1. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:
(a) the controlled release component comprises one or more cores;
(b) the controlled release component comprises oxycodone;
(c) the pharmaceutical formulation comprises a steady state plasma concentration profile of the oxycodone having a fluctuation index of about 90% or less; and
(d) the pharmaceutical formulation, when containing a total dose of about 20 mg of oxycodone and administered at a dosing interval of 12 hours, will produce an AUCss,\u03c4 that is about 100 ng*hmL to about 550 ng*hmL.
2. The pharmaceutical formulation of claim 1, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone and administered at a dosing interval of 12 hours, Css,max of oxycodone is about 10 ngmL to about 50 ngmL.
3. The pharmaceutical formulation of claim 1, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone and administered at a dosing interval of 12 hours, tss,max of oxycodone is about 1 hour to about 10 hours.
4. The pharmaceutical formulation of claim 1, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, AUCss,\u03c4 of oxycodone at the different total dose is proportional to AUCss,\u03c4 of oxycodone at 20 mg.
5. The pharmaceutical formulation of claim 2, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, Css,max of oxycodone at the different total dose is proportional to Css,max of oxycodone at 20 mg.
6. The pharmaceutical formulation of claim 1, wherein the controlled release component further comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.
7. The pharmaceutical formulation of claim 6, wherein the controlled release component comprises morphine or salts thereof.
8. The pharmaceutical formulation of claim 7, wherein the morphine is in the form of morphine sulfate and the oxycodone is in the form of oxycodone hydrochloride.
9. The pharmaceutical formulation of claim 1, in the form of a tablet or capsule.
10. The pharmaceutical formulation of claim 9, wherein the form is a tablet.
11. The pharmaceutical formulation of claim 1, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
12. The pharmaceutical formulation of claim 11, wherein the controlled release component is in the form of a beadlet.
13. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation further comprises an abuse deterrent component.
14. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.
15. The pharmaceutical formulation of claim 14, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.
16. The pharmaceutical formulation of claim 15, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.
17. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component comprises a coating.
18. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component further comprises an alkalizing agent.
19. The pharmaceutical formulation of claim 18, wherein the alkalizing agent is meglumine.
20. The pharmaceutical formulation of claim 13, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
21. The pharmaceutical formulation of claim 20, wherein the abuse deterrent component is in the form of a beadlet.
22. The pharmaceutical formulation of claim 1, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.
23. The pharmaceutical formulation of claim 22, wherein the one or more fillers or diluents comprises microcrystalline cellulose.
24. The pharmaceutical formulation of claim 22, wherein the one or more hydrophilic polymers comprises a carbomer.
25. The pharmaceutical formulation of claim 22, wherein the one or more disintegrants comprises croscarmellose sodium.
26. The pharmaceutical formulation of claim 22, wherein the one or more lubricants comprises magnesium stearate.
27. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:
(a) the controlled release component comprises one or more cores;
(b) the controlled release component comprises oxycodone; and
(c) the pharmaceutical formulation, when containing a total dose of about 20 mg of oxycodone, Cmax is about 5 ngmL to about 15 ngmL following a single administration of the pharmaceutical formulation.
28. The pharmaceutical formulation of claim 27, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone, tmax of oxycodone is about 4 hours to about 24 hours following a single administration of the pharmaceutical formulation.
29. The pharmaceutical formulation of claim 27, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone, AUCt of oxycodone is about 70 ng*hmL to about 352 ng*hmL following a single administration of the pharmaceutical formulation.
30. The pharmaceutical formulation of claim 27, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, Cmax of oxycodone at the different total dose is proportional to Cmax of oxycodone at 20 mg.
31. The pharmaceutical formulation of claim 29, wherein when the pharmaceutical formulation contains a different total dose of oxycodone than about 20 mg, AUCt of oxycodone at the different total dose is proportional to AUCt of oxycodone at 20 mg.
32. The pharmaceutical formulation of claim 27, wherein the controlled release component further comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.
33. The pharmaceutical formulation of claim 32, wherein the controlled release component comprises morphine or salts thereof.
34. The pharmaceutical formulation of claim 33, wherein the morphine is in the form of morphine sulfate and the oxycodone is in the form of oxycodone hydrochloride.
