Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof
Inventors
Smolenskaya, Valeriya N. • Al Shareffi, Kadum A. • Perez, Julio • Shah, Syed M. • Boyd, Thomas A.
Assignees
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Publication Number
US-9879024-B2
Publication Date
2018-01-30
Expiration Date
Abstract
The present invention provides a new forms of (R)-N-methylnaltrexone, and compositions thereof, useful as a peripheral mu opioid receptor antagonist.
Core Innovation
Solid forms of (R)-N-methylnaltrexone bromide are described, including XRPD/DSC-defined polymorph Form A and other solid-state forms of “Compound 1”. These solid forms include an amorphous form, hydrate/solvate forms, including Forms B and D as hydrate/solvate forms and Form C as a solvate form, and mixtures or compositions of such solid forms.
The described (R)-enantiomeric form and the inventive solid forms are linked to peripheral μ-opioid receptor antagonist activity. The document associates this activity with a reduction of opioid-associated side effects, particularly gastrointestinal dysfunction, and also refers to other adverse effects.
The document further provides pharmaceutical composition and formulation contexts and detailed characterization for the solid forms using XRPD and related thermal characterization, including DSC and thermogravimetry. The characterization includes specified XRPD patterns for the solid forms, and the document emphasizes that the defined solid forms support the stated activity and side-effect reduction.
Claims Coverage
The independent claims cover multiple distinct single crystalline forms of a formula 1 compound in the (R) configuration at nitrogen, each defined by an X-ray powder diffraction (XRPD) peak list or pattern collected at 150±1.0 K. The inventive features are the specific XRPD-defined crystalline forms and the (R) nitrogen configuration, with oral pharmaceutical compositions and a use method added in dependent claims.
Single crystalline form defined by XRPD pattern at 150±1.0 K
A composition comprising a single crystalline form of a compound having formula 1, wherein the compound is in the (R) configuration with respect to the nitrogen, and wherein the single crystalline form has an X-ray powder diffraction pattern comprising x-ray powder diffraction peaks, collected at 150±1° K, at five or more of 13.6, 13.9, 16.85, 17.35, 23, 23.85, 24.7, 26.75, and 34.75±0.2 degrees 2-theta.
Single crystalline form defined by specified XRPD peak set
A composition comprising a single crystalline form of a compound having formula 1, wherein the compound is in the (R) configuration with respect to the nitrogen, and wherein the single crystalline form has an X-ray powder diffraction pattern comprising x-ray powder diffraction peaks at 11.56, 13.44, 13.98, 15.52, 16.4, 17.31, 19.42, 20.06, 20.82, 21.90, 22.3, 23.34, 24.42, 24.84, 26.38, 27, 27.64, 28.62, 29.16, and 29.7±0.2 degrees 2-theta.
Single crystalline form defined by specified XRPD peak set
A composition comprising a single crystalline form of a compound having the formula 1, wherein the compound is in the (R) configuration with respect to the nitrogen, and wherein the single crystalline form has an X-ray powder diffraction pattern comprising x-ray powder diffraction peaks at 9.42, 11.56, 13.44, 13.98, 15.52, 16.4, 17.3, 17.78, 19.42, 20.06, 20.82, 21.9, 22.3, 23.34, 24.42, 24.84, 25.82, 26.38, 27, 27.64, 28.62, 29.16, 29.7, 30.04, 30.5, 31.1, 31.5, 32.28, 32.96, 34.34, 35.1, 36, 36.88, 38.16, 39.04, and 39.48±0.2 degrees 2-theta.
Single crystalline form defined by XRPD pattern at 150±1.0 K
A composition comprising a single crystalline form of a compound having the formula 1, wherein the compound is in the (R) configuration with respect to the nitrogen, and wherein the single crystalline form has an X-ray powder diffraction pattern comprising x-ray powder diffraction peaks, collected at 150±1° K, at 9.5, 11.65, 11.75, 13.3, 13.6, 13.9, 15.3, 16.85, 17.35, 17.95, 19.5, 20.3, 20.65, 21.15, 21.8, 22.75, 23, 23.3, 23.65, 23.85, 24.7, 24.95, 26.05, 26.35, 26.75, 27.2, 28.35, 29.25, 29.55, 30.1, 31.25, 31.8, 32.05, 32.55, 33.4, 34.3, and 34.75±0.2 degrees 2-theta.
Overall, the claim coverage is centered on single crystalline forms of a formula 1 compound having the (R) configuration with respect to nitrogen, where each crystalline form is distinguished by its XRPD peak pattern or peak list collected at 150±1.0 K for the claims that recite collection temperature. Dependent claims additionally cover oral pharmaceutical compositions, including tablet form and crospovidone as a disintegrant, and a method of reducing a side effect of opioid therapy by administering the oral pharmaceutical composition to a subject receiving opioid treatment.
Stated Advantages
Reduction of opioid-associated side effects, particularly gastrointestinal dysfunction.
Peripheral μ-opioid receptor antagonist activity.
Documented Applications
Reducing side effects of opioid therapy by administering an oral pharmaceutical composition to a subject receiving opioid treatment.
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