Combination formulation of two antiviral compounds

• US 10,039,779 B2
• Filed: 12/29/2016
• Issued: 08/07/2018
• 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, Oliyai, Reza, Pakdaman, Rowchanak, Stefanidis, Dimitrios, Zia, Vahid
• Primary Examiner(s): Pak, John
• Assistant Examiner(s): Schlientz, Nathan W
• Application Number:
  US15/393,847
• Publication Number:
  US 20170202865A1
• Time in Patent Office: 586 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 fixed dose combination tablet comprising:

a) from about 10% to about 25% w/w of a solid dispersion comprising ledipasvir dispersed within a polymer matrix formed by copovidone, wherein the weight ratio of ledipasvir to copovidone in the solid dispersion is about 1;

1 and greater than 70% of the ledipasvir is amorphous;

b) from about 35% to about 45% w/w of sofosbuvir wherein greater than 70% of the sofosbuvir is crystalline and the crystalline sofosbuvir has XRPD 2θ

-reflections (°

±

0.2θ

) at about;

6.1, 12.7, 20.1 and 20.8;

c) from about 5.0% to about 25% w/w of lactose monohydrate;

d) from about 5.0% to about 25% w/w of microcrystalline cellulose;

e) from about 1.0% to about 10% w/w of croscarmellose sodium;

f) from about 0.5% to about 3% w/w of colloidal silicon dioxide; and

g) from about 0.1% to about 3% w/w of magnesium stearate.

2. The fixed dose combination tablet of claim 1, which comprises

a) about 40% w/w of sofosbuvir and

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

3. The fixed dose combination tablet of claim 1, which comprises about 90 mg of ledipasvir and about 400 mg of sofosbuvir.

4. The fixed dose combination tablet of claim 3, which comprises:

(c) about 165 mg of lactose monohydrate;

(d) about 180 mg of microcrystalline cellulose;

(e) about 50 mg of croscarmellose sodium;

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

(g) about 15 mg of magnesium stearate.

5. The fixed dose combination tablet of claim 3 comprising a film coating.

6. A method of treating a patient infected with hepatitis C virus comprising administering to the patient a therapeutically effective amount of a fixed dose combination tablet of claim 1.

7. The method of claim 6, wherein the fixed dose combination tablet is administered for about 24 weeks or less.

8. The method of claim 6, wherein the fixed dose combination tablet is administered for about 12 weeks or less.

9. The method of claim 6, wherein the fixed dose combination tablet is administered for about 8 weeks or less.

10. The method of claim 6, wherein the fixed dose combination tablet is administered for about 6 weeks or less.

11. The method of claim 6, wherein the fixed dose combination tablet 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.

12. The method of claim 11, wherein the hepatitis C virus is genotype 1a or 1b.

13. The method of claim 6, wherein the fixed dose combination tablet 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.

14. The method of claim 6, wherein the fixed dose combination tablet 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.

15. A fixed dose combination tablet comprising:

a) about 18% w/w of a solid dispersion comprising ledipasvir dispersed within a polymer matrix formed by copovidone, wherein the weight ratio of ledipasvir to copovidone in the solid dispersion is about 1;

1 and wherein greater than 70% of the ledipasvir is amorphous;

b) about 40% w/w of sofosbuvir, wherein greater than 70% of the sofosbuvir is crystalline, wherein the crystalline sofosbuvir has XRPD 2θ

-reflections (°

±

0.2θ

) at about;

6.1, 12.7, 20.1 and 20.8;

c) about 16.5% w/w of lactose monohydrate;

d) about 18.0% w/w of microcrystalline cellulose;

e) about 5.0% w/w of croscarmellose sodium;

f) about 1.0% w/w of colloidal silicon dioxide; and

g) about 1.5% w/w of magnesium stearate.

16. A fixed dose combination tablet comprising:

a) about 180 mg of a solid dispersion comprising ledipasvir dispersed within a polymer matrix formed by copovidone, wherein the weight ratio of ledipasvir to copovidone in the solid dispersion is about 1;

1 and wherein greater than 70% of the ledipasvir is amorphous;

b) about 400 mg of sofosbuvir, greater than 70% of the wherein sofosbuvir is crystalline, wherein the crystalline sofosbuvir has XRPD 2θ

-reflections (°

±

0.2θ

) at about;

6.1, 12.7, 20.1 and 20.8;

c) about 165 mg of lactose monohydrate;

d) about 180 mg of microcrystalline cellulose;

e) about 50 mg of croscarmellose sodium;

f) about 10 mg of colloidal silicon dioxide; and

g) about 15 mg of magnesium stearate.