35. The pharmaceutical formulation of claim 27, in the form of a tablet or capsule.
36. The pharmaceutical formulation of claim 35, wherein the form is a tablet.
37. The pharmaceutical formulation of claim 27, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
38. The pharmaceutical formulation of claim 37, wherein the controlled release component is in the form of a beadlet.
39. The pharmaceutical formulation of claim 27, wherein the pharmaceutical formulation further comprises an abuse deterrent component.
40. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.
41. The pharmaceutical formulation of claim 40, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.
42. The pharmaceutical formulation of claim 41, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.
43. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component comprises a coating.
44. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component further comprises an alkalizing agent.
45. The pharmaceutical formulation of claim 44, wherein the alkalizing agent is meglumine.
46. The pharmaceutical formulation of claim 39, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
47. The pharmaceutical formulation of 46, wherein the abuse deterrent component is in the form of a beadlet.
48. The pharmaceutical formulation of claim 27, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.
49. The pharmaceutical formulation of claim 48, wherein the one or more fillers or diluents comprises microcrystalline cellulose.
50. The pharmaceutical formulation of claim 48, wherein the one or more hydrophilic polymers comprises a carbomer.
51. The pharmaceutical formulation of claim 48, wherein the one or more disintegrants comprises croscarmellose sodium.
52. The pharmaceutical formulation of claim 48, wherein the one or more lubricants comprises magnesium stearate.
53. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:
(a) the controlled release component comprises one or more cores;
(b) the controlled release component comprises morphine;
(c) the pharmaceutical formulation comprises a steady state plasma concentration profile of the morphine having a fluctuation index of about 90% or less; and
(d) the pharmaceutical formulation, when containing a total dose of about 30 mg of morphine and administered at a dosing interval of 12 hours, will produce an AUCss,\u03c4 that is about 60 ng*hmL to about 240 ng*hmL.
54. The pharmaceutical formulation of claim 53, wherein when the pharmaceutical formulation contains about 30 mg of morphine and administered at a dosing interval of 12 hours, Css,max of morphine is about 8 ngmL to about 29 ngmL.
55. The pharmaceutical formulation of claim 53, wherein when the pharmaceutical formulation contains about 30 mg of morphine and administered at a dosing interval of 12 hours, tss,max of morphine is about 1 hour to about 5 hours.
56. The pharmaceutical formulation of claim 53, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, AUCss,\u03c4 of morphine at the different total dose is proportional to AUCss,\u03c4 of morphine at 30 mg.
57. The pharmaceutical formulation of claim 54, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, Css,max of morphine at the different total dose is proportional to Css,max of morphine at 30 mg.
58. The pharmaceutical formulation of claim 53, wherein the controlled release component further comprises an opioid selected from the group consisting of oxycodone, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.
59. The pharmaceutical formulation of claim 58, wherein the controlled release component comprises oxycodone or salts thereof.
60. The pharmaceutical formulation of claim 59, wherein the oxycodone is in the form of oxycodone hydrochloride and the morphine is in the form of morphine sulfate.
61. The pharmaceutical formulation of claim 53, in the form of a tablet or capsule.
62. The pharmaceutical formulation of claim 61, wherein the form is a tablet.
63. The pharmaceutical formulation of claim 53, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
64. The pharmaceutical formulation of claim 63, wherein the controlled release component is in the form of a beadlet.
65. The pharmaceutical formulation of claim 53, wherein the pharmaceutical formulation further comprises an abuse deterrent component.
66. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.
67. The pharmaceutical formulation of claim 66, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.
68. The pharmaceutical formulation of claim 67, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.
69. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component comprises a coating.
70. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component further comprises an alkalizing agent.
71. The pharmaceutical formulation of claim 70, wherein the alkalizing agent is meglumine.
72. The pharmaceutical formulation of claim 65, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
73. The pharmaceutical formulation of 72, wherein the abuse deterrent component is in the form of a beadlet.
74. The pharmaceutical formulation of claim 53, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.
75. The pharmaceutical formulation of claim 74, wherein the one or more fillers or diluents comprises microcrystalline cellulose.
