1. A process for the preparation of small particles or microparticles containing fenofibrate and a phospholipid surface stabilizing substance comprising the steps of:
a) mixing at high shear an admixture of fenofibrate and a phospholipid substance in an aqueous carrier in the absence of an organic solvent and optionally in the presence of one or more than one surface active substances within a first temperature range at or above the melting point of the drug to form a heated suspension containing the drug, then
b) homogenizing said heated suspension in a first pressure range and within said first temperature range to form a heated homogenate containing the drug, then
c) spray drying the heated homogenate to form dried small particles containing the drug wherein one or more bulking agents is added at any stage of either of steps (a) or (b) and wherein at least one surface active agent is a phospholipid.
2. The process of claim 1 wherein the bulking agent is selected from the group consisting of a monosaccharide, a disaccharide, a trisaccharide, sucrose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, fructose, a sugar, a pentose, a hexose, xylitol, and mixtures thereof.
3. The process of claim 1 wherein the bulking agent is selected from the group consisting of sucrose, lactose, mannitol, sorbitol, trehalose, and mixtures thereof.
4. The process of claim 1 wherein the phospholipid is selected from the group consisting of Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, Lipoid SPC-3, and mixtures thereof.
5. The process of claim 1 wherein the phospholipid is Lipoid E80.
6. The process of claim 1 wherein the first temperature range is from the melting point of fenofibrate to 20 C. higher than the melting point of fenofibrate.
7. The process of claim 1 wherein the aqueous carrier is selected from the group consisting of water, sterile water, water for injection, and phosphate buffered water having a pH from 4 to 10.
8. The process of claim 1 wherein the aqueous carrier is phosphate buffered water having a pH from 7 to 9.
9. The process of claim 1 wherein the aqueous carrier is phosphate buffered water having a pH from 7.5 to 8.5.
10. The process of claim 1 wherein the first pressure range is from 2,000 to 30,000 psi.
11. The process of claim 1 wherein the small particles containing fenofibrate have an average size in the range from 0.1 to 10 micrometers.
12. The process of claim 1 wherein the small particles containing fenofibrate have an average size in the range from 0.1 to 5 micrometers.
13. The process of claim 1 wherein the small particles containing fenofibrate have an average size in the range from 0.1 to 2 micrometers.
14. A composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance that is prepared according to the process of claim 1 further containing from 0.1 to about 5% water.
15. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1, wherein a therapeutically effective amount of said pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by said fenofibrate that is greater than 90% of the quantity of said fenofibrate active species provided by said amount to said patient when fed a high fat meal.
16. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 25% of the level of said fibrate active species that said patient receives in a fed state.
17. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 20% of the level of said fibrate active species that said patient receives in a fed state.
18. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 15% of the level of said fibrate active species that said patient receives in a fed state.
19. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 10% of the level of said fibrate active species that said patient receives in a fed state.
20. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 5% of the level of said fibrate active species that said patient receives in a fed state.
21. A tablet dosage form of claim 16 that further comprises a dried film-coating.
22. A tablet dosage form of claim 16 that further comprises a pharmaceutically acceptable polymer in a coating.
23. A tablet dosage form claim 16 that further comprises a pharmaceutically acceptable carbohydrate in a coating.
24. The tablet dosage form of claim 23 where the carbohydrate in the coating is a sugar.
25. The dosage form of claim 16 further comprising one or more excipients selected from the group consisting of monosaccharides, disaccharides, trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, maltodextrose, fructose, sugars, pentoses, hexoses, xylitol, and mixtures thereof.
26. The dosage form of claim 16 wherein the phospholipid surface stabilizing substance comprises a mixture of phospholipids.
27. The dosage form of claim 16 wherein the phospholipid surface stabilizing substance is selected from the group consisting of egg phospholipid, Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, a hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid SPC-3, and mixtures thereof.
28. The dosage form of claim 16 wherein the fenofibrate is crystalline.
29. The dosage form of claim 16 wherein the microparticles are smaller than 5 micrometers.
30. The dosage form of claim 16 wherein the microparticles are smaller than 4 micrometers.
31. The dosage form of claim 16 wherein the microparticles are smaller than 3 micrometers.
32. The dosage form of claim 16 wherein the microparticles are smaller than 2 micrometers.
33. The dosage form of claim 16 wherein the microparticles are smaller than 1 micrometers.
34. The dosage form of claim 16 to further containing from 0.1 to about 5% water.
35. The dosage form of claim 16 wherein the therapeutically effective amount is selected from the group consisting of 50 mg of fenofibrate, 51 mg of fenofibrate, 52 mg of fenofibrate, 53 mg of fenofibrate, 54 mg of fenofibrate, 67 mg of fenofibrate, 100 mg of fenofibrate, 102 mg of fenofibrate, 103 mg of fenofibrate, 104 mg of fenofibrate, 134 mg of fenofibrate, 150 mg of fenofibrate, 153 mg of fenofibrate, 156 mg of fenofibrate, 159 mg of fenofibrate, 160 mg of fenofibrate, 200 mg of fenofibrate, 213 mg of fenofibrate, 250 mg of fenofibrate, and 300 mg of fenofibrate.
36. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein a therapeutically effective amount of said orally administered pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 85% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.
37. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein a therapeutically effective amount of said orally administered pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 90% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.
38. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein a therapeutically effective amount of said orally administered pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 95% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50% of which are from fat.
