Use of essential oils to increase bioavailability of oral pharmaceutical compounds

• US 5,665,386 A
• Filed: 06/07/1995
• Issued: 09/09/1997
• Est. Priority Date: 06/07/1995
• Status: Expired due to Term

• Current Assignee: Lyotropic Therapeutics Inc.
• Original Assignee: Avmax, Inc.
• Inventors: Benet, Leslie Z., Wacher, Vincent J., Benet, Reed M.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/486,186
• Time in Patent Office: 825 Days
• Field of Search: 424/456, 424/465, 424/449, 424/451, 424/455, 514/946
• US Class Current: 424/451
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14

Abstract

A method for increasing bioavailability and reducing inter- and intra-individual variability of an orally administered hydrophobic pharmaceutical compound, which comprises orally administering the pharmaceutical compound to a mammal in need of treatment with the compound concurrently with an essential oil or essential oil component in an amount sufficient to provide bioavailability of the compound in the presence of the essential oil or essential oil component greater than bioavailability of the compound in the absence of the essential oil or essential oil component, wherein the essential oil or essential oil component has an activity of at least 10% inhibition at a concentration of 0.01 wt. % or less in an assay that measures conversion of cyclosporine to hydroxylated products using an assay system containing 250 μg rat liver microsomes, 1 μM cyclosporine, and 1 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH) in 1 ml of 0.1M sodium phosphate buffer, pH 7.4.

Claims

1. A method for increasing bioavailability of an orally administered hydrophobic pharmaceutical compound, which comprises:

orally administering said pharmaceutical compound to a mammal in need of treatment with said pharmaceutical compound concurrently with an essential oil or a component of an essential oil in an amount of said essential oil or essential oil component sufficient to provide bioavailability of said pharmaceutical compound in the presence of said essential oil or essential oil component greater than bioavailability of said pharmaceutical compound in the absence of said essential oil or essential oil component, and sufficient to provide a concentration of said essential oil or essential oil component in the gut of said mammal equal to or greater than a concentration of said essential oil or essential oil component that reduces conversion of cyclosporine to hydxoxylated products by 10%, compared to controls, in an assay system containing 250 μ

g rat liver microsomes, 1 μ

M cyclosporine, and 1 mM reduced nicotinamide adenine dinucleotide phoshate (NADPH) in 1 ml of 0.1M sodium phosphate buffer, pH 7.4.

9. The method of claim 1, wherein said essential oil or essential oil component comprises 2,6-dimethyl-2,4,6-octatriene;

4-propenylanisole;

benzyl-3-phenylpropenoic acid;

1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol;

2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane;

1,7,7-trimethylbicyclo[2.2.1]heptane;

trans-8-methyl-n-vanillyl-6-nonenamide;

2,2,5-trimethylbicyclo[4.1.0]hept-5-ene;

5-isopropyl-2-methylphenol;

p-mentha-6,8-dien-2-ol;

p-mentha-6,8-dien-2-one;

β

-caryophyllene;

3-phenylpropenaldehyde;

mixed geranial and neral;

3,7-dimethyl-6-octenal;

3,7-dimethyl-6-octen-1-ol;

4-allylanisole;

ethyl 3-phenylpropenoic acid;

3-ethoxy-4-hydroxybenzaldehyde;

1,8-cineole;

4-allyl-2-methoxyphenol;

3,7,11-trimethyl-2,6,10-dodecatrien-1-ol;

1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol;

1,3,3-trimethylbicyclo[2.2.1]heptan-2-one;

trans-3,7-dimethyl-2,6-octadien-1-ol;

trans-3,7-dimethyl-2,6-octadien-1-yl acetate;

3-methyl-2-(2-pentenyl)-2-cyclopentene-1-one;

p-mentha-1,8-diene;

3,7-dimethyl-1,6-octadien-3-ol;

3,7-dimethyl-1,6-octadien-3-yl acetate;

p-menthan-3-ol;

p-menthan-3-one;

methyl 2-aminobenzoate;

methyl-3-oxo-2-(2-pentenyl)cyclopentane acetate;

methyl 2-hydroxybenzoate;

7-methyl-3-methylene-1,6-octadiene;

cis-3,7-dimethyl-2,6-octadien-1-ol;

2,6,6-trimethylbicyclo[3.1.1]hept-2-ene;

6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane;

p-menth-4(8)-en-3-one;

p-menth-1-en-4-ol;

p-mentha-1,3-diene;

p-menth-1-en-8-ol;

or 2-isopropyl-5-methylphenol.

