Polymorphs of suberoylanilide hydroxamic acid
First Claim
1. A pharmaceutical composition comprising an active ingredient comprising suberoylanilide hydroxamic acid (SAHA) Form I characterized by an X-ray diffraction pattern including characteristic peaks at about 9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0, and 43.3 degrees 2θ
- , wherein the X-ray diffraction is measured with a Copper X-ray source; and
further characterized by a Differential Scanning Calorimetry (DSC) thermogram having a single maximum value at about 164.4±
2.0, as measured by a Perkins Elmer DSC 6 Instrument, and a pharmaceutically acceptable carrier.
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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. The present invention also provides a novel Form I polymorph of SAHA, characterized by a unique X-ray diffraction pattern and Differential Scanning Calorimetry profile, as well a unique crystalline structure.
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Citations
43 Claims
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1. A pharmaceutical composition comprising an active ingredient comprising suberoylanilide hydroxamic acid (SAHA) Form I characterized by an X-ray diffraction pattern including characteristic peaks at about 9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0, and 43.3 degrees 2θ
- , wherein the X-ray diffraction is measured with a Copper X-ray source; and
further characterized by a Differential Scanning Calorimetry (DSC) thermogram having a single maximum value at about 164.4±
2.0, as measured by a Perkins Elmer DSC 6 Instrument, and a pharmaceutically acceptable carrier. - View Dependent Claims (4, 7, 8, 9, 30, 33, 34)
- , wherein the X-ray diffraction is measured with a Copper X-ray source; and
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2. A pharmaceutical composition comprising an active ingredient comprising suberoylanilide hydroxamic acid (SAHA) Form I characterized by an X-ray diffraction pattern including characteristic peaks at about 9.4, 17.5, 19.4, 20.0, 24.0, and 28.0 degrees 2θ
- , wherein the X-ray diffraction is measured with a Copper X-ray source; and
further characterized by a Differential Scanning Calorimetry (DSC) thermogram having a single maximum value at about 164.4±
2.0, as measured by a Perkins Elmer DSC 6 Instrument, and a pharmaceutically acceptable carrier. - View Dependent Claims (5, 10, 31)
- , wherein the X-ray diffraction is measured with a Copper X-ray source; and
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3. A pharmaceutical composition comprising an active ingredient comprising suberoylanilide hydroxamic acid (SAHA) Form I characterized by an X-ray diffraction pattern including characteristic peaks at about 9.4, 17.5, 19.4, 20.0, 24.0, and 28.0 degrees 2θ
- , and lacking peaks at about 13.4-14.0 and 22.7-23.0 degrees 2θ
, wherein the X-ray diffraction is measured with a Copper X-ray source, and a pharmaceutically acceptable carrier. - View Dependent Claims (6, 11, 32)
- , and lacking peaks at about 13.4-14.0 and 22.7-23.0 degrees 2θ
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12. A pharmaceutical composition comprising an active ingredient comprising a crystalline form of SAHA designated as Form I and a pharmaceutically acceptable carrier, wherein the SAHA Form I is characterized by an X-ray diffraction pattern including characteristic peaks at about 9.4, 17.5, 19.4, 20.0, 24.0, and 28.0 degrees 2θ
- , wherein the X-ray diffraction is measured with a Copper X-ray source, obtainable by a method comprising the step of recrystallizing a crude preparation of SAHA from an organic solvent, or a mixture of an organic solvent and water, wherein the organic solvent is at least one of methanol, ethanol or isopropanol.
- View Dependent Claims (13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 35, 36, 37, 38, 39, 40, 41, 42, 43)
Specification