76. The pharmaceutical formulation of claim 74, wherein the one or more hydrophilic polymers comprises a carbomer.
77. The pharmaceutical formulation of claim 74, wherein the one or more disintegrants comprises croscarmellose sodium.
78. The pharmaceutical formulation of claim 74, wherein the one or more lubricants comprises magnesium stearate.
79. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:
(a) the controlled release component comprises one or more cores;
(b) the controlled release component comprises morphine;
(c) the pharmaceutical formulation, when containing a total dose of about 30 mg of morphine, Cmax is about 1 ngmL to about 11 ngmL following a single administration of the pharmaceutical formulation.
80. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains about 30 mg of morphine, tmax of morphine is about 3 hours to about 25 hours following a single administration of the pharmaceutical formulation.
81. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains about 30 mg of morphine, AUCt of morphine is about 60 ng*hmL to about 433 ng*hmL following a single administration of the pharmaceutical formulation.
82. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, Cmax of morphine at the different total dose is proportional to Cmax of morphine at 30 mg.
83. The pharmaceutical formulation of claim 79, wherein when the pharmaceutical formulation contains a different total dose of morphine than about 30 mg, AUCt of morphine at the different total dose is proportional to AUCt of morphine at 30 mg.
84. The pharmaceutical formulation of claim 79, wherein the controlled release component further comprises an opioid selected from the group consisting of oxycodone, codeine, hydromorphone, hydrocodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.
85. The pharmaceutical formulation of claim 84, wherein the controlled release component comprises oxycodone or salts thereof.
86. The pharmaceutical formulation of claim 85, wherein the oxycodone is in the form of oxycodone hydrochloride and the morphine is in the form of morphine sulfate.
87. The pharmaceutical formulation of claim 79, in the form of a tablet or capsule.
88. The pharmaceutical formulation of claim 87, wherein the form is a tablet.
89. The pharmaceutical formulation of claim 79, wherein the controlled release component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
90. The pharmaceutical formulation of claim 89, wherein the controlled release component is in the form of a beadlet.
91. The pharmaceutical formulation of claim 79, wherein the pharmaceutical formulation further comprises an abuse deterrent component.
92. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component comprises a core comprising one or more materials that are both hydrophilic and hydrophobic.
93. The pharmaceutical formulation of claim 92, wherein the material that is both hydrophilic and hydrophobic is acrylic acid cross-linked with allyl ethers of polyalcohols.
94. The pharmaceutical formulation of claim 93, wherein the acrylic acid cross-linked with allyl ethers of polyalcohols is a carbomer.
95. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component comprises a coating.
96. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component further comprises an alkalizing agent.
97. The pharmaceutical formulation of claim 96, wherein the alkalizing agent is meglumine.
98. The pharmaceutical formulation of claim 91, wherein the abuse deterrent component is in a form selected from the group consisting of pellets, beads, beadlets, granules, powder, or a combination thereof.
99. The pharmaceutical formulation of 98, wherein the abuse deterrent component is in the form of a beadlet.
100. The pharmaceutical formulation of claim 79, further comprising one or more fillers or diluents, one or more hydrophilic polymers, one or more disintegrants, and one or more lubricants.
101. The pharmaceutical formulation of claim 100, wherein the one or more fillers or diluents comprises microcrystalline cellulose.
102. The pharmaceutical formulation of claim 100, wherein the one or more hydrophilic polymers comprises a carbomer.
103. The pharmaceutical formulation of claim 100, wherein the one or more disintegrants comprises croscarmellose sodium.
104. The pharmaceutical formulation of claim 100, wherein the one or more lubricants comprises magnesium stearate.
105. A pharmaceutical formulation for treatment of pain in a human, comprising a controlled release component, wherein:
(a) the controlled release component comprises one or more cores;
(b) the controlled release component comprises oxycodone hydrochloride and morphine sulfate;
(c) the pharmaceutical formulation, when containing a total dose of about 20 mg of oxycodone hydrochloride, Cmax of oxycodone is about 5 ngmL to about 15 ngmL following a single administration of the pharmaceutical formulation; and
(d) the pharmaceutical formulation, when containing a total dose of about 30 mg of morphine sulfate, Cmax of morphine is about 1 ngmL to about 11 ngmL following a single administration of the pharmaceutical formulation.