2. A method for increasing bioavailability of an orally administered hydrophobic pharmaceutical compound, which comprises:

orally administering said pharmaceutical compound to a mammal in need of treatment with said pharmaceutical compound concurrently with an essential oil or a component of an essential oil in an amount of said essential oil or essential oil component sufficient to provide bioavailability of said pharmaceutical compound in the presence of said essential oil or essential oil component greater than bioavailability of said pharmaceutical compound in the absence of said essential oil or essential oil component, and sufficient to provide a concentration of said essential oil or essential oil component in the lumen of the gut of said mammal of at least 0.1 times a K_i or apparent K_i of the essential oil or essential oil component as measured by an assay that measures reduced conversion of cyclosporine to hydroxylated product in an assay system containing 250 μ

g rat liver microsomes, 1 μ

M cyclosporine, anal 1 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH) in 1 ml of 0.1M sodium phosphate buffer, pH 7.4.

10. The method of claim 2, wherein said essential oil or essential oil component comprises 2,6-dimethyl-2,4,6-octatriene;

4-propenylanisole;

benzyl-3-phenylpropenoic acid;

1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol;

2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane;

1,7,7-trimethylbicyclo[2.2.1]heptane;

trans-8-methyl-n-vanillyl-6-nonenamide;

2,2,5-trimethylbicyclo[4.1.0]hept-5-ene;

5-isopropyl-2-methylphenol;

p-mentha-6,8-dien-2-ol;

p-mentha-6,8-dien-2-one;

β

-caryophyllene;

3-phenylpropenaldehyde;

mixed geranial and neral;

3,7-dimethyl-6-octenal;

3,7-dimethyl-6-octen-1-ol;

4-allylanisole;

ethyl 3-phenylpropenoic acid;

3-ethoxy-4-hydroxybenzaldehyde;

1,8-cineole;

4-allyl-2-methoxyphenol;

3,7,11-trimethyl-2,6,10-dodecatrien-1-ol;

1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol;

1,3,3-trimethylbicyclo[2.2.1]heptan-2-one;

trans-3,7-dimethyl-2,6-octadien-1-ol;

trans-3,7-dimethyl-2,6-octadien-1-yl acetate;

3-methyl-2-(2-pentenyl)-2-cyclopenten-1-one;

p-mentha-1,8-diene;

3,7-dimethyl-1,6-octadien-3-ol;

3,7-dimethyl-1,6-octadien-3-yl acetate;

p-menthan-3-ol;

p-menthan-3-one;

methyl 2-aminobenzoate;

methyl-3-oxo-2-(2-pentenyl)cyclopentane acetate;

methyl 2-hydroxybenzoate;

7-methyl-3-methylene-1,6-octadiene;

cis-3,7-dimethyl-2,6-octadien-1-ol;

2,6,6-trimethylbicyclo[3.1.1]hept-2-ene;

6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane;

p-menth-4(8)-en-3-one;

p-menth-1-en-4-ol;

p-mentha-1,3-diene;

p-menth-1-en-8-ol;

or 2-isopropyl-5-methylphenol.

3. A method of formulating an oral pharmaceutical composition, which comprises:

admixing a pharmaceutical compound, a pharmaceutical carrier, and an essential oil or essential oil component, said essential oil or essential oil component being present in an amount sufficient to provide bioavailability of said pharmaceutical compound in the presence of said essential oil or essential oil component greater than the bioavailability of said pharmaceutical compound in the absence of said essential or oil essential oil component when said pharmaceutical composition is administered orally to a mammal, wherein said essential oil or essential oil component is present in an amount sufficient to provide a concentration of said essential oil or essential oil component in the lumen of the gut of said mammal equal to or greater than a concentration of said essential oil or essential oil component that reduces conversion of cyclosporine to hydroxylated products by 10% in an assay system containing 250 μ

g rat liver microsomes, 1 μ

M cyclosporine, and 1 mM NADPH in 1 ml of 0. 1M sodium phosphate buffer, pH 7.4.

5. The method of claim 3, wherein said essential oil or essential oil component is present as a counter ion of said pharmaceutical compound.

6. The method of claim 3, wherein said essential oil or essential oil component is covalently bound to said pharmaceutical compound.

4. A method of formulating an oral pharmaceutical composition, which comprise:

admixing a pharmaceutical compound, a pharmaceutical, carrier, and an essential oil or essential oil component, said essential oil or essential oil component being present in an amount sufficient to provide bioavailability of said pharmaceutical compound in the presence of said essential oil or essential oil component greater than the bioavailability of said pharmaceutical compound in the absence of said essential oil or essential oil component when said pharmaceutical composition is administered orally to a mammal, wherein said amount is sufficient to provide a concentration of said essential oil or essential oil component in the lumen of the gut of said mammal of at least 0.1 times said K_i or apparent K_i of said essential oil or essential oil component.

7. The method of claim 4, wherein said essential oil or essential oil component is present as a counter ion of said pharmaceutical compound.

8. The method of claim 4, wherein said essential oil or essential oil component is covalently bound to said pharmaceutical compound.