Pulmonary Surfactant Formulations

Abstract

Synthetic pulmonary surfactant compositions comprising dipalmitoyl phosphatidylcholine, phosphatidylglycerol, and essentially neutral lipid, and having essentially no 1-palmitoyl 2-oleoyl phosphatidylglycerol and essentially no palmitic acid are provided. Methods for treating respiratory disease are also provided comprising administering a therapeutically effective amount of a synthetic pulmonary surfactant comprising dipalmitoyl phosphatidylcholine, phosphatidylglycerol, and essentially neutral lipid, and having essentially no 1-palmitoyl 2-oleoyl phosphatidylglycerol and essentially no palmitic acid.

What is claimed: 
     
         1 . A synthetic pulmonary surfactant comprising dipalmitoyl phosphatidylcholine, phosphatidylglycerol, and essentially neutral lipid, and having essentially no 1-palmitoyl 2-oleoyl phosphatidylglycerol and essentially no palmitic acid. 
     
     
         2 . The pulmonary surfactant of  claim 1 , wherein the phosphatidylglycerol is saturated, non-saturated or semi-saturated. 
     
     
         3 . The pulmonary surfactant of  claim 2 , wherein the saturated phosphatidylglycerol is dipalmitoyl phosphatidylglycerol. 
     
     
         4 . The pulmonary surfactant of  claim 1 , wherein each of 1-palmitoyl 2-oleoyl phosphatidylglycerol and palmitic acid are present in an amount less than about five mole percent of total phospholipid. 
     
     
         5 . The pulmonary surfactant of  claim 1 , wherein essentially neutral lipid comprises cholesterol. 
     
     
         6 . The pulmonary surfactant of  claim 1 , wherein essentially neutral lipid comprises a fatty acid, a fatty acid ester, a fatty acid alcohol, cholesterol, corticosteroid, glucocorticosteroid, trifluorinate glucocorticoid, agonist, plant sterol, phospholipid, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidylinositol, sphingomyelin, diglycerides, diolein, dipalmitolein, mixed caprylin-caprin, triglycerides, triolein, tripalmitolein, trilinolein, tricaprylin, or trilaurin. 
     
     
         7 . The pulmonary surfactant of  claim 5 , wherein the cholesterol concentration is from about 0.1 mol % to about 50 mol %. 
     
     
         8 . The pulmonary surfactant of  claim 5 , wherein the cholesterol concentration is from about 1 mol % to about 20 mol %. 
     
     
         9 . The pulmonary surfactant of  claim 5 , wherein the cholesterol concentration is cholesterol concentration from about 8 mol % to about 15 mol %. 
     
     
         10 . The pulmonary surfactant of  claim 3 , wherein the molar ratio of dipalmitoyl phosphatidylcholine to dipalmitoyl phosphatidylglycerol is 4 to 1. 
     
     
         11 . The pulmonary surfactant of  claim 3 , wherein the molar ratio of dipalmitoyl phosphatidylcholine to dipalmitoyl phosphatidylglycerol is 7 to 3. 
     
     
         12 . The pulmonary surfactant of  claim 3 , wherein the molar ratio of dipalmitoyl phosphatidylcholine to dipalmitoyl phosphatidylglycerol is 3 to 1. 
     
     
         13 . The pulmonary surfactant of  claim 1 , wherein the total concentration of dipalmitoyl phosphatidylcholine and phosphatidylglycerol is from about 10 mg/ml to about 150 mg/ml. 
     
     
         14 . The pulmonary surfactant of  claim 13 , wherein the total concentration of dipalmitoyl phosphatidylcholine and phosphatidylglycerol is from about 50 mg/ml to about 125 mg/ml. 
     
     
         15 . The pulmonary surfactant of  claim 1 , wherein a dynamic surface tension of the surfactant as measured by pulsating bubble surface tensionometry is about 10 mN or less. 
     
     
         16 . The pulmonary surfactant of  claim 1 , further comprising a surfactant polypeptide. 
     
     
         17 . The pulmonary surfactant of  claim 16 , wherein the surfactant polypeptide comprises at least 10 amino acid residues and no more than about 60 amino acid residues, the polypeptide including a sequence having alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z a  U b ) c  Z a , wherein:
 Z is a hydrophilic amino acid residue independently selected from the group consisting of R and K;   U is a hydrophobic amino acid residue independently selected from the group consisting of L and C;   a is 1 or 2;   b has an average value of about 3 to about 8;   c is 1 to 10; and   d is 0 to 2.   
     
