Tesofensine and beta blocker combination formulations

1. A method of treating obesity, an obesity-associated disorder, diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, drug-induced obesity, an overeating disorder, bulimia nervosa, binge eating disorder, compulsive over-eating, impaired appetite regulation, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis in a subject comprising administering to the subject a pharmaceutical composition comprising

a. a first composition constituting a tablet core and comprising an extended release (ER) composition of a beta blocker or a pharmaceutically acceptable salt thereof,

b. a second composition comprising tesofensine or a pharmaceutically acceptable salt thereof, and

c. a third composition comprising an immediate release (IR) composition of a beta blocker of a pharmaceutically acceptable salt thereof;

wherein the first composition is coated with a coating comprising the second composition and the third composition.

2. The method of claim 1 , wherein the beta blocker in the first composition and the third composition is metoprolol or metoprolol tartrate.

3. The method of claim 1 , wherein the beta blocker in the first composition and the third composition is carvedilol or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the beta blocker in the first composition and the third composition is alprenolol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, or timolol, or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the beta blocker in the first composition and the third composition is acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, metoprolol, nebivolol, or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the beta blocker in the first composition and the third composition is carvedilol, celiprolol, labetalol, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the tesofensine is tesofensine free base, tesofensine citrate, or tesofensine tartrate.

8. The method of claim 1 , wherein the second composition is a first coating applied to the first composition.

9. The method of claim 1 , wherein the third composition is a second coating applied to a first coating comprising the second composition.

10. The method of claim 1 , wherein the first composition comprises pellets comprising:

a. an inert pellet core;

b. a drug layer comprising the beta blocker or a pharmaceutically acceptable salt thereof, which layer covers the inert core; and

c. a controlled release layer thereon.

11. The method of claim 10 , wherein the inert pellet core comprises

sugar spheres coated with a plasticized film sub-coat of a hydrophobic film coating polymer plasticized with a hydrophilic and a hydrophobic plasticizer;

the drug layer comprises the beta blocker or a pharmaceutically acceptable salt thereof and a binder;

the controlled release layer comprises a plasticized film coat of a hydrophobic film coating polymer plasticized with a hydrophilic and a hydrophobic plasticizer,

and wherein the pellets are mixed with a final tableting blend comprising a powder mixture of one or more fillers, disintegrants, glidants, or lubricants, or a combination thereof.

12. The method of claim 1 , wherein the first composition comprises a controlled release layer comprising an admixture of:

an ethylacrylate/methylmethacrylate copolymer,

a surfactant, and

sodium stearyl fumarate,

wherein the controlled release layer has been deposited from a water-containing liquid and the amount of the ethylacrylate/methylmethacrylate copolymer in the film coat is in the range of 80-99.5% (w/w).

13. The method of claim 1 , wherein the composition is in the form of a pharmaceutical dosage form.

14. The method of claim 13 , wherein the dosage form comprises an amount of 25-200 mg of the beta blocker or a pharmaceutically acceptable salt thereof in the first composition.

15. The method of claim 13 , wherein the dosage form comprises an amount of 0.1-1 mg of the tesofensine of a pharmaceutically acceptable salt thereof in the second composition.

16. The method of claim 13 , wherein the dosage form comprises an amount of 5-100 mg of the beta blocker or a pharmaceutically acceptable salt thereof in the third composition.

17. The method of claim 1 , wherein the diabetes is type 2 diabetes.

18. The method of claim 1 , wherein the diabetes is pre-diabetes.

19. The method of claim 1 , wherein the pharmaceutical composition is administered once daily.