Granted Patent B2

US 12,291,708 · App. 17/547,879 · Granted May 6, 2025

Inventors: Henrik Oerum (Copenhagen, DK); Stewart Alwyn Noble (San Diego, CA); Charles Lester Shear (Collegeville, PA)

Assignee: CiVi Biopharma, Inc.

C12N15/113A61K31/7088A61P3/06A61P43/00C12N15/111C12N2310/11C12N2310/313C12N2310/315C12N2310/321C12N2310/3231C12N2310/341C12N2310/351C12N2320/33

Abstract

Claims (24)

1. A pharmaceutical composition for oral delivery to a subject comprising

(i) an antisense oligonucleotide of formula I (SEQ ID NO: 19)

and,

(ii) N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) or a salt thereof,

in a tablet or capsule comprising a pH-sensitive enteric coating, wherein the pharmaceutical composition is formulated to release the antisense oligonucleotide of formula I in the subject's small intestine following oral administration.

2. The pharmaceutical composition of claim 1 , wherein the salt is a monosodium salt or a disodium salt, or a combination thereof.

3. The pharmaceutical composition of claim 1 , wherein the pH sensitive enteric coating comprises a pH-sensitive hydrogel, pH-activated drug delivery system, pH-sensitive liposome, pH-sensitive micelle, pH-sensitive lipid nanoparticle, pH-sensitive microsphere, pH-sensitive nanoparticle, or any combination thereof.

4. The pharmaceutical composition of claim 1 , further comprising one or more therapeutic agents selected from the group consisting of a statin, ezetimibe, a bile sequestering resin, nicotinic acid, a fibric acid derivative, probucol, neomycin, dextrothyroxine, a plant stanol ester, a cholesterol absorption inhibitor, implitapide, an inhibitor of bile acid transporters, a regulator of hepatic CYP7a, an estrogen replacement therapeutic, and an anti-inflammatory.

5. The pharmaceutical composition of claim 4 , wherein the statin is selected from the group consisting of lovastatin, cerivastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin, and fluvastatin.

6. The pharmaceutical composition of claim 1 , wherein the tablet or capsule comprises between 5 and 30 mg of antisense oligonucleotide of formula I and between 100 and 200 mg of 5-CNAC.

7. The pharmaceutical composition of claim 1 , wherein the antisense oligonucleotide of formula I and the 5-CNAC are in a dry blend.

8. The pharmaceutical composition of claim 1 , wherein the capsule is a gelatin capsule.

9. The pharmaceutical composition of claim 1 , wherein the tablet or capsule comprises about 5 mg, about 10 mg, about 20 mg, about 25 mg, or about 30 mg of the antisense oligonucleotide of formula I.

10. The pharmaceutical composition of claim 1 , wherein the tablet or capsule comprises

(i) 10 mg of the antisense oligonucleotide of formula I and 100 mg of 5-CNAC;

(ii) 20 mg of the antisense oligonucleotide of formula I and 200 mg of 5-CNAC;

(iii) 5 mg of the antisense oligonucleotide of formula I and 200 mg of 5-CNAC;

(iv) 10 mg of the antisense oligonucleotide of formula I and 200 mg of 5-CNAC;

(v) 25 mg of the antisense oligonucleotide of formula I and 200 mg of 5-CNAC; or,

(vi) 30 mg of the antisense oligonucleotide of formula I and 200 mg of 5-CNAC.

11. The pharmaceutical composition of claim 1 , wherein the tablet or capsule has a weight between 5 mg and 1000 mg.

12. A method of treating a disorder selected from the group consisting of atherosclerosis, hyperlipidemia, hypercholesterolemia, HDL/LDL cholesterol imbalance, coronary artery disease (CAD), or coronary heart disease (CHD) in a subject in need thereof, the method comprising administering a pharmaceutical composition of claim 1 to the subject.

13. The method of claim 12 , wherein the tablet or capsule is administered at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes prior to a meal.

14. A method of reducing expression levels and/or activity of PCSK9 or cholesterol levels in a subject in need thereof comprising administering the pharmaceutical composition of claim 1 to the subject.

Assignments (1)

Continuity (5)

References Cited (178)