Diketopiperazine microparticles with defined isomer contents
View Patent ↗Disclosed herein are fumaryl diketopiperazine (FDKP) compositions and microparticles having a specific trans isomer content of about 45% to about 65%. The FDKP microparticles can comprise a drug such as an endocrine hormone, including, peptide, including, insulin, glucagon, parathyroid hormones and the like and can be used to make a powder formulation for pulmonary delivery of the drug.
1. A fumaryl diketopiperazine (FDKP) composition comprising a trans isomer content of about 45% to about 65%.
2. The FDKP composition according to claim 1 , wherein said trans isomer content is from about 50% to about 65%.
3. The FDKP composition according to claim 1 , wherein said trans isomer content is from about 53% to about 63%.
4. Fumaryl diketopiperazine (FDKP) microparticles comprising the FDKP composition of claim 1 .
5. FDKP microparticles according to claim 4 , wherein said trans isomer content is from about 50% to about 65%.
6. FDKP microparticles according to claim 4 , wherein said trans isomer content is from about 53% to about 63%.
7. FDKP microparticles according to claim 4 , further comprising a drug or an active agent.
8. FDKP microparticles according to claim 7 , wherein said drug or active agent is a peptide or protein.
9. FDKP microparticles according to claim 8 , wherein said peptide is an endocrine hormone.
10. FDKP microparticles according to claim 9 , wherein said endocrine hormone is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, an analog or active fragment of said endocrine hormone.
11. The microparticles of claim 4 , wherein the drug is present in an amount greater than 0.01 wt % of the microparticles.
12. A dry powder comprising the microparticles of claim 4 .
13. A dry powder comprising the microparticles of claim 7 .
14. A method of treating an endocrine-related disease or disorder comprising administering to a person in need thereof a dry powder formulation comprising fumaryl diketopiperazine (FDKP) microparticles comprising an FDKP trans isomer content of about 45% to about 65% and an endocrine hormone suitable to treat said disease or disorder.
15. The method of claim 14 , wherein the endocrine hormone is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, or an analog of said endocrine hormone.
16. The method of claim 14 , wherein the endocrine-related disease is diabetes.
17. A method of making microparticles suitable for pulmonary administration as a dry powder comprising:
a) synthesizing an FDKP compound having an FDKP trans isomer content of about 45% to about 65%;
b) dissolving the FDKP compound in a solution having a basic pH to form an FDKP solution;
c) providing a solution of a volatile acid, and
d) mixing the solutions together in a high-shear mixer to produce said microparticles in a suspension.
18. The method of claim 17 , further comprising determining the trans isomer content of the FDKP.
19. The method of claim 18 , wherein the step of determining the trans isomer content of the FDKP is performed using high pressure liquid chromatography.
20. The method of claim 17 , further comprising mixing said microparticles with a solution comprising a drug.
21. The method of claim 17 , wherein the drug is an endocrine hormone.
22. The method of claim 21 , wherein the drug is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, or an analog of said drug.
23. A method for synthesizing a diketopiperazine having a trans isomer content of about 45% to about 65% comprising:
a) saponifying an ester of a diketopiperazine in a mixture of water and a water-miscible solvent at a basic pH; and
b) recrystallizing the diketopiperazine in a reaction mixture comprising trifluoroacetic acid and glacial acid at a resultant ratio ranging from about 0.4 to about 0.7.
24. The method of claim 23 , wherein the water-miscible solvent is an alcohol, tetrahydrofuran, dioxane, and acetonitrile.
25. The method of claim 24 , wherein the alcohol is methanol, ethanol, or isopropanol.
26. The method of claim 25 , wherein the methanol is in a water:methanol ratio ranging from 1:1 to about 3:1.
27. The method of claim 23 , further comprising the step of determining the trans isomer content of the diketopiperazine.
28. The method of claim 23 , wherein the diketopiperazine is of the formula 2,5-diketo-3,6-bis(N—X-4-aminobutyl)piperazine, wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, and glutaryl.
29. The method of claim 23 , wherein the diketopiperazine is 2,5-diketo-3,6-bis(N-fumaryl-4-aminobutyl)piperazine.
30. The method of claim 23 , wherein the reaction mixture in the recrystallizing step is held for a period of about 4 hours or greater than 4 hours.