What is claimed is:
1. A controlled release drug delivery composition comprising at least one hydroxyapatite complexed with at least one first pharmacologically active agent to provide at least one controlled release microparticulate compartment that controllably releases the first pharmacologically active agent when administered to a patient, the controlled release microparticulate compartment complexed with at least one controlled release polymeric carrier that further controllably modulates the release of the first pharmacologically active agent from the composition.
2. The composition of claim 1 wherein the first pharmacologically active agent comprises an oligonucleotide therapeutic and the composition further comprises at least one second pharmacologically active agent comprising at least one of an anti-proliferative drug and an anti-inflammatory drug, wherein the composition controllably modulates the release of the second pharmacologically active agent from the composition.
3. The composition of claim 1 or 2 wherein the oligonucleotide therapeutic comprises at least one of a ribozyme and an antisense oligonucleotide.
4. The composition of claim 1 or 2 wherein the second pharmacologically active agent comprises at least one of paclitaxel and methotrexate.
5. The composition of claim 4 wherein the composition controllably releases chemotherapeutic levels of the second pharmacologically active agent.
6. The composition of claim 1 or 2 wherein the second pharmacologically active agent is at least one of an anti-diabetic, antimicrobial, anesthetic, vasoconstrictor, vasodilator, cardiotonic, enzyme, anti-inflammatory, hormone, bone metabolism controlling agent, hypotensive, sedative, anti-cancer agent, antihistamine, antitussive, vaccine, and asthma treatment.
7. The composition of claim 1 or 2 wherein the controlled release polymeric carrier is a paste.
8. The composition of claim 7 wherein the paste encapsulates the controlled release microparticulate compartment.
9. The composition of claim 1 or 2 wherein the composition is a homogenous paste.
10. The composition of claim 1 or 2 wherein the composition is a non-homogenous paste.
11. The composition of claim 1 or 2 wherein the composition is an ointment, cream, capsule, lotion, gel, spray, foam, mousse, coating, wrap, barrier, implant, microsphere, or film.
12. The composition of claim 11 wherein the composition is a film less than about 2 mm thick comprising a tensile strength greater than about 70 Ncm2.
13. The composition of claim 2 wherein the composition is formulated to release greater than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of about five to fifteen days.
14. The composition of claim 2 wherein the composition is formulated to release less than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of at least about fifteen days
15. The composition of claim 1 or 2 wherein the hydroxyapatite comprises porous microparticles.
16. The composition of claim 1 or 2 wherein the controlled release microparticulate compartment is micronized.
17. The composition of claim 1 or 2 wherein the composition is sized and formulated for oral, nasal, or rectal administration to a patient.
18. The composition of claim 1 or 2 wherein the composition is sized and formulated for administration intravenous, intraperitoneal, intramuscular, subcutaneous, or intraarticular administration to a patient.
19. The composition of claim 1 or 2 wherein the composition is sized and formulated for topical administration to a patient.
20. The composition of claim 1 or 2 wherein the composition is sized and formulated to be injected through a syringe needle.
21. The composition of claim 1 or 2 wherein the composition further comprises a cell permeation enhancing agent.
22. The composition of claim 1 or 2 wherein the composition does not comprise a cell permeation enhancing agent.
23. The composition of claim 1 or 2 wherein the composition further comprises at least one phosphate ion source able to provide a mildly alkaline local environment relative to an in vivo environment.
24. A pharmaceutical composition comprising a pharmaceutically effective amount of hydroxyapatite complexed with a pharmaceutically effective amount of at least one oligonucleotide therapeutic having less than about 100 nucleotides, the composition further comprising at least one of a pharmaceutically acceptable adjuvant, excipient, buffer and diluent, wherein the composition is formulated to controllably modulate the release of the oligonucleotide from the composition.
25. The composition of claim 24 wherein the composition further comprises at least one pharmaceutically acceptable controlled release polymeric carrier that further modulates the release of the first pharmacologically active agent.
26. The composition of claim 25 wherein the composition further comprises at least a second pharmacologically active agent comprising at least one of an anti-proliferative drug and an anti-inflammatory drug, and wherein the composition controllably modulates the release of the second pharmacologically active agent from the composition.
