Crystalline solvate forms of a pharmaceutical
Inventors
White, Steven K • Ivanisevic, Igor • Stephens, Kyle • Andres, Mark • Wolfe, Brenton Skylar
Assignees
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Publication Number
US-9850271-B2
Publication Date
2017-12-26
Expiration Date
Abstract
The invention provides and describes solid state 17α-ethynyl-androst-5-ene-3β,7β,17β-triol including amorphous and crystalline forms and specific polymorphic forms thereof. Anhydrates and solvates of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol include Form I anhydrate and Form IV and Form V solvates. The invention further relates to solid and suspension formulations containing 17α-ethynyl-androst-5-ene-3β,7β,17β-triol in a described solid state form and use of the formulations to treat hyperglycemic conditions, such as type 2 diabetes and metabolic syndrome, and autoimmune conditions, such as rheumatoid arthritis, ulcerative colitis and type 1 diabetes, among other inflammation related conditions in subjects or human patients. The invention also relates to methods to make liquid formulations from solid state forms of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol and uses of such formulations in treating the described conditions.
Core Innovation
The patent discloses crystalline solvates and solid-state forms of 17α-ethynylandrost-5-ene-3β,7β,17β-triol, including amorphous and crystalline forms, crystalline Form I, II, III and IV, and crystalline anhydrate forms. Form III and Form IV are characterized as solvates or pseudopolymorphs, and the disclosure also refers to ethanol/methanol and water of hydration relationships among crystalline forms.
The disclosure links these solid-state forms and purified mixtures to formulation performance, including stability, dissolution, and bioavailability. It describes diagnostic characterization approaches to distinguish and identify the solid-state forms, including XRPD, DSC/DTA, TGA, Raman spectroscopy, and SS-NMR, and includes crystallographic identification such as space group P212121 and unit cell parameter information for crystalline anhydrates.
The patent further includes formulation concepts tied to the defined solid-state forms, including solid and liquid/suspension formulations with pharmaceutically acceptable excipients, surface active agents, and cyclodextrins. It also defines solid state concepts and related terminology, including solid state, crystalline, amorphous, substantially free or essentially free, and hydrates or solvates.
Claims Coverage
The independent claim coverage centers on crystalline solvate identity for 17α-ethynylandrost-5-ene-3β,7β,17β-triol, with dependent claims refining solvate type, pharmaceutical-composition context, and impurity limitations. Across the items, 6 inventive features are identified.
Crystalline solvate identity of 17α-ethynylandrost-5-ene-3β,7β,17β-triol
A crystalline solvate identified as 17α-ethynylandrost-5-ene-3β,7β,17β-triol.
Crystalline ethanolate solvate
The crystalline solvate is crystalline ethanolate of 17α-ethynylandrost-5-ene-3β,7β,17β-triol.
Crystalline hydrate solvate
The crystalline solvate is crystalline hydrate of 17α-ethynylandrost-5-ene-3β,7β,17β-triol.
Pharmaceutical composition with pharmaceutically acceptable excipients
A pharmaceutical composition comprises the crystalline solvate and one or more pharmaceutically acceptable excipients.
Specified relative amounts of CH3OH and H2O per compound
The pharmaceutical composition further comprises 1 CH3OH, 0.5 CH3OH, 1 H2O, 0.5 H2O or 2 H2O per 17β-ethynylandrost-5-ene-3β,7β,17β-triol.
Impurity limit in pharmaceutical composition
The pharmaceutical composition contains less than about 3% by weight of impurities.
Overall, the claims are anchored on specific crystalline solvate identities of 17α-ethynylandrost-5-ene-3β,7β,17β-triol, with refinements specifying crystalline ethanolate and crystalline hydrate forms, adding a pharmaceutical-composition framework with pharmaceutically acceptable excipients, and imposing relative amount and impurity thresholds.
Stated Advantages
Improved formulation performance including stability.
Improved dissolution.
Improved bioavailability.
Documented Applications
Treatment of hyperglycemia and metabolic syndrome.
Treatment of type 1 diabetes.
Treatment of type 2 diabetes.
Treatment of autoimmune/inflammatory conditions, including rheumatoid arthritis, multiple sclerosis, and ulcerative colitis.
Treatment of Crohn’s disease and inflammatory bowel disease.
Treatment of hyperproliferation conditions, including prostate cancer, breast cancer, and benign prostatic hyperplasia.
Treatment of lung inflammation, including asthma, COPD, and cystic fibrosis.
Treatment of neurodegenerative conditions, including Parkinson’s, Alzheimer’s, and ALS.
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