39. The orally administered pharmaceutical composition of claim 36 further comprising one or more excipients selected from the group consisting of monosaccharides, disaccharides, trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, maltodextrose, fructose, sugars, pentoses, hexoses, xylitol, and mixtures thereof.
40. The orally administered pharmaceutical composition of claim 36 wherein the phospholipid surface active substance is selected from the group consisting of egg phospholipid, Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H a hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid SPC-3, and mixtures thereof.
41. The process of claim 1 wherein the phospholipid is present in an amount from about 0.1% to about 15%.
42. The process of claim 1 wherein the phospholipid is present in an amount from about 0.5% to about 5%.
43. The process of claim 1 wherein the dried small particles further contain from 0.1 to 5% water.
44. The process of claim 1 wherein the dried small particles further contain from 0.1% to 3% water.
45. The process of claim 1 wherein the dried small particles further contain from 0.1% to 2% water.
46. The process of claim 1 wherein the dried small particles further contain from 0.1% to 1% water.
47. A method of treating dyslipidemia and dyslipoproteinemia in a mammal which comprises administering to said mammal once a day a therapeutically effective oral dosage form comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said dosage form provides into the blood of said patient in a fasted state a therapeutically effective amount of fenofibrate active species that is at least 90% of the AUC amount of fenofibrate active species provided by said dosage form into the blood of said patient in a fed state.
48. The method of claim 47 wherein dyslipidemia comprises hypercholesterolemia, hyperlipidemia, hypertrigylceridaemia or combinations thereof.
49. The process of claim 1 where the heated homogenate further comprises a statin.
50. The process of claim 49 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
51. A composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance that is prepared according to the process of claim 1 further containing a statin.
52. The composition of claim 51 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
53. The orally administered pharmaceutical composition of claim 15 further comprising a statin present in a therapeutically effect dose range.
54. The orally administered pharmaceutical composition of claim 53 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
55. The capsule or tablet or powder or granular dosage form of claim 16 further comprising a statin present in a therapeutically effect dose range.
56. The capsule or tablet or powder or granular dosage form of claim 5 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
57. The orally administered pharmaceutical composition of claim 36 further comprising a statin present in a therapeutically effect dose range.
58. The orally administered pharmaceutical composition of claim 57 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin present in a therapeutically effect dose range.
59. The method of claim 47 further comprising a statin present in a therapeutically effect dose range.
60. The method of claim 59 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of forming a semiconductor device, comprising:
forming a photoresist layer on a surface of a wafer, the wafer comprising an array of die that includes a plurality of complete die and at least one partial edge die, the wafer having an edge that has a substantially rounded cross-sectional profile causing undersized patterns in semiconductor devices formed on partial edge die;
assigning a first exposure intensity to a first group of die on the surface of the wafer, the first group of die comprising a group of complete die, the assignment of the first exposure intensity based at least in part on the location of the first group of die on the surface of the wafer;
assigning a second exposure intensity to a second group of die on the surface of the wafer, the second group of die comprising at least one partial edge die, the second exposure intensity less than the first exposure intensity to compensate for reduced line width due to the wafer edge topography; and
directing energy at the second group of die at the second exposure intensity to avoid over-exposure of the second group of die.
2. The method of claim 1, wherein each of the first and second groups of die correspond with a shot area associated with a light source.
3. The method of claim 1, wherein forming the photoresist layer on the surface of the wafer comprises forming the photoresist layer proximate to a polysilicion layer formed on the surface of the wafer.
4. The method of claim 3, wherein the polysilicon layer forms a layer within a semiconductor device having a line width on the order of 10 to 100 nm.
5. The method of claim 1, wherein forming the photoresist layer on the surface of the wafer comprises forming the photoresist layer proximate to a metal or metal-alloy layer formed on the surface of the wafer.
6. The method of claim 1 wherein the second exposure intensity is less than the first exposure intensity by 1 to 50 percent.
7. The method of claim 1, further comprising;
positioning a mask comprising at least one aperture and at least one blocking portion proximate to the surface of the wafer; and
directing energy through the mask to underexpose an area of the photoresist layer that corresponds with the second group of die.
8. The method of claim 1, wherein directing energy at the second group of die comprises directing energy from a light source operable to photochemically decompose one or more dissolution inhibitors in the photoresist layer.
9. A method of forming a semiconductor device, comprising:
forming a photoresist layer on a surface of a wafer, the wafer comprising an array of die that includes a plurality of complete die and at least one partial edge die, the wafer having an edge that has a substantially rounded cross-sectional profile causing undersized patterns in semiconductor devices formed on partial edge die;
assigning a first exposure intensity to a first group of die on the surface of the wafer, the first group of die comprising a group of complete die, the assignment of the first exposure intensity based at least in part on the location of the first group of die on the surface of the wafer;
assigning a second exposure intensity to a second group of die on the surface of the wafer, the second group of die comprising at least one partial edge die, the second exposure intensity greater than the first exposure intensity to compensate for reduced line width due to the wafer edge topography; and
directing energy at the second group of die at the second exposure intensity to avoid under-exposure of the second group of die.
10. The method of claim 9, wherein each of the first and second groups of die correspond with a shot area associated with a light source.
11. The method of claim 9, wherein the second exposure intensity is greater than the first exposure intensity by 1 to 50 percent.
12. The method of claim 9, further comprising:
positioning a mask comprising at least one aperture and at least one blocking portion proximate to the surface of the wafer; and
directing energy through the mask to underexpose an area of the photoresist layer that corresponds with the second group of die.