27. The composition of claim 26 wherein the oligonucleotide therapeutic comprises at least one of a ribozyme, an antisense oligonucleotide and an immune modulating oligonucleotide.
28. The composition of claim 26 wherein the second pharmacologically active agent comprises at least one of paclitaxel and methotrexate.
29. The composition of claim 26 wherein the composition is at least one of a film less than about 2 mm thick comprising a tensile strength greater than about 70 Ncm2 and a paste.
30. The composition of claim 26 wherein the composition is formulated to release greater than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of about five to fifteen days.
31. The composition of claim 26 wherein the composition is formulated to release less than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of at least about fifteen days
32. The composition of claim 26 wherein the composition further comprises a cell permeation enhancing agent.
33. The composition of claim 26 wherein the composition does not comprise a cell permeation enhancing agent.
34. The composition of claim 26 wherein the composition further comprises at least one phosphate ion source able to provide a mildly alkaline local environment relative to an in vivo environment.
35. A controlled release drug delivery composition comprising at least one hydroxyapatite complexed with at least one first, anionic pharmacologically active agent to provide at least one controlled release microparticulate compartment that controllably releases the first pharmacologically active agent when administered to a patient, the controlled release microparticulate compartment complexed with at least one controlled release polymeric carrier complexed with at least one second pharmacologically active agent, the controlled release polymeric carrier modulating the release of the first and second pharmacologically active agents from the composition, and wherein the composition further comprises at least one phosphate ion source able to provide a mildly alkaline local environment relative to an in vivo environment.
36. The composition of claim 35 wherein the first pharmacologically active agent comprises an oligonucleotide therapeutic and the second pharmacologically active agent comprises at least one of an anti-proliferative drug and an anti-inflammatory drug, wherein the composition controllably modulates the release of the second pharmacologically active agent from the composition.
38. The composition of claim 36 wherein the oligonucleotide therapeutic comprises at least one of a ribozyme and an antisense oligonucleotide.
39. The composition of claim 36 wherein the composition further comprises a cell permeation enhancing agent.
40. The composition of claim 36 wherein the composition does not comprise a cell permeation enhancing agent.
41. A surgical device suitable for implantation in a patient, the surgical device comprising a controlled release drug delivery composition according to any one of claims 1, 2, 24, 25, 26, 35, and 36.
42. The surgical device of claim 41 wherein the surgical device is a stent, catheter, port, shunt, device for continuous subarachnoid infusion, feeding tube, solid implant to prevent surgical adhesion, uterine implant, artificial sphincter, periurethral implant, splint, ophthalmic implant, contact lens, or plastic surgery implant.
43. The surgical device of claim 42 wherein the stent is an esophageal stent, gastrointestinal stent, vascular stent, biliary stent, colonic stent, pancreatic stent, ureteric stent, urethral stent, lacrimal stent, Eustachian tube stent, fallopian tube stent, nasal stent, sinus stents, tracheal stent, or bronchial stent.
44. The surgical device of claim 41 wherein the surgical device is a venous access device comprising an external tunneled catheter, implanted port, epidural catheter or central catheter (PICC).
45. A kit comprising a composition according to any one of claims 1, 2, 24, 25, 26, 35, and 36 in a pharmaceutically acceptable container.
46. The kit of claim 45 wherein the container is a syringe or a vial.
47. The kit of claim 45 or 46 wherein the kit further comprises a notice associated with the container, the notice in a form prescribed by a governing agency regulating the composition.
48. The kit of claim E3 wherein the kit further comprises instructions about at least one of use of the composition, dosing a patient and mode of administration.
49. A kit comprising a surgical device according to any one of claims 41 to 44 in a pharmaceutically acceptable container.
50. The kit of claim 49 or 50 wherein the kit further comprises a notice associated with the container, the notice in a form prescribed by a governing agency regulating the composition.
51. The kit of claim 49 or 50 wherein the kit further comprises instructions about at least one of use of the composition, dosing a patient and mode of administration.
