US2004072735A1PendingUtilityA1
Methods of inducing terminal differentiation
Priority: Mar 4, 2002Filed: Mar 4, 2003Published: Apr 15, 2004
Est. expiryMar 4, 2022(expired)· nominal 20-yr term from priority
A61P 9/10A61P 43/00A61P 37/02A61P 3/10A61P 37/06A61P 9/04A61P 7/00A61P 35/04A61P 9/00A61P 29/00A61P 31/04A61P 31/18A61P 35/02A61P 25/16A61P 35/00A61P 25/28A61P 25/00A61P 25/04A61K 31/13A61P 19/00A61P 17/00A61P 17/02A61P 13/12A61P 17/04A61P 17/06A61K 31/165A61P 19/10A61K 38/12A61K 47/38A61K 31/44A61P 11/06A61K 31/164A61K 9/4866A61K 9/0019A61P 1/04A61K 31/19A61P 21/02A61K 47/12A61K 9/1652A61P 21/00A61P 1/16A61P 11/00A61P 19/02C07C 259/04
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Claims
Abstract
The present invention provides methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylase (HDAC) by administration of pharmaceutical compositions comprising potent HDAC inhibitors. The oral bioavailability of the active compounds in the pharmaceutical compositions of the present invention is surprisingly high. Moreover, the pharmaceutical compositions unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
2 . The method according to claim 1 , wherein the pharmaceutical composition is administered orally.
3 . The method according to claim 1 , wherein the mean plasma concentration of said HDAC inhibitor is at least about 10 nM.
4 . The method according to claim 1 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 10 nM in vivo for a period of at least 10 hours following administration.
5 . The method according to claim 1 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 2.5 μM over a period of at least 2 hours following administration.
6 . The method according to claim 1 , wherein said composition is contained within a gelatin capsule.
7 . The method according to claim 1 , wherein said carrier or diluent is microcrystalline cellulose.
8 . The method according to claim 1 , further comprising sodium croscarmellose as a disintegrating agent.
9 . The method according to claim 1 , further comprising magnesium stearate as a lubricant.
10 . The method according to claim 1 , wherein said composition is administered once-daily, twice-daily or three times-daily.
11 . The method of claim 1 , wherein said HDAC inhibitor is administered to the subject at a total daily dosage of between about 25-4000 mg/m 2 .
12 . The method according to claim 1 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
13 . The method according to claim 1 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
14 . The method according to claim 1 , wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA):
15 . The method according to claim 1 , wherein said HDAC inhibitor is pyroxamide, represented by the structure:
16 . The method according to claim 1 , wherein said HDAC inhibitor is represented by the structure:
wherein R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to 8.
17 . The method according to claim 1 , wherein said HDAC inhibitor is represented by the structure:
wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.
18 . The method according to claim 1 , wherein said HDAC inhibitor is represented by the structure:
wherein A is an amide moiety, R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
19 . A method of producing a mean plasma concentration of at least about 10 nM of suberoylanilide hydroxamic acid (SAHA) in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
20 . The method according to claim 19 , wherein the pharmaceutical composition is administered orally.
21 . The method according to claim 19 , wherein said composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo for a period of at least 10 hours following administration.
22 . The method according to claim 19 , wherein said composition provides a mean plasma concentration of SAHA of at least about 2.5 μM over a period of at least 2 hours following administration.
23 . The method according to claim 19 , wherein said composition is contained within a gelatin capsule.
24 . The method according to claim 19 , wherein said carrier or diluent is microcrystalline cellulose.
25 . The method according to claim 19 , further comprising sodium croscarmellose as a disintegrating agent.
26 . The method according to claim 19 , further comprising magnesium stearate as a lubricant.
27 . The method according to claim 19 , wherein said composition is administered once-daily, twice-daily or three times-daily.
28 . The method of claim 19 , wherein SAHA is administered to the subject at a total daily dosage of between about 25-4000 mg/m 2 .
29 . The method according to claim 19 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
30 . The method according to claim 19 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
31 . A method of selectively inducing terminal differentiation of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
32 . The method according to claim 31 , wherein the pharmaceutical composition is administered orally.