     
         18 . The pulmonary surfactant of  claim 17 , having an amino acid residue sequence represented by the formula: KLLLLKLLLLKLLLLKLLLLK. 
     
     
         19 . A synthetic pulmonary surfactant consisting essentially of dipalmitoyl phosphatidylcholine, non-saturated phosphatidylglycerol, essentially neutral lipid and surfactant polypeptide. 
     
     
         20 . The pulmonary surfactant of  claim 19 , wherein the non-saturated phosphatidylglycerol is palmitoyl oleyl phosphatidylglycerol. 
     
     
         21 . The pulmonary surfactant of  claim 19 , wherein the essentially neutral lipid is cholesterol. 
     
     
         22 . The pulmonary surfactant of  claim 19 , wherein the surfactant polypeptide has an amino acid residue sequence represented by the formula: KLLLLKLLLLKLLLLKLLLLK. 
     
     
         23 . A synthetic pulmonary surfactant consisting essentially of dipalmitoyl phosphatidylcholine, nonsaturated phosphatidylglycerol, palmitic acid, essentially neutral lipid and surfactant polypeptide. 
     
     
         24 . The surfactant of  claim 23 , wherein the nonsaturated phosphatidylglycerol is palmitoyl oleyl phosphatidylglycerol 
     
     
         25 . The pulmonary surfactant of  claim 23 , wherein the neutral lipid is cholesterol. 
     
     
         26 . The pulmonary surfactant of  claim 23 , wherein the surfactant polypeptide has an amino acid residue sequence represented by the formula: KLLLLKLLLLKLLLLKLLLLK. 
     
     
         27 . A synthetic pulmonary surfactant consisting essentially of dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, essentially neutral lipid and surfactant polypeptide. 
     
     
         28 . The pulmonary surfactant of  claim 27 , wherein essentially neutral lipid is cholesterol. 
     
     
         29 . The pulmonary surfactant of  claim 27  wherein essentially neutral lipid comprises a fatty acid, a fatty acid ester, a fatty acid alcohol, cholesterol, corticosteroid, glucocorticosteroid, trifluorinate glucocorticoid, β2 agonist, plant sterol, phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, diglycerides, fatty alcohols, diolein, dipalmitolein, mixed caprylin-caprin, triglycerides, triolein, tripalmitolein, trilinolein, tricaprylin, or trilaurin. 
     
     
         30 . The pulmonary surfactant of  claim 27  wherein the surfactant polypeptide comprises at least 10 amino acid residues and no more than about 60 amino acid residues, the polypeptide including a sequence having alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z a  U b ) c  Z d , wherein:
 Z is a hydrophilic amino acid residue independently selected from the group consisting of R and K; 
 U is a hydrophobic amino acid residue independently selected from the group consisting of L and C; 
 a is 1 or 2; 
 b has an average value of about 3 to about 8; 
 c is 1 to 10; and 
 d is 0 to 2. 
 
     
     
         31 . The pulmonary surfactant of  claim 30 , having an amino acid residue sequence represented by the formula: KLLLLKLLLLKLLLLKLLLLK. 
     
     
         32 . A synthetic pulmonary surfactant consisting of dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, and essentially neutral lipid. 
     
     
         33 . The pulmonary surfactant of  claim 32 , wherein essentially neutral lipid comprises cholesterol. 
     
     
         34 . The pulmonary surfactant of  claim 32 , wherein essentially neutral lipid comprises a fatty acid, a fatty acid ester, a fatty acid alcohol, cholesterol, corticosteroid, glucocorticosteroid, trifluorinate glucocorticoid, β2 agonist, plant sterol, phospholipid, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidylinositol, sphingomyelin, diglycerides, diolein, dipalmitolein, mixed caprylin-caprin, triglycerides, triolein, tripalmitolein, trilinolein, tricaprylin, or trilaurin. 
     
     
         35 . A method of treating infant respiratory distress syndrome comprising administering a therapeutically effective amount of a synthetic pulmonary surfactant comprising dipalmitoyl phosphatidylcholine, phosphatidylglycerol, and essentially neutral lipid, and having essentially no 1-palmitoyl 2-oleoyl phosphatidylglycerol and essentially no palmitic acid. 
     