52. A method of manufacturing a controlled release drug delivery composition comprising:
a) complexing hydroxyapatite with at least one first pharmacologically active agent to provide at least one controlled release microparticulate compartment that controllably releases the first pharmacologically active agent when administered to a patient;
b) complexing the controlled release microparticulate compartment with at least one controlled release polymeric carrier that further controllably modulates the release of the first pharmacologically active agent from the composition.
53. The method of claim 52 wherein the first pharmacologically active agent comprises an oligonucleotide therapeutic and the method further comprises complexing the composition with at least one second pharmacologically active agent comprising at least one of an anti-proliferative drug and an anti-inflammatory drug such that the composition controllably modulates the release of the second pharmacologically active agent from the composition.
54. The method of claim 52 or 53 wherein the oligonucleotide therapeutic comprises at least one of a ribozyme and an antisense oligonucleotide.
55. The method of claim 52 or 53 wherein the second pharmacologically active agent comprises at least one of paclitaxel and methotrexate.
56. The method of claim 55 wherein the composition controllably releases chemotherapeutic levels of the second pharmacologically active agent.
57. The method of claim 52 or 53 wherein the controlled release polymeric carrier is a paste.
58. The method of claim 52 or 53 wherein the composition is an ointment, cream, capsule, lotion, gel, spray, foam, mousse, coating, wrap, barrier, implant, microsphere, or film.
59. The method of claim 53 wherein the composition is formulated to release greater than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of about five to fifteen days.
60. The method of claim 53 wherein the composition is formulated to release less than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of at least about fifteen days
61. The method of claim 52 or 53 wherein the composition is sized and formulated to be injected through a syringe needle.
62. The method of claim 52 or 53 wherein the method further comprises adding at least one cell permeation enhancing agent to the composition.
63. The method of claim 52 or 53 wherein the method does not further comprise adding at least one cell permeation enhancing agent to the composition.
64. The method of claim 52 or 53 wherein the method further comprises adding at least one phosphate ion source able to provide a mildly alkaline local environment relative to an in vivo environment.
65. The method of claim 52 or 53 wherein the method further comprises adding the composition to a surgical device suitable for implantation in a patient.
66. A method of making a pharmaceutical composition comprising complexing a pharmaceutically effective amount of hydroxyapatite with a pharmaceutically effective amount of at least one oligonucleotide therapeutic having less than about 100 nucleotides, the composition further comprising at least one of a pharmaceutically acceptable adjuvant, excipient, buffer and diluent, wherein the composition is formulated to controllably modulate the release of the oligonucleotide from the composition.
67. The method of claim 66 wherein the composition further comprises at least one pharmaceutically acceptable controlled release polymeric carrier that further modulates the release of the first pharmacologically active agent.
68. The method of claim 67 wherein the composition further comprises at least a second pharmacologically active agent comprising at least one of an anti-proliferative drug and an anti-inflammatory drug, and wherein the composition controllably modulates the release of the second pharmacologically active agent from the composition.
69. The method of claim 68 wherein the composition further comprises at least one phosphate ion source able to provide a mildly alkaline local environment relative to an in vivo environment.
70. A method of controlling release of a pharmacologically active agent from a controlled release pharmaceutical composition comprising a pharmaceutically effective amount of hydroxyapatite complexed with a pharmaceutically effective amount of at least one oligonucleotide therapeutic having less than about 100 nucleotides, the composition further comprising at least one of a pharmaceutically acceptable adjuvant, excipient, buffer and diluent, the method comprising adjusting the ratio of hydroxyapatite to oligonucleotide therapeutic to provide a desired rate of release.
71. The method of claim 70 wherein the composition further comprises at least one pharmaceutically acceptable controlled release polymeric carrier that further modulates the release of the oligonucleotide therapeutic, and adjusting the ratio of the controlled release polymeric carrier to oligonucleotide therapeutic to provide a desired rate of release.
72. The method of claim 71 wherein the composition further comprises at least a second pharmacologically active agent comprising at least one of an anti-proliferative drug and an anti-inflammatory drug, and wherein the composition controllably modulates the release of the second pharmacologically active agent from the composition.
73. The method of claim 72 wherein the method further comprises providing at least one phosphate ion source able to provide a mildly alkaline local environment relative to an in vivo environment.
