Lipid formulations for nucleic acid delivery

Abstract

The present invention provides novel, stable lipid particles comprising one or more active agents or therapeutic agents, methods of making the lipid particles, and methods of delivering and/or administering the lipid particles. More particularly, the present invention provides stable nucleic acid-lipid particles (SNALP) comprising a nucleic acid (such as one or more interfering RNA), methods of making the SNALP, and methods of delivering and/or administering the SNALP.

1 - 46 . (canceled) 
     
     
         47 . A nucleic acid-lipid particle comprising:
 (a) an RNA;   (b) a cationic lipid;   (e) a mixture of a phospholipid and cholesterol comprising up to 55 mol % of the total lipid present in the particle, wherein the phospholipid comprises from 10 mol to 30 mol % of the total lipid present in the particle and the cholesterol comprises from 25 mol % to 45 mol % of the total lipid present in the particle; and   (d) a conjugated lipid that inhibits aggregation of particles comprising 0.1 mol % to 2 mol % of the total lipid present in the particle.   
     
     
         48 . The nucleic acid-lipid particle of  claim 47 , wherein the phospholipid comprises from 15 mol % to 25 mol % of the total lipid present in the particle. 
     
     
         49 . The nucleic acid-lipid particle of  claim 47 , wherein cholesterol comprises from 35 mol % to 45 mol % of the total lipid present in the particle. 
     
     
         50 . The nucleic acid-lipid particle of  claim 47 , wherein the conjugated lipid that inhibits aggregation of particles comprises from 0.5 mol % to 2 mol % of the total lipid present in the particle. 
     
     
         51 . The nucleic acid-lipid particle of  claim 47 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid conjugate. 
     
     
         52 . The nucleic acid-lipid particle of  claim 51 , wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof. 
     
     
         53 . The nucleic acid-lipid particle of  claim 51 , wherein the PEG has an average molecular weight of about 2,000 daltons. 
     
     
         54 . The nucleic acid-lipid particle of  claim 51 , wherein the PEG has a terminal methoxy group. 
     
     
         55 . The nucleic acid-lipid particle of  claim 47 , wherein the RNA is fully encapsulated in the nucleic acid-lipid particle. 
     
     
         56 . A pharmaceutical composition comprising a nucleic acid-lipid particle of  claim 47  and a pharmaceutically acceptable carrier. 
     
     
         57 . The nucleic acid-lipid particle of  claim 47 , wherein the RNA comprises an mRNA. 
     
     
         58 . The nucleic acid-lipid particle of  claim 57 , wherein the phospholipid comprises from 15 mol % to 25 mol % of the total lipid present in the particle. 
     
     
         59 . The nucleic acid-lipid particle of  claim 57 , wherein cholesterol comprises from 35 mol % to 45 mol % of the total lipid present in the particle. 
     
     
         60 . The nucleic acid-lipid particle of  claim 57 , wherein the conjugated lipid that inhibits aggregation of particles comprises from 0.5 mol % to 2 mol % of the total lipid present in the particle. 
     
     
         61 . The nucleic acid-lipid particle of  claim 57 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid conjugate. 
     
     
         62 . The nucleic acid-lipid particle of  claim 61 , wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof. 
     
     
         63 . The nucleic acid-lipid particle of  claim 61 , wherein the PEG has an average molecular weight of about 2,000 daltons. 
     
     
         64 . The nucleic acid-lipid particle of  claim 61 , wherein the PEG has a terminal methoxy group. 
     
     
         65 . The nucleic acid-lipid particle of  claim 57 , wherein the mRNA is fully encapsulated in the nucleic acid-lipid particle. 
     
     
         66 . A pharmaceutical composition comprising a nucleic acid-lipid particle of  claim 57  and a pharmaceutically acceptable carrier.