Methods related to bioactive agents that convert from anions to molecules

Patent metadata

Field	Value
Publication number	US-2023089351-A1
Application number	US-202117797088-A
Country	US
Kind code	A1
Filing date	Feb 2, 2021
Priority date	Feb 3, 2020
Publication date	Mar 23, 2023
Grant date	—

Abstract

Various aspects of this patent document relate to bioactive compositions comprising anions that are converted into hydrophobic bioactive molecules either ex vivo prior to administration to a subject or in situ subsequent to administration to a subject. Such compositions display improved bioavailability and pharmacokinetics relative to compositions that comprise the hydrophobic bioactive molecules instead of the anions.

First claim

What is claimed is:

1 . A method to sedate or anesthetize a subject, comprising providing a composition comprising 2,6-diisopropylphenolate and administering the composition to the subject in an amount that is effective to sedate or anesthetize the subject.

2 . The method of claim 1 , wherein the composition comprises water; the 2,6-diisopropylphenolate is dissolved in the water; and the water has a pH that is greater than 8.5 when the composition is provided.

3 . The method of claim 1 or 2 , wherein the composition comprises the 2,6-diisopropylphenolate at a concentration of at least 15 grams per liter.

4 . The method of any one of claims 1 - 3 , wherein the composition lacks triglycerides, fatty acids, and phospholipids at a combined concentration greater than 50 grams per liter.

5 . The method of any one of claims 1 - 4 , wherein the composition comprises 2,6-diisopropylphenol, and the composition comprises the 2,6-diisopropylphenolate at a greater molar concentration than the 2,6-diisopropylphenol when the composition is provided.

6 . The method of any one of claims 1 - 5 , comprising contacting the 2,6-diisopropylphenolate with a Brønsted acid to convert the 2,6-diisopropylphenolate into 2,6-diisopropylphenol.

7 . The method of any one of claims 1 - 6 , comprising contacting the composition with a liquid comprising bicarbonate to convert the 2,6-diisopropylphenolate into 2,6-diisopropylphenol.

8 . The method of any one of claims 1 - 7 , comprising converting the 2,6-diisopropylphenolate into 2,6-diisopropylphenol in situ subsequent to administering the composition to the subject.

9 . The method of any one of claims 1 - 8 , wherein the amount comprises at least 0.5 micrograms and no greater than 5 milligrams of 2,6-diisopropylphenolate per kilogram bodyweight of the subject per minute.

10 . The method of any one of claims 1 - 7 , comprising converting the 2,6-diisopropylphenolate into 2,6-diisopropylphenol ex vivo prior to administering the composition to the subject.

11 . The method of claim 10 , wherein the amount comprises at least 0.5 micrograms and no greater than 5 milligrams of 2,6-diisopropylphenol per kilogram bodyweight of the subject per minute.

12 . A method to modulate international normalized ratio (“INR”) in a subject, comprising providing a composition comprising 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide and administering the composition to the subject in an amount that is effective to either increase INR to greater than 1.2 in the subject or maintain INR at greater than 1.2 in the subject.

13 . The method of claim 12 , wherein the amount is effective to increase INR to at least 1.5 and no greater than 4.0 in the subject or maintain INR at at least 1.5 and no greater than 4.0 in the subject.

14 . The method of claim 12 or 13 , wherein the amount is effective to either prophylactically prevent or treat (a) thromboembolic events, (b) venous thrombus, (c) pulmonary embolism, (d) thromboembolic complications associated with atrial fibrillation or cardiac valve replacement in the subject, (e) myocardial infarction, (f) ischemic stroke, (g) ischemia-related death, or (h) two or more of the foregoing in the subject.

15 . The method of any one of claims 12 - 14 , wherein the composition comprises 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol, and the composition comprises the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide at a greater molar concentration than the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol when the composition is provided.

16 . The method of any one of claims 12 - 15 , comprising contacting the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide with a Brønsted acid to convert the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide into 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol.

17 . The method of any one of claims 12 - 16 , comprising converting the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide into 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol in situ subsequent to administering the composition to the subject.

18 . The method of any one of claims 12 - 17 , wherein the amount comprises at least 0.1 milligrams and no greater than 20 milligrams of 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide per day.

19 . The method of any one of claims 12 - 16 , comprising converting the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide into 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol ex vivo prior to administering the composition to the subject.

20 . The method of claim 19 , wherein the amount comprises at least 0.1 milligrams and no greater than 20 milligrams of 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol per day.

21 . The method of any one of claims 12 - 20 , wherein the composition is formulated for oral administration; the composition is formulated to allow the conversion of the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide into 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol before the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-oxide reaches the stomach of the subject; and the composition is formulated to allow absorption of the 2-oxo-3-(1-phenylpropyl)-2H-chromen-4-ol by the epithelial lining of the gastrointestinal tract between the lips and the stomach, excluding the stomach and the outer surfaces of the lips, and including the esophagus and the inner surfaces of the lips.

22 . The method of any one of claims 12 - 20 , wherein the administering is inhalational administering or injecting.

23 . The method of any one of claims 12 - 22 , wherein the composition is a liquid, and the 2-oxo (1-phenylpropyl)-2H-chromen-4-oxide is dissolved in the liquid.

24 . A method to increase estrogen in a subject, comprising providing a composition comprising an estrogen anion and administering the composition to the subject in an amount that is effective to increase estrogen in the subject, wherein the estrogen anion is (8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3-oxide; (8R,9S,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-3-oxide; or (8R,9S,13S,14S,16R,17R)-16,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3-oxide.

25 . The method of claim 24 , comprising contacting the estrogen anion with a Brønsted acid to convert the estrogen anion into an estrogen molecule.

26 . A method to administer an estrogen to a subject, comprising providing a composition comprising an estrogen anion and orally administering the composition to the subject, wherein: the estrogen anion has a conjugate acid that is an estrogen molecule; the estrogen molecule has an acid dissociation constant in water of at least 50 femtomolar and no greater than 50 nanomolar for conversion of the estrogen molecule into the estrogen anion; the composition is formulated to allow the conversion of the estrogen anion into the estrogen molecule before the estrogen anion reaches the stomach of the subject; and the composition is formulated to allow absorption of the estrogen molecule by the epithelial lining of the gastrointestinal tract between the lips and the stomach, excluding the stomach and the outer surfaces of the lips, and including the esophagus and the inner surfaces of the lips.

27 . The method of claim 26 , wherein:
the estrogen anion is (8R,9S,13S,14S,17S)-13-methyl-17-[(1-oxopentyl)oxy]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3-oxide, and the estrogen molecule i

Assignees

• Natural Extraction Sys Llc

Inventors

• Metcalf Douglas G

Classifications

• A61K31/05 Primary

  Phenols {(cannabinoids A61K31/658)} · CPC title

• A61K31/57

  substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone · CPC title

• A61K31/353

  3,4-Dihydrobenzopyrans, e.g. chroman, catechin · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title