Stabilized vancomycin formulations
In one aspect, the invention provides a stabilized lipid-based glycopeptide antibiotic composition and a process for producing the same. In another aspect, the invention provides methods for treating a bacterial pulmonary infection by administering to a subject in need thereof a therapeutically effective amount of the stabilized lipid-based glycopeptide antibiotic composition.
1. A stabilized lipid-based glycopeptide antibiotic composition comprising:
a lipid component;
a glycopeptide antibiotic; and
an amino acid or a derivative thereof selected from the group consisting of gamma-aminobutyric acid (GABA), D-alanine (D-ALA), D-glutamic acid (D-GLU), aspartic acid (ASP), D-aspartic acid (D-ASP), bicine, tricine, iminodiacetic acid (IDAA), glycylgiycine (Gly-Gly), and glutamic acid (GLU),
wherein the amino acid or the derivative thereof reduces the degradation rate of the glycopeptide antibiotic.
2. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the amino acid or the derivative thereof binds to the glycopeptide antibiotic and forms a stabilized glycopeptide antibiotic-amino acid complex and wherein the stabilized glycopeptide antibiotic-amino acid complex is entrapped by the lipid component.
3. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the antibiotic composition is at least 44% more stable or at least 77% more stable, or at least 88% more stable, than an antibiotic composition comprising the same lipid component and the same glycopeptide antibiotic component, that does not comprise the amino acid or the derivative thereof.
4. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the composition produces product degradants at a rate less than 0.05% by weight per week at 4° C., or a rate less than 0.02% by weight per week at 4° C., or a rate less than 0.01% by weight per week at 4° C.
5. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the lipid component comprises a phospholipid.
6. The stabilized lipid-based glycopeptide antibiotic composition according to claim 5 , wherein the phospholipid is selected from the group consisting of phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), and a mixture thereof.
7. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the lipid component comprises a sterol.
8. The stabilized lipid-based glycopeptide antibiotic composition according to claim 7 , wherein the sterol is cholesterol.
9. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the lipid component comprises a phospholipid and a sterol.
10. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the lipid component comprises dipalmitoylphosphatidylcholine (DPPC).
11. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the lipid component comprises dipalmitoylphosphatidylcholine (DPPC) and cholesterol.
12. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the lipid component comprises dipalmitoylphosphatidylglycerol (DPPG).
13. The stabilized lipid-based glycopeptide antibiotic composition according to a claim 1 , wherein the lipid component comprises dipalmitoylphosphatidylglycerol (DPPG) and cholesterol.
14. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the lipid component comprises dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), and cholesterol.
15. The stabilized lipid-based glycopeptide antibiotic composition according to claim 2 , wherein the lipid component is a liposome, a lipid clathrate or a proliposome.
16. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein the glycopeptide antibiotic is vancomycin.
17. The stabilized lipid-based glycopeptide antibiotic composition according to claim 1 , wherein a molar ratio of the glycopeptide antibiotic to the amino acid or derivative thereof is from about 1:1 to about 1:4, from about 1:1 to about 1:2, about 1:1 or about 1:2.
18. A method for treating a bacterial infection in a patient in need thereof, the method comprising administering to the patient, a therapeutically effective amount of a stabilized lipid-based glycopeptide antibiotic composition comprising a lipid component, a glycopeptide antibiotic, and an amino acid or derivative thereof, wherein the amino acid or the derivative thereof is selected from the group consisting of gamma-aminobutyric acid (GABA), D-alanine (D-ALA), D-glutamic acid (D-GLU), aspartic acid (ASP), D-aspartic acid (D-ASP), bicine, tricine, iminodiacetic acid (IDAA), glycylgiycine (Gly-Gly), and glutamic acid (GLU) and the amino acid or the derivative thereof reduces the degradation rate of the glycopeptide antibiotic.