COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS

• US 20170202865A1
• Filed: 12/29/2016
• Published: 07/20/2017
• Est. Priority Date: 01/31/2013
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Chal, Ben, Mogalian, Erik, Pakdaman, Rowchanak, Stefanidis, Dimitrios, Oliyai, Reza, Zia, Vahid
• Granted Patent: US 10,039,779 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 : Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 : containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/28 : Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 1/16 : for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses

Abstract

Disclosed are pharmaceutical compositions having an effective amount of substantially amorphous ledipasvir and an effective amount of substantially crystalline sofosbuvir.

Claims

1. A pharmaceutical composition comprising:

a) an effective amount of ledipasvir having the formula;

2. The pharmaceutical composition of claim 1, wherein ledipasvir is formulated as a solid dispersion comprising ledipasvir dispersed within a polymer matrix formed by a pharmaceutically acceptable polymer.

3. The pharmaceutical composition of claim 2, wherein the polymer is copovidone.

4. The pharmaceutical composition of claim 3, wherein the weight ratio of ledipasvir to copovidone in the solid dispersion is about 1:

1.

5. The pharmaceutical composition of claim 3, comprising

a) about 40% w/w of sofosbuvir and

b) about 18% w/w of the solid dispersion comprising ledipasvir.

6. The pharmaceutical composition of claim 5, further comprising

a) about 5 to about 25% w/w lactose monohydrate,

b) about 5 to about 25% w/w microcrystalline cellulose,

c) about 1 to about 10% w/w croscarmellose sodium,

d) about 0.5 to about 3% w/w colloidal silicon dioxide, and

e) about 0.1 to about 3% w/w magnesium stearate.

7. A pharmaceutical dosage form comprising the pharmaceutical composition of claim 1, comprising about 90 mg of ledipasvir and about 400 mg of sofosbuvir.

8. The pharmaceutical dosage form of claim 7, wherein the ledipasvir is formulated as a solid dispersion within a polymer matrix of copovidone.

9. The pharmaceutical dosage form of claim 8, wherein the amount of copovidone is about 90 mg.

10. The pharmaceutical dosage form of claim 9, further comprising:

(a) about 165 mg of lactose monohydrate;

(b) about 180 mg of microcrystalline cellulose;

(c) about 50 mg of croscarmellose sodium;

(d) about 10 mg of colloidal silicon dioxide; and

(e) about 15 mg of magnesium stearate.

11. The pharmaceutical dosage form of claim 9 which is in the form of a tablet comprising a film coating.

12. A method of treating a patient infected with hepatitis C virus comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of claim 1.

13. The method of claim 12, wherein the pharmaceutical composition is administered for about 24 weeks or less.

14. The method of claim 12, wherein the pharmaceutical composition is administered for about 12 weeks or less.

15. The method of claim 12, wherein the pharmaceutical composition is administered for about 8 weeks or less.

16. The method of claim 12, wherein the pharmaceutical composition is administered for about 6 weeks or less.

17. The method of claim 12, wherein the pharmaceutical composition is administered once daily for about 12 weeks or less and wherein the hepatitis C virus is genotype 1, 2, 3, 4, 5, or 6.

18. The method of claim 12, wherein the pharmaceutical composition is administered once daily for about 8 weeks or less and wherein the hepatitis C virus is genotype 1, 2, 3, 4, 5, or 6.

19. The method of claim 12, wherein the pharmaceutical composition is administered once daily for about 6 weeks or less and wherein the hepatitis C virus is genotype 1, 2, 3, 4, 5, or 6.

20. The method of claim 17, wherein the hepatitis C virus is genotype 1a or 1b.

21-30. -30. (canceled)