106. The pharmaceutical formulation of claim 105, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone hydrochloride and 30 mg of morphine sulfate, tmax is about 4 hours to about 24 hours for oxycodone and about 3 hours to about 25 hours for morphine following a single administration of the pharmaceutical formulation.
107. The pharmaceutical formulation of claim 105, wherein when the pharmaceutical formulation contains about 20 mg of oxycodone hydrochloride and 30 mg of morphine sulfate, AUCt is about 70 ng*hmL to about 352 ng*hmL for oxycodone and about 60 ng*hmL to about 433 ng*hmL for morphine following a single administration of the pharmaceutical formulation.
108. The pharmaceutical formulation of claim 105, wherein the pharmaceutical formulation further comprises an abuse deterrent component.
109. A method of controlling release of one or more compounds having opioid receptor agonist activity for absorption in a human, wherein the method comprises administering the pharmaceutical formulation of claim 1, 27, 53, 79, or 105.
110. A method of treating pain in a human, comprising administering the pharmaceutical formulation of claim 1, 27, 53, 79, or 105.
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. An electrosurgical instrument having an end effector, the end effector configured to simultaneously provide radio frequency power and a fluid to treat tissue, the power sufficient to cause a dimensional change of the tissue, the end effector comprising:
at least one electrode to deliver the radio frequency power to the tissue;
at least one fluid outlet to deliver the fluid to the tissue;
a dimensional change sensor configured to grasp the tissue and move relative to a dimensional change of the tissue while having a grasp of the tissue;
wherein the dimensional change sensor comprises a first clamp having a first jaw member and a second jaw member and a second clamp having a first jaw member and a second jaw member, the first and second jaw members of the first clamp being configured in an opposing manner to grasp tissue therebetween when the first and second jaws of the first clamp are moved together, and the first and second jaw members of the second clamp being configured in to grasp tissue therebetween when the first and second jaws of the second clamp are moved together; and
wherein the first jaw members of the first and second clamps are configured to move in correspondence with the dimensional change of the tissue, wherein the at least one electrode is disposed between either the first jaw members of the first and second clamps or the second jaw members of the first and second clamps to treat tissue grasped by the jaw members of the first and second clamps such that the dimensional change in the tissue caused by such treatment will cause a corresponding change in the distance between the first jaw members of the first and second clamps.
2. The electrosurgical instrument of claim 1 wherein:
the dimensional change sensor is configured to provide feedback to vary the radio frequency power according to the dimensional change of the tissue.
3. The electrosurgical instrument of claim 1 wherein:
the dimensional change sensor is configured to provide feedback to treat the tissue to a predetermined dimensional change.
4. The electrosurgical instrument of claim 1 wherein:
the dimensional change sensor is configured to provide feedback to measure the dimensional change.
5. The electrosurgical instrument of claim 1 wherein:
the dimensional change sensor is operatively associated with a device to provide a measurement of the dimensional change.
6. The electrosurgical instrument of claim 1 wherein:
the dimensional change sensor is operatively associated with means to provide a measurement of the dimensional change.
7. The electrosurgical instrument of claim 1 wherein:
the dimensional change sensor comprises a contact sensor.
8. The electrosurgical instrument of claim 1 wherein:
the dimensional change sensor comprises a shrinkage sensor; and
the dimension change of the tissue comprises a shrinkage of the tissue.
9. The electrosurgical instrument of claim 8 wherein:
the shrinkage sensor is configured to move relative to the shrinkage of the tissue.
10. The electrosurgical instrument of claim 8 wherein:
the shrinkage sensor is configured to provide feedback to vary the radio frequency power according to the shrinkage of the tissue.
11. The electrosurgical instrument of claim 8 wherein:
the shrinkage sensor is configured to provide feedback to treat the tissue to a predetermined shrinkage.
12. The electrosurgical instrument of claim 8 wherein:
the shrinkage sensor is configured to provide feedback to measure the shrinkage.
