Therapeutic compounds, formulations, and uses thereof
Inventors
Alibhai, Imran • De Achaval, Sofia • LANGEVIN, Beverly C. • Zhou, Tian
Assignees
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Publication Number
US-11077077-B1
Publication Date
2021-08-03
Expiration Date
Abstract
Provided herein are compositions, formulations, and (e.g., oral) dosage forms comprising a compound of Formula (I). In specific instances, such compositions comprise an emulsifier, a solubilizer, a polyethylene glycol, a surfactant, and an antioxidant. In some instances, such compositions are useful for the treatment of fibrosis, cancer, and/or chronic inflammation.
Core Innovation
The invention relates to oral pharmaceutical compositions comprising a compound of Formula (I) together with a glyceride emulsifier, polyoxyl castor oil as a solubilizer, polyethylene glycol, polysorbate as a surfactant, and an antioxidant. The compositions include at least 50 mg of the compound of Formula (I) and are described as oral dosage forms, including capsule formulations.
The disclosure emphasizes that the compound of Formula (I) is poorly soluble and that the formulation is designed to provide high drug loading, improved solubility and/or bioavailability for oral administration, and acceptable stability. It further describes smaller droplet size and/or lower polydispersity in simulated GI fluids, together with formulation-based improvements in pharmacokinetics, including improved Cmax and AUC measures versus a reference PEG400/Labrasol formulation.
In addition to the pharmaceutical composition, the disclosure includes crystalline forms of the compound of Formula (I), characterized by X-ray powder diffraction peak positions. The disclosure also links the compositions and crystalline forms to treatment of STAT3-mediated disorders, including cancer, fibrosis, and chronic inflammation.
Claims Coverage
The document includes one independent claim covering a specific oral pharmaceutical composition. The independent claim contains six inventive features: defined excipient selection, defined weight-ratio relationships, and at least 50 mg of the compound of Formula (I).
Defined composition with minimum compound of Formula (I)
A pharmaceutical composition comprising at least 50 mg of a compound of Formula (I).
Glyceride emulsifier at 1:1 weight ratio
A glyceride emulsifier present in the composition in a weight ratio of compound of Formula (I) to emulsifier of about 1:1.
Polyoxyl castor oil solubilizer at 1:3 weight ratio
A solubilizer present in the composition in a weight ratio of compound of Formula (I) to solubilizer of about 1:3, wherein the solubilizer is polyoxyl castor oil.
PEG at 1:4 weight ratio
A polyethylene glycol (PEG) present in the composition in a weight ratio of compound of Formula (I) to polyethylene glycol of about 1:4.
Polysorbate surfactant at 1:2 weight ratio
A surfactant present in the composition in a weight ratio of compound of Formula (I) to surfactant of about 1:2, wherein the surfactant is polysorbate.
Antioxidant at 20:1 weight ratio
An antioxidant present in the composition in a weight ratio of compound of Formula (I) to antioxidant of about 20:1.
Overall, claim coverage is centered on a specific oral pharmaceutical composition defined by at least 50 mg of a compound of Formula (I) and selected excipients at weight ratios of about 1:1, 1:3, 1:4, 1:2, and 20:1.
Stated Advantages
Improved PK exposure, including improved Cmax and AUC0-∞ versus a reference PEG400/Labrasol formulation.
Improved solubility and/or bioavailability for oral administration.
Reduced pill burden.
Acceptable stability.
Smaller droplet size and/or reduced polydispersity in simulated GI fluids.
Dose feasibility enabled by high-dose administration with limited numbers of oral dosage forms per day.
Documented Applications
Treatment of fibrosis, including pulmonary fibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneal fibrosis, myelofibrosis, dermal fibrosis, non-alcoholic fatty liver disease, steatohepatitis, and systemic sclerosis.
Treatment of cancer.
Treatment of chronic inflammation.
Treatment of STAT3-mediated disorders.
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