33 . The method according to claim 31 , wherein the mean plasma concentration of said HDAC inhibitor is at least about 10 nM.
34 . The method according to claim 31 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 10 nM in vivo for a period of at least 10 hours following administration.
35 . The method according to claim 31 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 2.5 μM over a period of at least 2 hours following administration.
36 . The method according to claim 31 , wherein said composition is contained within a gelatin capsule.
37 . The method according to claim 31 , wherein said carrier or diluent is microcrystalline cellulose.
38 . The method according to claim 31 , further comprising sodium croscarmellose as a disintegrating agent.
39 . The method according to claim 31 , further comprising magnesium stearate as a lubricant.
40 . The method according to claim 31 , wherein said composition is administered once-daily, twice-daily or three times-daily.
41 . The method of claim 31 , wherein said HDAC inhibitor is administered to the subject at a total daily dosage of between 25-4000 mg/m 2 .
42 . The method according to claim 31 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
43 . The method according to claim 31 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
44 . The method according to claim 31 , wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA):
45 . The method according to claim 31 , wherein said HDAC inhibitor is pyroxamide, represented by the structure:
46 . The method according to claim 31 , wherein said HDAC inhibitor is represented by the structure:
wherein R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to 8.
47 . The method according to claim 31 , wherein said HDAC inhibitor is represented by the structure:
wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.
48 . The method according to claim 31 , wherein said HDAC inhibitor is represented by the structure:
wherein A is an amide moiety, R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
49 . A method of selectively inducing terminal differentiation of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising producing a mean plasma concentration of at least about 10 nM of suberoylanilide hydroxamic acid (SAHA) in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
50 . The method according to claim 49 , wherein the pharmaceutical composition is administered orally.
51 . The method according to claim 49 , wherein said composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo for a period of at least 10 hours following administration.
52 . The method according to claim 49 , wherein said composition provides a mean plasma concentration of SAHA of at least about 2.5 μM over a period of at least 2 hours following administration.
53 . The method according to claim 49 , wherein said composition is contained within a gelatin capsule.
54 . The method according to claim 49 , wherein said carrier or diluent is microcrystalline cellulose.
55 . The method according to claim 49 , further comprising sodium croscarmellose as a disintegrating agent.
56 . The method according to claim 49 , further comprising magnesium stearate as a lubricant.
57 . The method according to claim 49 , wherein said composition is administered once-daily, twice-daily or three times-daily.
58 . The method of claim 49 , wherein SAHA is administered to the subject at a total daily dosage of between 25-4000 mg/m 2 .
59 . The method according to claim 49 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
60 . The method according to claim 49 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
61 . A method of inducing differentiation of tumor cells in a subject having a tumor, said method comprising producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
62 . The method according to claim 61 , wherein the pharmaceutical composition is administered orally.
63 . The method according to claim 61 , wherein the mean plasma concentration of said HDAC inhibitor is at least about 10 nM.
64 . The method according to claim 61 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 10 nM in vivo for a period of at least 10 hours following administration.
65 . The method according to claim 61 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 2.5 μM over a period of at least 2 hours following administration.
66 . The method according to claim 61 , wherein said composition is contained within a gelatin capsule.
67 . The method according to claim 61 , wherein said carrier or diluent is microcrystalline cellulose.
68 . The method according to claim 61 , further comprising sodium croscarmellose as a disintegrating agent.
69 . The method according to claim 61 , further comprising magnesium stearate as a lubricant.
70 . The method according to claim 61 , wherein said composition is administered once-daily, twice-daily or three times-daily.
71 . The method of claim 61 , wherein said HDAC inhibitor is administered to the subject at a total daily dosage of between about 25-4000 mg/m 2 .
72 . The method according to claim 61 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
73 . The method according to claim 61 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
74 . The method according to claim 61 , wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA):
75 . The method according to claim 61 , wherein said HDAC inhibitor is pyroxamide, represented by the structure:
76 . The method according to claim 61 , wherein said HDAC inhibitor is represented by the structure:
wherein R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to 8.
77 . The method according to claim 61 , wherein said HDAC inhibitor is represented by the structure:
wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.