74. A method of treating a proliferative disease comprising administering to a patient at least potentially having the disease a therapeutically effective amount of the composition of any one of claims 1, 2, 24, 25, 26, 35, and 36.
75. A method of treating an inflammatory disease comprising administering to a patient at least potentially having the disease a therapeutically effective amount of the composition of any one of claims 1, 2, 24, 25, 26, 35, and 36.
76. A method of at least one of inhibiting or treating at least one of a proliferative or inflammatory disease in a patient, the method comprising administering a controlled release drug delivery composition produced according to any one of claims 52, 53, 66, 67, 70, 71, and 72 to the patient.
77. The method of claim 76 wherein the composition is administered to release greater than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of about five to fifteen days.
78. The method of claim 76 wherein the composition is administered to release greater than about 10% ww of the oligonucleotide therapeutic and the second pharmacologically active agent over a period of at least about fifteen days
79. The method of claim 76 wherein the composition is administered at least one of topically, via injection through a syringe needle, intra-tumorally into a tumor, and by implanting a surgical device comprising the composition.
80. An isolated and purified composition according to any one of claims 1, 2, 24, 25, 26, 35, and 36 for use in the manufacture of a medicament for inhibiting, preventing or treating a proliferative or inflammatory disease in a human patient.
81. The composition of claim 80 wherein the disease is selected from the group consisting of cancer, arthritis, psoriasis, and surgical adhesion.
82. A method of manufacturing a medicament able to reduce symptoms associated with proliferative or inflammatory disease in a human patient, comprising combining a pharmaceutically effective amount of a composition according to any one of claims 1, 2, 24, 25, 26, 35, and 36, and a pharmaceutically acceptable adjuvant, excipient, buffer or diluent.
83. The composition of claim 82 wherein the disease is selected from the group consisting of cancer, arthritis, psoriasis, and surgical adhesion.
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 fabricating a lanthanum oxide layer in a semiconductor device comprising the sequential steps of:
a) disposing a semiconductor substrate into a chamber;
b) injecting a lanthanum precursor into the chamber such that a layer of the lanthanum precursor is chemisorbed on the semiconductor substrate, wherein the lanthanum precursor consists essentially of tris(bis(trimethylsilyl)amino)Lanthanum;
c) conducting a first purge of the chamber;
d) injecting at least one oxidizer into the chamber such that the oxidizer is chemisorbed with the lanthanum precursor on the semiconductor substrate;
e) conducting a second purge of the chamber; and,
f) repeating steps (b) through (e) until a lanthanum oxide layer of a desired multi-atomic layer thickness is obtained.
2. The method according to claim 1, wherein the step of injecting the lanthanum precursor into the chamber is performed using a bubbler type technique or an injector type technique.
3. The method according to claim 2, wherein an injector type technique is used and the solution for dissolving the lanthanum precursor is at least one member selected from the group consisting of THF, THP and TFP.
4. The method according to claim 1, wherein the first purge step and the second purge step are performed by passing an inert gas or a nitrogen gas into and through the chamber.
5. The method according to claim 1, wherein the oxidizer is at least one member selected from the group consisting of H2O, H2O2, O3, O2, and N2O.
6. The method according to claim 5, wherein the oxidizer is activated through a plasma treatment or a ultraviolet ray irradiation treatment.
7. The method according to claim 1, wherein the step of injecting the at least one oxidizer into the chamber comprises the sequential steps of:
injecting a first oxidizer that includes an \u2014OH group into the chamber;
purging the chamber using an inert gas or a nitrogen gas; and
injecting a second oxidizer that includes O3 or O2 into the chamber.
8. The method according to claim 7, wherein the first oxidizer is H2O and the second oxidizer is O3.
9. A method of fabricating a MOSFET for semiconductor applications comprising the sequential steps of:
forming an isolation layer to define an active region in a semiconductor substrate;
forming a gate dielectric layer that includes a lanthanum oxide layer on the active region, wherein the lanthanum oxide layer is formed by an ALD technique using tris(bis(trimethylsilyl)amino)Lanthanum as a lanthanum precursor; and
forming a gate electrode crossing the active region on the gate dielectric layer.
