Ba and Ca.
32. The method according to claim 30, wherein M is at least one selected from the group consisting of Mn and Co.
33. The article according to claim 25, wherein said lanthanum metal oxide epitaxial buffer layer has a resistivity at 300 K of less than 1 mOhm-cm.
34. The article according to claim 25, wherein said lanthanum metal oxide epitaxial buffer layer has a resistivity at 300 K of less than 0.1 mOhm-cm.
35. The method according to claim 25, wherein said electromagnetically active layer includes a superconducting layer.
36. The method according to claim 35, wherein superconductor layer comprises an oxide superconductor.
37. The method according to claim 36, wherein said oxide superconductor comprises at least one oxide superconductor selected from the group consisting of REBa2Cu3O7, where RE is a rare earth element, Tl1Ba2Can1CunO2n3, where n is an integer between 1 and 4; Tl2Ba2Can1CunO2n4, where n is an integer between 1 and 4, and Hg1Ba2Can1CunO2n2, where n is an integer between 1 and 4.
38. The method according to claim 25, wherein said lanthanum metal oxide epitaxial buffer layer is deposited by a sputtering process.
39. The method according to claim 38, wherein said sputtering process comprises rf-magnetron sputtering.
40. The method according to claim 25, wherein said electromagnetically active layer is deposited by a process comprising piulsed laser ablation.
41. A method for preparing an epitaxial article, comprising the steps of:
providing a substrate with a textured metal surface;
depositing a single lanthanum metal oxide epitaxial buffer layer on and in contact with said surface of said substrate;
depositing at least one epitaxial capping layer on said single lanthanum metal oxide epitaxial buffer layer, said epitaxial capping layer being of a different composition than said single lanthanum metal oxide epitaxial buffer layer, and
depositing a electromagnetically active layer on said epitaxial capping layer.
42. The method according to claim 41, further comprising the step of providing a biaxially-textured metal surface.
43. The method according to claim 42, further comprising the step of rolling and annealing a metal material to form said biaxially-textured substrate.
44. The method according to claim 41, further comprising the step of rolling and annealing a metal substrate, said metal substrate comprising at least one metal selected from the group consisting of Cu, Cu-based alloy, Co, Mo, Cd, Pd, Pt, Ag, Al, Ni, and Ni-based alloys.
45. The method according to claim 41, further comprising the step of rolling and annealing a metal substrate, said metal substrate comprising at least one metal selected from the group consisting of Ni and Ni-based alloy with at least one alloying agent selected from the group consisting of Co, Cr, V, Mo, W, and rare earth elements.
46. The method according to claim 41, wherein said lanthanum metal oxide epitaxial buffer layer is selected from compounds having the general formula La1xAxMO3, where A and M are metals and 0x0.8.
47. The method according to claim 46, wherein A is at least one selected from the group consisting of Sr, Ba and Ca.
48. The method according to claim 46, wherein M is at least one selected from the group consisting of Mn and Co.
49. The method according to claim 41, wherein said electromagnetically active layer includes a superconducting layer.
50. The method according to claim 49, wherein superconductor layer comprises an oxide superconductor.
51. The method according to claim 50, wherein said oxide superconductor layer comprises at least one oxide superconductor selected from the group consisting of REBa2Cu3O7, where RE is a rare earth element, Tl1Ba2Can1CunO2n3, where n is an integer between 1 and 4, Tl2Ba2Can1CunO2n4, where n is an integer between 1 and 4 and Hg1Ba2Can1CunO2n2, where n is an integer between 1 and 4.
52. The method according to claim 41, wherein said lanthanum metal oxide epitaxial buffer layer is deposited by a sputtering process.
53. The method according to claim 52, wherein said sputtering process comprises rf-magnetron sputtering.
54. The method according to claim 41, wherein said electromagnetically active layer is deposited by a process comprising pulsed laser ablation.
55. The method according to claim 41, wherein said epitaxial capping layer comprises at least one material selected from the group consisting of SRO, LNO, YSZ, CeO2 and Y2O3 and rare earth oxides.
56. An epitaxial article for providing a foundation for applying electromagnetically active layers directly thereon, comprising:
a substrate having a textured metal surface, and
a single lanthanum metal oxide epitaxial buffer layer disposed on and in contact with said surface of said substrate, whereby another buffer layer is not required.
57. The article according to claim 56, wherein said lanthanum metal oxide epitaxial buffer layer is selected from compounds having the general formula where La1xAxMO3, wherein A and M are metals and 0x0.8.
58. The article according to claim 57, wherein A is at least one selected from the group consisting of Sr, Ba and Ca.
59. The article according to claim 57, wherein M is at least one selected from the group consisting of Mn and Co.
60. A method for preparing an epitaxial article for applying electromagnetically active layers directly thereon, comprising the steps of:
providing a substrate with a textured metal surface, and
depositing a single lanthanum metal oxide epitaxial layer on said substrate.
61. The method according to claim 60, wherein said metal surface is a biaxially-textured metal surface.
62. The method according to claim 60, further comprising the step of rolling and annealing a metal material to form a biaxially-textured substrate having a surface.
63. The method according to claim 60, further comprising the step of rolling and annealing at least one metal selected from the group consisting of Cu, Cu-based alloys, Ag, Al, Co, Mo, Cd, Pd, Pt, Ni, and Ni-based alloys.
64. The method according to claim 60, further comprising the step of rolling and annealing at least one metal selected from the group consisting of Ni and Ni-based alloy with at least one alloying agent selected from the group consisting of Co, Cr, V, Mo, W, and rare earth elements.
65. The method according to claim 60, wherein said lanthanum metal oxide epitaxial layer is selected from compounds having the general formula La1xAxMO3, herein A and M are metals and 0x0.8.
66. The method according to claim 60, wherein said lanthanum metal oxide epitaxial layer is deposited using a sputtering process.
67. The method according to claim 66, wherein said sputtering comprises rf-magnetron sputtering.
68. An epitaxial article, comprising:
a substrate having a metal surface;
a single electrically conductive epitaxial buffer layer disposed on and in contact with said surface of said substrate, and
an electromagnetically active layer disposed on and in contact with said single epitaxial buffer layer, said epitaxial buffer layer being substantially crack-free.
69. The article according to claim 68, wherein said epitaxial buffer layer is at least 100 nm thick.
70. The article according to claim 68, wherein said epitaxial buffer layer has a resistivity at 300 K of less than 1 mOhm-cm.
71. The article according to claim 68, wherein said epitaxial buffer layer has a resistivity at 300 K of less than 0.1 mOhm-cm.
72. The article according to claim 68, wherein said electromagnetically active layer includes a superconducting layer.