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-12226423-B2
Publication Date
2025-02-18
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 pharmaceutical compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salt thereof combined with at least one cyclic oligosaccharide, such as a cyclodextrin (CD) or its derivative. These compositions may optionally also include propylene glycol and are formulated to improve delivery and efficacy while minimizing toxicity. The disclosed compositions are designed for local or systemic administration via oral, topical, intravenous, or injectable formulations including lotions, creams, suspensions, or controlled release formulations.
The problem addressed is the need for improved compositions of 25HC3S that enhance solubility, isotonicity, storage stability, and therapeutic efficacy. While 25HC3S is known to mediate inflammation and treat various diseases including organ failure and high cholesterol, existing drug formulations do not adequately provide optimal delivery with high efficacy and low toxicity. The invention seeks to solve this by providing compositions containing 25HC3S complexed with cyclic oligosaccharides to enhance solubility and stability, enabling better prophylactic and therapeutic treatment of conditions involving inflammation and organ dysfunction.
Claims Coverage
The patent presents one independent claim covering a pharmaceutical composition with key components and formulation parameters. The main inventive features relate to the composition's constituents, concentrations, and physiochemical properties.
Pharmaceutical composition comprising 25HC3S or salt thereof
The composition comprises 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or a pharmaceutically acceptable salt thereof at a concentration ranging from 0.1 mg/mL to 50 mg/mL.
Use of cyclic oligosaccharides as solubilizing agents
The aqueous vehicle comprises at least one buffer and at least one cyclic oligosaccharide, wherein the cyclic oligosaccharide includes hydroxypropyl β-cyclodextrin and/or sulfobutyl ether β-cyclodextrin, present at concentrations from 0.1% (w/w) to 90% (w/w).
Isotonic formulation with specified osmolality
The composition is formulated to have an osmolality ranging from 270 mmol/kg to 340 mmol/kg to ensure isotonicity and minimize injection site pain.
Preferred salt and buffer specifications
The salt form is preferably a sodium salt of 25HC3S. The buffer is present at concentrations from 0.1 mM to 50 mM, maintaining physiological pH.
Formulation volume and concentration ranges
Pharmaceutical composition volumes range from 0.5 mL to 5 mL with cyclic oligosaccharides at 1% to 40% (w/w), or from 50 mL to 1000 mL with cyclic oligosaccharides at 0.1% to 4% (w/w), adapted for various administration routes.
The independent claim defines compositions comprising 25HC3S or its salt in combination with specific cyclic oligosaccharides and buffers at defined concentrations, formulated to be isotonic, stable, and suitable for different administration volumes, thereby addressing solubility and delivery limitations.
Stated Advantages
The compositions achieve high efficacy in delivering 25HC3S for treating a variety of diseases related to inflammation and organ failure.
The invention provides low toxicity and improved safety profiles for administration of 25HC3S.
The compositions display improved storage stability under various temperature conditions.
The use of cyclic oligosaccharides enhances solubility of 25HC3S, facilitating different routes of administration including injection and topical application.
Isotonic formulations reduce pain upon injection and eliminate the need for additional isotonic agents.
Documented Applications
Prevention and treatment of organ dysfunction and failure including acute liver failure, kidney failure, heart failure, pancreas and brain dysfunction.
Treatment and prophylaxis of conditions caused by ischemia and ischemia/reperfusion injury affecting various organs.
Prevention and treatment of unwanted cell death including apoptosis and necrosis in tissues and organs.
Treatment and prevention of inflammatory conditions such as sepsis, systemic inflammatory response syndrome (SIRS), and endotoxemia.
Treatment of hyperlipidemia, including lowering cholesterol and lipid levels to prevent associated diseases such as atherosclerosis and metabolic disorders.
Treatment of liver disorders including non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis, cirrhosis, and other liver injuries.
Treatment of leptin deficiency, leptin resistance, and lipid storage diseases characterized by abnormal lipid accumulation.
Treatment of inflammatory skin diseases and skin lesions including atopic dermatitis, psoriasis, eczema, and skin necrosis.
Use in therapeutic regimens involving multiple diseases or conditions, allowing simultaneous or sequential administration of different formulations for different conditions.
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