Antisense oligonucleotide compositions

Abstract

The present disclosure provides compositions comprising an antisense oligonucleotide and one or more excipients that modulates viscosity, turbidity or both viscosity and turbidity. In certain embodiments, compositions comprising an antisense oligonucleotide and one or more excipients having low viscosity are provided. In certain embodiments, compositions comprising an antisense oligonucleotide and one or more excipients having low turbidity are provided. In certain embodiments, pharmaceutical compositions comprising an antisense oligonucleotide and one or more excipients having low viscosity and turbidity are provided.

1 .- 275 . (canceled) 
     
     
         276 . A compound comprising a modified oligonucleotide 20 linked nucleosides in length complementary to target nucleic acid apolipoprotein (a) and having a nucleobase sequence consisting of the sequence recited in SEQ ID NO:3, wherein the modified oligonucleotide comprises:
 a gap segment consisting often linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar.   
     
     
         277 . The compound of  claim 276 , wherein the modified oligonucleotide is at least 90%, at least 95% or 100% complementary to the target nucleic acid apolipoprotein (a). 
     
     
         278 . The compound of  claim 276 , wherein at least one internucleoside linkage is a phosphorothioate linkage. 
     
     
         279 . The compound of  claim 278 , wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
         280 . The compound of  claim 276 , wherein each cytosine residue is a 5-methylcytosine. 
     
     
         281 . A compound comprising a modified oligonucleotide 20 linked nucleosides in length complementary to target nucleic acid apolipoprotein (a) and having a nucleobase sequence consisting of the sequence recited in SEQ ID NO:3, wherein the modified oligonucleotide comprises:
 a gap segment consisting often linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides;   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein at least one internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         282 . A composition comprising a compound of  claim 276 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         283 . A composition comprising a compound of  claim 281 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         284 . The composition of  claim 282 , wherein the compound is present in a therapeutically effective amount for preventing, alleviating or ameliorating coronary artery disease (CAD). 
     
     
         285 . The composition of  claim 283 , wherein the compound is present in a therapeutically effective amount for preventing, alleviating or ameliorating coronary artery disease (CAD). 
     
     
         286 . The composition of  claim 282 , wherein the pharmaceutically acceptable carrier or diluent is sterile saline or sterile water. 
     
     
         287 . The composition of  claim 283 , wherein the pharmaceutically acceptable carrier or diluent is sterile saline or sterile water. 
     
     
         288 . An aqueous solution comprising the compound of  claim 276  and at least one excipient that modulates viscosity, turbidity or both viscosity and turbidity, wherein the dynamic viscosity of the solution is less than 40 cP at 25° C. 
     
     
         289 . An aqueous solution comprising the compound of  claim 281  and at least one excipient that modulates viscosity, turbidity or both viscosity and turbidity, wherein the dynamic viscosity of the solution is less than 40 cP at 25° C. 
     
     
         290 . The solution of  claim 288 , wherein at least one of the excipients that modulates viscosity, turbidity or both viscosity and turbidity is selected from the group consisting of Adenine, Benzyl Alcohol, m-Cresol, Cytidine, Cytidine Monophosphate, Cytosine, Dextran, Guanine Monophosphate, D-Mannitol, Methylparaben, Nicotinamide, Phenol, 2-Phenoxyethanol, L-Phenylalanine, Pyridoxine, Sodium Chloride, Thymine, tryptophan, L-Tryptophan, L-Tyrosine, Ascorbic Acid, Benzamide, o-Benzenediol, Benzenehexol, L-Histidine, Hydroxypyridine, Indole, D-Mannitol+Phenol mixture, D-Mannitol+Pyridine mixture, 2H-Pyran, Pyrazinamide, Pyridine, Pyrimidine, 2-Pyrone, Riboflavin, Thiamine, Tryptamine, ethanol, (2-Hydroxypropyl)-β-cyclodextrin, Niacin, Polyethylene Glycol 600, Polyethylene Glycol 4600, Propylene Glycol, Pyridoxine, Sucrose, Thymidine, Tween 80, Uridine, Thymine, caffeine, acridine orange, ethidium bromide, propidium iodide, cyanine dyes such as PicoGreen®, thiamine hydrochloride, ethylene diamine tetraacetic acid, 1,2-dihydroxybenzene, 1,2-dihydroxybenzene (catechol), D-Mannitol+phenol mixture, D-Mannitol+niacinamide mixture, calcium folinate, L-phenylalanine+pyridoxine mixture, pyridoxine+benzyl alcohol mixture, pyridoxine HCl+benzyl alcohol mixture, niacin sodium salt, dextran 1500, and pyridoxine HCl+phenylalanine mixture. 
     
     
         291 . The solution of  claim 289 , wherein at least one of the excipients that modulates viscosity, turbidity or both viscosity and turbidity is selected from the group consisting of Adenine, Benzyl Alcohol, m-Cresol, Cytidine, Cytidine Monophosphate, Cytosine, Dextran, Guanine Monophosphate, D-Mannitol, Methylparaben, Nicotinamide, Phenol, 2-Phenoxyethanol, L-Phenylalanine, Pyridoxine, Sodium Chloride, Thymine, tryptophan, L-Tryptophan, L-Tyrosine, Ascorbic Acid, Benzamide, o-Benzenediol, Benzenehexol, L-Histidine, Hydroxypyridine, Indole, D-Mannitol+Phenol mixture, D-Mannitol+Pyridine mixture, 2H-Pyran, Pyrazinamide, Pyridine, Pyrimidine, 2-Pyrone, Riboflavin, Thiamine, Tryptamine, ethanol, (2-Hydroxypropyl)-β-cyclodextrin, Niacin, Polyethylene Glycol 600, Polyethylene Glycol 4600, Propylene Glycol, Pyridoxine, Sucrose, Thymidine, Tween 80, Uridine, Thymine, caffeine, acridine orange, ethidium bromide, propidium iodide, cyanine dyes such as PicoGreen®, thiamine hydrochloride, ethylene diamine tetraacetic acid, 1,2-dihydroxybenzene, 1,2-dihydroxybenzene (catechol), D-Mannitol+phenol mixture, D-Mannitol+niacinamide mixture, calcium folinate, L-phenylalanine+pyridoxine mixture, pyridoxine+benzyl alcohol mixture, pyridoxine HCl+benzyl alcohol mixture, niacin sodium salt, dextran 1500, and pyridoxine HCl+phenylalanine mixture. 
     
     
         292 . The solution of  claim 290 , wherein at least one of the excipients that modulates viscosity, turbidity or both viscosity and turbidity is sodium chloride. 
     
     
         293 . The solution of  claim 291 , wherein at least one of the excipients that modulates viscosity, turbidity or both viscosity and turbidity is sodium chloride.