Compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide
Inventors
Ren, Shunlin • Xu, Leyuan • Ning, Yanxia • KIM, Jin Koung • Lin, WeiQi • Miksztal, Andrew R. • Wu, Hongwei • Lee, Min L.
Assignees
Virginia Commonwealth University • Durect Corp • US Department of Veterans Affairs
Publication Number
US-11406646-B2
Publication Date
2022-08-09
Expiration Date
2037-08-01
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Abstract
Compositions comprising 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide, e.g., a cyclodextrin (CD), are provided. The compositions may be used to prevent and/or treat a variety of diseases and conditions, including organ failure (e.g. acute liver failure), high cholesterol/high lipids, and various inflammatory diseases and conditions.
Core Innovation
The invention provides compositions comprising 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salts thereof in combination with at least one cyclic oligosaccharide, such as cyclodextrins or their derivatives. These compositions may additionally include propylene glycol and are formulated to enhance therapeutic use. The compositions exhibit improved solubility, stability, and isotonicity due to the complexation with cyclodextrins, addressing prior formulation challenges with 25HC3S.
The problem addressed is the difficulty in developing pharmaceutical compositions of 25HC3S with high efficacy, low toxicity, storage stability, high solubility, and isotonicity suitable for various routes including intravenous administration. Existing formulations do not adequately solve solubility and delivery issues for 25HC3S, limiting its therapeutic application for diseases related to inflammation and organ dysfunction.
The disclosure details methods to treat a wide range of diseases and conditions by administering therapeutically effective amounts of these compositions. These include treatment and prophylaxis of acute liver failure, hyperlipidemia, inflammatory diseases, organ dysfunction or failure (including kidney, liver, pancreas, heart, lung, and brain), sepsis, ischemia and reperfusion injury, unwanted cell death, and inflammatory skin diseases among others. The compositions are described in various formulations such as solutions, suspensions, creams, lotions, and controlled release forms suitable for oral, topical, intravenous, intramuscular, or subcutaneous administration.
Claims Coverage
The patent includes one independent method claim directed to treating alcoholic hepatitis by administering an aqueous pharmaceutical composition comprising 25HC3S or a salt thereof, at least one buffer, and at least one cyclic oligosaccharide.
Use of 25HC3S or pharmaceutically acceptable salt thereof in treatment of alcoholic hepatitis
A method of treating alcoholic hepatitis comprising intravenous administration of an aqueous pharmaceutical composition comprising 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or a pharmaceutically acceptable salt thereof.
Inclusion of at least one cyclic oligosaccharide comprising specific cyclodextrins
The composition includes at least one buffer and at least one cyclic oligosaccharide comprising at least one of hydroxypropyl β-cyclodextrin and sulfobutyl ether β-cyclodextrin, improving solubility and stability.
Concentration ranges of components within the pharmaceutical composition
The cyclic oligosaccharide is present at concentrations ranging from 0.1% to 90% (w/w), 25HC3S or salt thereof is present at 0.01% to 3% (w/w) or 0.1 mg/mL to 50 mg/mL, and buffers are present at 0.1 mM to 50 mM, establishing specific formulation parameters.
Dose ranges for administration of 25HC3S or pharmaceutically acceptable salt thereof
25HC3S or pharmaceutically acceptable salt thereof is administered at a dose ranging from 0.001 mg/kg to 100 mg/kg, with specific preferred ranges from 0.001 mg/kg to 10 mg/kg or from 0.1 mg/kg to 10 mg/kg.
The claims cover a method for intravenous treatment of alcoholic hepatitis with a pharmaceutical composition containing 25HC3S or its salt, a buffer, and specific cyclodextrins in defined concentration ranges and dosage regimens, focusing on formulation aspects that improve delivery and efficacy.
Stated Advantages
The compositions possess high efficacy and low toxicity.
They exhibit storage stability improved by complexation with cyclodextrins.
The compositions have high solubility and are isotonic, suited for intravenous administration.
They enable prevention and treatment of acute liver failure and other inflammatory and organ dysfunction diseases effectively.
Documented Applications
Prevention and treatment of acute liver failure including acetaminophen-induced liver failure.
Treatment of hyperlipidemia and associated lipid metabolism disorders.
Treatment of organ dysfunction or failure in kidney, liver, pancreas, heart, lung, and brain.
Treatment of diseases caused by or related to inflammation, including inflammatory skin diseases such as psoriasis and atopic dermatitis.
Treatment of ischemia, ischemia/reperfusion injury, sepsis, acute radiation syndrome, and unwanted cell death conditions.
Use as medicament for prevention or treatment of the stated diseases and conditions by oral, intravenous, topical, or other administration routes.
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