13. The electrosurgical instrument of claim 8 wherein:
the shrinkage sensor is operatively associated with a device to provide a measurement of the shrinkage.
14. The electrosurgical instrument of claim 8 wherein:
the shrinkage sensor is operatively associated with means to provide a measurement of the shrinkage.
15. The electrosurgical instrument of claim 1 further comprising:
a monopolar electrosurgical instrument.
16. The electrosurgical instrument of claim 1 further comprising:
a bipolar electrosurgical instrument.
17. The electrosurgical instrument of claim 1 wherein:
the at least one fluid outlet is positioned to provide the fluid onto the at least one electrode.
18. The electrosurgical instrument of claim 1 wherein:
the at least one fluid outlet is at least partially defined by the at least one electrode.
19. The electrosurgical instrument of claim 1 wherein:
the at least one fluid outlet is at least partially defined by a hole in the at least one electrode.
20. The electrosurgical instrument of claim 1 wherein:
the at least one fluid outlet is configured to provide the fluid to wet the at least one electrode.
21. The electrosurgical instrument of claim 1 wherein:
the at least one electrode comprises a plurality of electrodes.
22. The electrosurgical instrument of claim 1 wherein:
the at least one fluid outlet comprises a plurality of fluid outlets.
23. The electrosurgical instrument of claim 1 wherein:
the at least one electrode comprises a first electrode and a second electrode; and the at least one fluid outlet comprises a first fluid outlet and a second fluid outlet.
24. The electrosurgical instrument of claim 23 wherein:
the first fluid outlet is positioned to provide the fluid onto the first electrode; and the second fluid outlet is positioned to provide the fluid onto the second electrode.
25. The electrosurgical instrument of claim 23 wherein:
the first fluid outlet is configured to provide the fluid to wet the first electrode; and the second fluid outlet is configured to provide the fluid to wet the second electrode.
26. The electrosurgical instrument of claim 1 wherein:
wherein the second jaw members of the first and second clamps are configured to move in correspondence with the dimensional change of the tissue, wherein the dimensional change in the tissue will cause a corresponding change in the distance between the second jaw members of the first and second clamps.
27. The electrosurgical instrument of claim 1 wherein:
a distance between the first and second jaw member of the first clamp is selectively adjustable to either increase or decrease a compressive force applied to the tissue being treated, and
a distance between the first and second jaw member of the second clamp is selectively adjustable to either increase or decrease a compressive force applied to the tissue being treated.
28. An electrosurgical instrument comprising:
at least one electrode;
a dimensional change sensor configured to grasp the tissue and move relative to a dimensional change of the tissue while having a grasp of the tissue;
wherein the dimensional change sensor comprises a first clamp having a first jaw member and a second jaw member and a second clamp having a first jaw member and a second jaw member, the first and second jaw members of the first clamp being configured in an opposing manner to grasp tissue therebetween when the first and second jaws of the first clamp are moved together, and the first and second jaw members of the second clamp being configured in an opposing manner to grasp tissue therebetween when the first and second jaws of the second clamp are moved together; and
wherein the first jaw members of the first and second clamps are configured to move in correspondence with the dimensional change of the tissue, wherein the at least one electrode is disposed between either the first jaw members of the first and second clamps or the second jaw members of the first and second clamps to treat tissue grasped by the jaw members of the first and second clamps such that the dimensional change in the tissue caused by such treatment will cause a corresponding change in the distance between the first jaw members of the first and second clamps.
29. The electrosurgical instrument of claim 28 further comprising:
at least one fluid outlet positioned to provide a fluid onto the at least one electrode.
30. The electrosurgical instrument of claim 28 wherein:
a distance between the first and second jaw members of the first clamp is selectively adjustable to either increase or decrease a compressive force applied to the tissue being treated, and
a distance between the first and second jaw members of the second clamp is selectively adjustable to either increase or decrease a compressive force applied to the tissue being treated.
31. The electrosurgical instrument of claim 28 wherein:
wherein the second jaw members of the first and second clamps are configured to move in correspondence with the dimensional change of the tissue, wherein the dimensional change in the tissue will cause a corresponding change in the distance between the second jaw members of the first and second clamps.