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Compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25hc3s) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide

a technology of cholesten and sulfate, which is applied in the direction of antibacterial agents, immunological disorders, metabolism disorders, etc., can solve the problem of not being able to predict ab initio the most appropriate strategy

Inactive Publication Date: 2019-09-05
VIRGINIA COMMONWEALTH UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present disclosure provides compositions comprising a combination of 5-cholesten-3, 25-diol, 3-sulfate (25HC3S) or a pharmaceutically acceptable salt thereof, and at least one cyclic oligosaccharide, such as a cyclodextrin or derivative thereof. These compositions have been found to be effective in preventing and treating acute liver failure, but can also be used for other conditions such as high cholesterol / high lipids, inflammatory diseases, and organ failure of other types (e.g. kidney). The compositions can be formulated for local or systemic administration, and can be in the form of a lotion, cream, or controlled release formulation. The patent also provides methods for making and using the compositions.

Problems solved by technology

However, it is not straightforward to predict ab initio the most appropriate strategy to apply to a new drug compound.

Method used

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  • Compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25hc3s) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide
  • Compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25hc3s) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide
  • Compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25hc3s) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide

Examples

Experimental program
Comparison scheme
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example 1

y Studies

[0181]This Example describes pharmaceutically appropriate aqueous based solution compositions comprising 25HC3S and various cyclodextrins.

[0182]This Example documents the determination that the solubility of 25HC3S forms stable inclusion complexes with cyclodextrins, and that such inclusion complexes are highly water soluble relative to the non-complexed drug.

Solubility in Cyclodextrins

[0183]A total of six suspensions of 25HC3S sodium salt were prepared in water containing 0, 50, 100, 200, 250 and 400 mg / mL hydroxypropyl-β-cyclodextrin (HPbCD, hydroxypropyl betadex) or sulfobutyl ether β-cyclodextrin (SBECD, Captisol®). Both cyclodextrins are used in approved pharmaceutical products and are manufactured as Good Manufacturing Practice (GMP) excipients. Each suspension was agitated at room temperature, aliquots were centrifuged, and the supernatant solutions assayed for 25HC3S concentrations by a reverse phase HPLC method. The solubility data of 25HC3S as a function of HPbCD ...

example 2

ring of 25HC3S Cyclodextrin Formulations

[0194]I. Manufacturing 25HC3S Sodium Salt for Injection, 30 mg / mL after Constitution

Preparation of Sterile Vehicle (250 mg / mL HPbCD with 10 mM Phosphate Buffers in Water)

[0195]Sterile water for injection, USP (6.14 kg) was added into a 10 L stainless steel vessel. Sodium phosphate monobasic monohydrate, USP (2.05 g) and 8.42 g of sodium phosphate dibasic anhydrous, USP were added to the water with slow stirring of an overhead mixer at 100-200 rpm for a minimum of 5 minutes to create a clear solution. HPbCD, NF (1851.85 g) was added in small portions over 15 minutes with slow stirring into the beaker. The stirring was increased to 250-350 rpm for an additional minimum 30 minutes to form a clear solution. The solution was filtered through a 0.22 micron filter. Filtered vehicle (7 mL) was filled into 10 mL glass vials, which were sealed with 20 mm stoppers, and crimp sealed. The vehicle vials were sterilized with gamma irradiation at approximatel...

example 3

25HC3S Administration on Acetaminophen (APAP) Overdose

Materials and Methods

[0202]The ability of 25HC3S to treat symptoms of APAP overdose was examined. 12-week-old male C57BL / 6J mice were fasted overnight and injected (intraperitoneally) with APAP: 600 mg / kg (high dose) for mortality studies or 350 mg / kg (low dose) for liver function and gene studies. Control mice received only vehicle (20% (v / v) a propylene glycol, 4% (w / v) cyclodextrin (powdered hydroxypropyl beta cyclodextrin in sterile 10% (w / v) glucose.

[0203]A composition comprising 25 mg / kg of 25HC3S sodium salt in vehicle was administered intravenously to the experimental mice 0.5 hours after APAP administration. Mortality was monitored in the high dose mice. In the low dose mice, the liver function markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALK) and lactate dehydrogenase (LDH), were measured in serum. Impacts on gene expression were determined by Quantitative Real-time PCR...

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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.

Description

FIELD OF THE DISCLOSURE[0001]The present disclosure generally relates to compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide, e.g., at least one cyclodextrin (CD) and / or derivative thereof. The compositions may be used to treat and / or prophylactically treat a wide variety of diseases and conditions, such as conditions that are caused by or related to inflammation.INTRODUCTION[0002]5-cholesten-3, 25-diol, 3-sulfate (25HC3S) or pharmaceutically acceptable salt thereof is known to prevent and treat a wide variety of diseases and conditions. For instance, 25HC3S or pharmaceutically acceptable salt thereof is known to be a potent mediator of inflammation and successfully used to prevent and treat diseases caused by or exacerbated by inflammation. These diseases include a wide range of maladies, for example heart disease and organ failure.[0003]There are a wide range of strategies known for ...

Claims

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Application Information

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IPC IPC(8): A61K31/565A61P1/16A61P17/06A61P3/06A61P31/04A61K31/724A61K47/10
CPCA61K31/565A61P1/16A61P17/06A61K47/10A61P31/04A61K31/724A61P3/06A61K31/575A61K47/40A61K9/10A61P13/12A61P29/00A61P9/10A61P17/00A61K8/738C07J31/006A61K8/63A61Q19/00A61Q19/004A61Q19/007A61K9/0019A61K9/19A61P11/00A61P3/00A61P37/08A61P9/00A61K47/26A61K9/06A61K2300/00C07J9/00A61K47/02A61K47/6951
Inventor REN, SHUNLINXU, LEYUANNING, YANXIAKIM, JIN KOUNGLIN, WEIQIKIM, MEE JEANMIKSZTAL, ANDREW R.WU, HONGWEILEE, MIN L.TAMRAZ, WILMA
Owner VIRGINIA COMMONWEALTH UNIV
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