# US 10,308,937 B2 · Combination long acting compositions and methods for Hepatitis C

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- Number: US 10,308,937 B2
- Document ID: US10308937B2
- Status: Granted
- Kind: B2
- Application number: 15/525,926
- Filed: 2015-10-30
- Published: 2017-11-02
- Granted: 2019-06-04
- Earliest claimed: 2014-11-10
- Assignees: GlaxoSmithKline Intellectual Property (No. 2) Limited
- Applicants: GlaxoSmithKline Intellectual Property (No. 2) Limited
- Inventors: Zhi Hong; Martin R. Leivers
- Web page: https://patentgrep.com/patent/US10308937B2

## CPC

- C12N 15/1131: {against viruses}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/549: having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
- A61K 31/69: Boron compounds
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs
- C12N 2310/351: Conjugate
- C12N 2320/31: Combination therapy
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present Invention relates to pharmaceutical compositions useful in the treatment or prevention or cure of viral infections, such as HCV infections, and diseases associated with such infections.

## Claims

### Claim 1

A method for the treatment of an HCV infection in a human having an HCV infection, comprising:
administering to the human a long acting parenteral (LAP) pharmaceutical composition comprising a LAP HCV active agent, or a pharmaceutically acceptable salt thereof, wherein the LAP HCV agent is 6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1 ,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, in combination with a compound of Formula IIA or IIB:

### Claim 2 (depends on 1)

The method according to claim 1, wherein R is a 5′-3′ anti-miR-122 oligonucleotide and wherein the anti-miR-122 oligonucleotide comprises at least one modified internucleoside linkage, modified sugar moiety, or modified nucleobase.

### Claim 3 (depends on 1)

The method according to claim 1, wherein R is a 5′-3′ anti-miR-122 oligonucleotide and wherein the anti-miR-122 oligonucleotide comprises at least one of a 2′-O-methoxyethyl sugar moiety, a constrained ethyl sugar moiety, a phosphorothioate internucleoside linkage, or a 5-methylcytosine.

### Claim 4 (depends on 1)

A method for the treatment of an HCV infection in a human having an HCV infection according to claim 1, comprising:
administering just once to the human the pharmaceutical composition comprising the long acting parenteral (LAP) HCV active agent of claim 1, in combination with a compound selected from Formula IIA or IIB:
further comprising a LAP HCV active agent selected from:
Telaprevir (Incivek®), Boceprevir (Victrelis®), ABT-450, Faldaprevir (BI-201335), Asunaprevir (BMS-650032), GS-9256, GS-9857, ABT-493,
Vedroprevir (GS-9451), Danoprevir (ITM N-191, RG7227), (Grazoprevir) MK-5172, Vaniprevir (MK-7009), Sovaprevir (ACH-1625), Deldeprevir (Neceprevir) (ACH-2684), Narlaprevir (SCH 900518), Simeprevir (TMC 435), ABT-267,ABT-530, Daclatasvir, Velpatasvir, Ledipasvir, ACH-2928, odalasvir (ACH-3102), PPI-668, AZD-7295, Elbasvir (MK-8742), MK-8408, BMS-986094, MK-3862(IDX-21437), Sofosbuvir, AL-335, GS-0938, Mericitabine, BCX-5191, IDX-184, ALS-2200(VX-135), ALS-2158, TMC649128, VX-222, ABT-072, ABT-333,
Deleobuvir (BI-207127), Tegobuvir (GS-9190), Setrobuvir (ANA-598), CC-31244, Filibuvir (PF-868554), VCH-916, VCH-759, BMS-791325, TMC-647055, TKM-HCV, or a pharmaceutically salt thereof.

### Claim 5 (depends on 4)

The method according to claim 4, wherein R is a 5′-3′ anti-miR-122 oligonucleotide and wherein the anti-miR-122 oligonucleotide comprises at least one modified internucleoside linkage, modified sugar moiety, or modified nucleobase.

### Claim 6 (depends on 4)

The method according to claim 4, wherein R is a 5′-3′ anti-miR-122 oligonucleotide and wherein the anti-miR-122 oligonucleotide.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the LAP pharmaceutical composition further comprises a surfactant system.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the surfactant system comprises a surfactant in an amount ranging from about 0.1% (w/v) to about 10% (w/v) surfactant, about 1% (w/v) to about 8% (w/v) surfactant, or about about 2% (w/v) surfactant.

### Claim 9 (depends on 7)

The method according to claim 7, wherein the surfactant system comprises a surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, poloxamers, sorbitan esters of fatty acids (SPAN), polyethoxylated castor oil and its derivatives, tocopheryl polyethylene glycol succinate, and polyvinyl alcohols.

### Claim 10 (depends on 7)

The method according to claim 7, wherein the surfactant system comprises a surfactant that is polysorbate 20, polysorbate 80 or polyethylene glycol.

### Claim 11 (depends on 7)

The method according to claim 7, wherein the surfactant system comprises a stabilizer that is selected from the group consisting of polyethylene glycols, carboxymethylcellulose calcium, Carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose, polysaccharides, hyarluronic acid, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP).

### Claim 12 (depends on 7)

The method according to claim 7, wherein the surfactant system comprises a stabilizer that is PEG-3350.

### Claim 13 (depends on 7)

The method according to claim 7, wherein the surfactant system comprises a stabilizer in an amount that ranges from about 1% (w/v) to about 5% (w/v) stabilizer or about 2% (w/v) stabilizer.

### Claim 14 (depends on 7)

The method according to claim 7, wherein the surfactant system comprises a buffer salt at a concentration of about 10 mM.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the surfactant system comprises a buffer salt that is acetate buffered saline.

### Claim 16 (depends on 1)

The method according to claim 1, the LAP HCV active agent of claim 1 is in a crystalline form.

### Claim 17 (depends on 1, 16)

The method according to claim 16, wherein the LAP HCV active agent of claim 1 is in a crystalline microparticle form.

### Claim 18 (depends on 1, 17)

The method according to claim 17, wherein the LAP HCV active agent of claim 1 is in a crystalline microparticle form and wherein the crystalline microparticles of a LAP HCV active agent range in size from about 0.05 μm to about 100 μm, or from about 0.1 μm to about 5 μm.

### Claim 19 (depends on 1, 16)

The method according to claim 16, wherein the LAP HCV active agent of claim 1 in the crystalline form prior to encapsulating into a microparticle and combining with a surfactant system.

### Claim 20 (depends on 1, 19)

The method according to claim 19, wherein the LAP HCV active agent of claim 1 is encapsulated in a polymer.

### Claim 21 (depends on 1, 20)

The method according to claim 20, wherein the LAP HCV active agent of claim 1 is encapsulated in a polymer that comprises poly (lactic-co-glycolic) acid.

### Claim 22 (depends on 1)

The method according to claim 1, wherein the human is administered the LAP pharmaceutical composition comprising the LAP HCV active agent of claim 1, on a dosing regimen ranging from about every week to about every three months, on a dosing regimen ranging from about every week to about every two months, on a dosing regimen that is monthly, on a dosing regimen that is only one to two administrations or on a dosing regimen that is only one administration.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the administration comprises an injection.

### Claim 24 (depends on 23)

The method according to claim 23, wherein the administration comprises an intramuscular injection.