10. The method according to claim 9, wherein the gate dielectric layer consists of a single layer of a lanthanum oxide layer.
11. The method according to claim 9, wherein the gate dielectric layer consists of stacked layers including at least a lanthanum oxide layer and a dielectric layer.
12. The method according to claim 11, wherein the dielectric layer is a layer selected from the group consisting of a silicon oxide layer, a silicon nitride layer, a silicon oxynitride layer, a hafnium oxide layer, a zirconium oxide layer, a tantalum oxide layer, a titanium oxide layer, and a stacked layer consisting of combinations thereof.
13. The method according to claim 9, further comprising a step of performing an annealing process on the gate dielectric layer before the step of forming the gate electrode.
14. The method according to claim 13, wherein the annealing process is performed under vacuum or in the presence of an inert gas.
15. The method according to claim 13, wherein the annealing process is performed at a temperature of about 300 to 900\xb0 C. and at a pressure equal to or less than 10\u22123 Torr.
16. The method according to claim 9, further comprising a step of forming sourcedrain regions in the active region adjacent to the gate electrode after the step of forming the gate electrode.
17. A method of fabricating a capacitor for semiconductor applications comprising the sequential steps of:
forming a lower electrode;
forming a capacitor dielectric layer that includes a lanthanum oxide layer on the lower electrode, wherein the lanthanum oxide layer is formed by an ALD technique using tris(bis(trimethylsilyl)amino)Lanthanum as a lanthanum precursor; and
forming an upper electrode on the capacitor dielectric layer.
18. The method according to claim 17, wherein the lower electrode is formed as a structure selected from the group consisting of a stack structure, a cylinder structure, and a concave structure.
19. The method according to claim 17, wherein the lower electrode consists of a conductive layer selected from the group consisting of a metal layer, a metal nitride layer, a metal oxide layer, a metal oxynitride layer, an impurity-doped polysilicon layer, and a stacked layer consisting of combinations thereof.
20. The method according to claim 17, wherein the capacitor dielectric layer consists of a single layer of a lanthanum oxide layer.
21. The method according to claim 17, wherein the capacitor dielectric layer consists of stacked layers including at least a lanthanum oxide layer and a dielectric layer.
22. The method according to claim 21, wherein the dielectric layer is a layer selected from the group consisting of a silicon oxide layer, a silicon nitride layer, a silicon oxynitride layer, a hafnium oxide layer, a zirconium oxide layer, a tantalum oxide layer, a titanium oxide layer, and a stacked layer consisting of combinations thereof.
23. The method according to claim 17, wherein the upper electrode consists of a conductive layer selected from the group consisting of a metal layer, a metal nitride layer, a metal oxide layer, a metal oxynitride layer, an impurity-doped polysilicon layer, and a stacked layer consisting of combinations thereof.
24. The method according to claim 17, further comprising a step of forming a reaction barrier layer on the lower electrode before the step of forming the dielectric layer including a lanthanum oxide layer.
25. The method according to claim 24, wherein the reaction barrier layer is formed by treating the lower electrode by means of an RTN (rapid thermal nitridation) process or an RTO (rapid thermal oxidation) process.
26. The method according to claim 24, wherein the reaction barrier layer is formed of a silicon oxide layer, a silicon nitride layer, or a silicon oxynitride layer using a CVD method.
27. The method according to claim 17, further comprising a step of performing an annealing process on the capacitor dielectric layer before the step of forming the upper electrode.
28. The method according to claim 27, wherein the annealing process is performed under vacuum or in the presence of an inert gas.
29. The method according to claim 27, wherein the annealing process is performed at a temperature of about 300 to 900\xb0 C. and at a pressure equal to or less than 10\u22123 Torr.
30. A semiconductor device comprising a dielectric layer that at least includes a lanthanum oxide layer fabricated in accordance with the method of claim 1.
31. A MOSFET element for use in semiconductor applications comprising a gate dielectric layer that at least includes a lanthanum oxide layer formed in accordance with the method of claim 9.
32. A capacitor element for use in semiconductor applications comprising a capacitor dielectric layer that at least includes a lanthanum oxide layer formed in accordance with the method of claim 17