78 . The method according to claim 61 , wherein said HDAC inhibitor is represented by the structure:
wherein A is an amide moiety, R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
79 . A method of inducing differentiation of tumor cells in a subject having a tumor, said method comprising producing a mean plasma concentration of at least about 10 nM of suberoylanilide hydroxamic acid (SAHA) in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
80 . The method according to claim 79 , wherein the pharmaceutical composition is administered orally.
81 . The method according to claim 79 , wherein said composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo for a period of at least 10 hours following administration.
82 . The method according to claim 79 , wherein said composition provides a mean plasma concentration of SAHA of at least about 2.5 μM over a period of at least 2 hours following administration.
83 . The method according to claim 79 , wherein said composition is contained within a gelatin capsule.
84 . The method according to claim 79 , wherein said carrier or diluent is microcrystalline cellulose.
85 . The method according to claim 79 , further comprising sodium croscarmellose as a disintegrating agent.
86 . The method according to claim 79 , further comprising magnesium stearate as a lubricant.
87 . The method according to claim 79 , wherein said composition is administered once-daily, twice-daily or three times-daily.
88 . The method of claim 79 , wherein SAHA is administered to the subject at a total daily dosage of between about 25 to about 4000 mg/m 2 .
89 . The method according to claim 79 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
90 . The method according to claim 79 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
91 . A method of selectively inducing cell growth arrest of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
92 . The method according to claim 91 , wherein the pharmaceutical composition is administered orally.
93 . The method according to claim 91 , wherein the mean plasma concentration of said HDAC inhibitor is at least about 10 nM.
94 . The method according to claim 91 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 10 nM in vivo for a period of at least 10 hours following administration.
95 . The method according to claim 91 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 2.5 μM over a period of at least 2 hours following administration.
96 . The method according to claim 91 , wherein said composition is contained within a gelatin capsule.
97 . The method according to claim 91 , wherein said carrier or diluent is microcrystalline cellulose.
98 . The method according to claim 91 , further comprising sodium croscarmellose as a disintegrating agent.
99 . The method according to claim 91 , further comprising magnesium stearate as a lubricant.
100 . The method according to claim 91 , wherein said composition is administered once-daily, twice-daily or three times-daily.
101 . The method of claim 91 , wherein said HDAC inhibitor is administered to the subject at a total daily dosage of between about 25-4000 mg/m 2 .
102 . The method according to claim 91 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
103 . The method according to claim 91 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
104 . The method according to claim 91 , wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA):
105 . The method according to claim 91 , wherein said HDAC inhibitor is pyroxamide, represented by the structure:
106 . The method according to claim 91 , wherein said HDAC inhibitor is represented by the structure:
wherein R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to 8.
107 . The method according to claim 91 , wherein said HDAC inhibitor is represented by the structure:
wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.
108 . The method according to claim 91 , wherein said HDAC inhibitor is represented by the structure:
wherein A is an amide moiety, R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
109 . A method of selectively inducing cell growth arrest of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising producing a mean plasma concentration of at least about 10 nM of suberoylanilide hydroxamic acid (SAHA) in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
110 . The method according to claim 109 , wherein the pharmaceutical composition is administered orally.
111 . The method according to claim 109 , wherein said composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo for a period of at least 10 hours following administration.
112 . The method according to claim 109 , wherein said composition provides a mean plasma concentration of SAHA of at least about 2.5 μM over a period of at least 2 hours following administration.
113 . The method according to claim 109 , wherein said composition is contained within a gelatin capsule.
114 . The method according to claim 109 , wherein said carrier or diluent is microcrystalline cellulose.
115 . The method according to claim 109 , further comprising sodium croscarmellose as a disintegrating agent.
116 . The method according to claim 109 , further comprising magnesium stearate as a lubricant.
117 . The method according to claim 109 , wherein said composition is administered once-daily, twice-daily or three times-daily.
118 . The method of claim 109 , wherein SAHA is administered to the subject at a total daily dosage of between about 25-4000 mg/m .