     
         36 . The method of  claim 35 , wherein the phosphatidylglycerol is saturated, non-saturated or semi-saturated. 
     
     
         37 . The method of  claim 36 , wherein the saturated phosphatidylglycerol is dipalmitoyl phosphatidylglycerol. 
     
     
         38 . The method of  claim 35 , wherein essentially neutral lipid comprises cholesterol. 
     
     
         39 . The method of  claim 35 , wherein essentially neutral lipid comprises a fatty acid, a fatty acid ester, a fatty acid alcohol, cholesterol, corticosteroid, plant sterol, phospholipid, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidylinositol, sphingomyelin, diglycerides, diolein, dipalmitolein, mixed caprylin-caprin, triglycerides, triolein, tripalmitolein, trilinolein, tricaprylin, or trilaurin. 
     
     
         40 . A method of treating infant respiratory distress syndrome comprising administering a therapeutically effective amount of a synthetic pulmonary surfactant, the surfactant consisting essentially of dipalmitoyl phosphatidylcholine, phosphatidylglycerol, essentially neutral lipid and a surfactant polypeptide, the polypeptide having alternating hydrophobic and hydrophilic amino acid residue regions, represented by the formula (Z a  U b ) c  Z d , wherein:
 Z is a hydrophilic amino acid residue independently selected from the group consisting of R and K;   U is a hydrophobic amino acid residue independently selected from the group consisting of L and C;   a is 1 or 2;   b has an average value of about 3 to about 8;   c is 1 to 10; and   d is 0 to 2.   
     
     
         41 . The method of  claim 40 , wherein the phosphatidylglycerol is saturated, non-saturated or semi-saturated. 
     
     
         42 . The method of  claim 41 , wherein the saturated phosphatidylglycerol is dipalmitoyl phosphatidylglycerol. 
     
     
         43 . The method of  claim 40 , wherein essentially neutral lipid comprises cholesterol. 
     
     
         44 . The method of  claim 40 , wherein the polypeptide has an amino acid residue sequence represented by the formula: KLLLLKLLLLKLLLLKLLLLK. 
     
     
         45 . A method of treating respiratory distress syndrome comprising administering a therapeutically effective amount of a synthetic pulmonary surfactant comprising dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, and essentially neutral lipid, and having essentially no 1-palmitoyl 2-oleoyl phosphatidylglycerol and essentially no palmitic acid. 
     
     
         46 . A method of treating respiratory distress syndrome comprising administering a therapeutically effective amount of a synthetic pulmonary surfactant, the surfactant comprising one or more pharmaceutically acceptable phospholipids admixed with a polypeptide having alternating hydrophobic and hydrophilic amino acid residue regions, represented by the formula (Z a  U b ) c  Z d , wherein:
 Z is a hydrophilic amino acid residue independently selected from the group consisting of R and K;   U is a hydrophobic amino acid residue independently selected from the group consisting of L and C;   a is 1 or 2;   b has an average value of about 3 to about 8;   c is 1 to 10; and   d is 0 to 2.   
     
     
         47 . The method of  claim 46 , wherein the polypeptide has an amino acid residue sequence represented by the formula: KLLLLKLLLLKLLLLKLLLLK. 
     
     
         48 . A method of manufacturing a synthetic pulmonary surfactant comprising terminally sterilizing the surfactant of  claim 1  by autoclaving. 
     
     
         49 . A method for drug delivery to the pulmonary system comprising administering to a patient in need of treatment an effective amount of a synthetic pulmonary surfactant of  claim 1 , wherein the microparticles have a diameter between 0.5 microns and 5 microns and viscosity less than 6 cp at a cholesterol concentration from about 8 mole % to about 15 mole %, in a pharmaceutically acceptable carrier for administration to the lungs. 
     
     
         50 . A method for reducing viscosity of a drug delivery formulation to the pulmonary system comprising adding cholesterol at a concentration from about 8 mol % to about 15 mol % to the synthetic pulmonary surfactant of  claim 1 . 
     
     
         51 . A method for increasing aerosolization of a drug delivery formulation to the pulmonary system comprising adding cholesterol at a concentration from about 8 mol % to about 15 mol % to the synthetic pulmonary surfactant of  claim 1 . 
     
     
         52 . A method for increasing storage stability of a drug delivery formulation to the pulmonary system comprising adding cholesterol at a concentration from about 8 mol % to about 15 mol % to the synthetic pulmonary surfactant of  claim 1 .