Pulmonary Surfactant Formulations
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.
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 .