119 . The method according to claim 109 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
120 . The method according to claim 109 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
121 . A method of selectively inducing apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
122 . The method according to claim 121 , wherein the pharmaceutical composition is administered orally.
123 . The method according to claim 121 , wherein the mean plasma concentration of said HDAC inhibitor is at least about 10 nM.
124 . The method according to claim 121 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 10 nM in vivo for a period of at least 10 hours following administration.
125 . The method according to claim 121 , wherein said composition provides a mean plasma concentration of said HDAC inhibitor of at least about 2.5 μM over a period of at least 2 hours following administration.
126 . The method according to claim 121 , wherein said composition is contained within a gelatin capsule.
127 . The method according to claim 121 , wherein said carrier or diluent is microcrystalline cellulose.
128 . The method according to claim 121 , further comprising sodium croscarmellose as a disintegrating agent.
129 . The method according to claim 121 , further comprising magnesium stearate as a lubricant.
130 . The method according to claim 121 , wherein said composition is administered once-daily, twice-daily or three times-daily.
131 . The method of claim 121 , wherein said HDAC inhibitor is administered to the subject at a total daily dosage of between about 25-4000 mg/m 2 .
132 . The method according to claim 121 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
133 . The method according to claim 121 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
134 . The method according to claim 121 , wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA):
135 . The method according to claim 121 , wherein said HDAC inhibitor is pyroxamide, represented by the structure:
136 . The method according to claim 121 , wherein said HDAC inhibitor is represented by the structure:
wherein R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to 8.
137 . The method according to claim 121 , wherein said HDAC inhibitor is represented by the structure:
wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.
138 . The method according to claim 121 , wherein said HDAC inhibitor is represented by the structure:
wherein A is an amide moiety, R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
139 . A method of selectively inducing apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising producing a mean plasma concentration of at least about 10 nM of suberoylanilide hydroxamic acid (SAHA) in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
140 . The method according to claim 139 , wherein the pharmaceutical composition is administered orally.
141 . The method according to claim 139 , wherein said composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo for a period of at least 10 hours following administration.
142 . The method according to claim 139 , wherein said composition provides a mean plasma concentration of SAHA of at least about 2.5 μM over a period of at least 2 hours following administration.
143 . The method according to claim 139 , wherein said composition is contained within a gelatin capsule.
144 . The method according to claim 139 , wherein said carrier or diluent is microcrystalline cellulose.
145 . The method according to claim 139 , further comprising sodium croscarmellose as a disintegrating agent.
146 . The method according to claim 139 , further comprising magnesium stearate as a lubricant.
147 . The method according to claim 139 , wherein said composition is administered once-daily, twice-daily or three times-daily.
148 . The method of claim 139 , wherein SAHA is administered to the subject at a total daily dosage of between about 25-4000 mg/m 2 .
149 . The method according to claim 139 , wherein said composition is administered to the subject at a total daily dose of 200 mg.
150 . The method according to claim 139 , wherein said composition is administered to the subject at a total daily dose of 400 mg.
151 . A pharmaceutical composition for oral administration comprising:
a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof; microcrystalline cellulose; croscarmellose sodium; and magnesium stearate.
152 . The composition according to claim 151 , wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA).
153 . The composition according to claim 151 , comprising:
50-70% by weight of said histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof; 20-40% by weight microcrystalline cellulose; 5-15% by weight croscarmellose sodium; and 0.1-5% by weight magnesium stearate.
154 . The composition according to claim 151 , comprising about 50-200 mg of said HDAC inhibitor.
155 . The composition according to claim 151 contained within a gelatin capsule.
156 . A pharmaceutical composition for oral administration comprising:
suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof; microcrystalline cellulose; croscarmellose sodium; and magnesium stearate.
157 . The composition according to claim 156 , comprising:
50-70% by weight of SAHA or a pharmaceutically acceptable salt or hydrate thereof; 20-40% by weight microcrystalline cellulose; 5-15% by weight croscarmellose sodium; and 0.1-5% by weight magnesium stearate.
158 . The composition according to claim 156 , comprising about 50-200 mg of SAHA.
159 . The composition according to claim 156 contained within a gelatin capsule.Join the waitlist — get patent alerts
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