Method for making self-assembling diketopiperazine drug delivery system

• US 5,503,852 A
• Filed: 09/01/1994
• Issued: 04/02/1996
• Est. Priority Date: 03/11/1992
• Status: Expired due to Term

• Current Assignee: Mannkind Corporation
• Original Assignee: Pharmaceutical Discovery Corporation (Mannkind Corporation)
• Inventors: McCabe, R. Tyler, Steiner, Solomon S., Rhodes, Christopher A., Shen, Gregory S.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/299,842
• Time in Patent Office: 579 Days
• Field of Search: 424/493, 424/489, 424/490
• US Class Current: 424/493
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats

Abstract

Drug delivery systems have been developed based on the formation of diketopiperazine (or analogs) microparticles. In the preferred embodiment the microparticle is stable at low pH and disintegrates at physiological pH, and is particularly useful for oral drug delivery. In other embodiments, the microparticles are stable at high pH and disintegrate at neutral or basic pH, or are stable at neutral pH and disintegrate at high or low pH. In the most preferred embodiment the microparticles are formed in the presence of the drug to be delivered, for example, insulin, felbamate, calcitonin or heparin. The diketopiperazine synthetic intermediates are preferably formed by cyclodimerization to form diketopiperazine derivatives at elevated temperatures under dehydrating conditions, functionalized on the side chains, and then precipitated with drug to be incorporated into microparticles.

Claims

1. A microparticulate system for drug delivery comprising:

diketopiperazine microparticles, wherein the microparticles are stable at a first defined pH due to association and precipitation of the diketopiperazines and unstable at a second defined pH due to dissociation of the diketopiperazines, and

wherein the diketopiperazine has the general structure ##STR3## Wherein n is between 0 and 7, Q is, independently, a C_1-20 straight, branched or cyclic alkyl, aralkyl, alkaryl, alkenyl, alkynyl, heteroalkyl, heterocyclic, alkyl-heterocyclic, or heterocyclic-alkyl;

T is --C(O)O, --OC(O), --C(O)NH, --NH, --NQ, --OQO, --O, --NHC(O), --OP(O), --P(O)O, --OP(O)₂, --P(O)₂ O, --OS(O)₂, or --S(O)₃ ;

U is an acid group, a basic group or a zwitterionic C_1-2 0 chain containing at least one acidic group and at least one basic group, wherein the side chains can be further functionalized with an alkene or alkyne group at any position, one or more of the carbons on the side chain can be replaced with an oxygen, one or more of the carbons can be functionalized with an acidic or basic group, and wherein the ring atoms X at positions 1 and 4 are either O or N.

2. The system of claim 1 wherein Q is selected from the group consisting of cis and trans --CH═

CH--CO₂ H, --CH(NHC(O)CF₃ )--CH₂ --CO₂ H, --CH(NH₂)--CH₂ --CO₂ H, --CH(CH₃)═

CH(CH₃)--CO₂ H, --(CH₂)₃ --CO₂ H, --CH₂ CH(CH₃)--CO₂ H, --CH(CH₂ CO₂ H)═

CH₂, -(tetrafluoro)benzoic acid, and -benzoic acid.

3. The system of claim 1 wherein the diketopiperazine is formed from amino acids selected from the group consisting of glutamic acid, aspartic acid, lysine, asparagine, ornithine and diaminopropionic acid.

4. The system of claim 3 wherein the structure is selected from the group consisting of 2,5-diketo-3,6-di(fumarylaminobutyl)piperazine, 2,5-diketo-3,6-di(glutarylaminobutyl)piperazine and 2,5-diketo-3,6-di(4-maleylaminobutyl)piperazine.

5. The system of claim 1 wherein the microparticles are stable at acidic pH and unstable at a more basic pH.

6. The system of claim 1 wherein the microparticles are unstable at acidic pH and stable at a more basic pH.

7. The system of claim 1 wherein the microparticles are stable at neutral pH and unstable at acidic and basic pH.

8. The microparticles of claim 1 further comprising a biologically active agent selected from the group consisting of proteins, peptides, polysaccharides, lipids, lipopolysaccharides, nucleic acids and other biologically active organic molecules.

9. The system of claim 8 wherein the biological agent is selected from the group consisting of insulin, calcitonin, felbamate, heparin, parathyroid hormone and fragments thereof, growth hormone, erythropoietin, AZT, DDI, G CSF, lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β

-galactosidase and Argatroban.

13. The method of claim 9 wherein the structure is selected from the group consisting of 2,5-diketo-3,6-di(fumarylaminobutyl)piperazine, 2,5-diketo-3,6-di(glutarylaminobutyl)piperazine and 2,5-diketo-3,6-di(4-maleylaminobutyl)piperazine.

10. A method for making a microparticulate system for drug delivery comprising:

forming diketopiperazines in a solution with a first defined pH, adding a solution having a second defined pH, and precipitating the diketopiperazines to form microparticles, wherein the diketopiperazine has the general structure ##STR4## Wherein n is between 0 and 7, Q is, independently, a C_1-20 straight, branched or cyclic alkyl, aralkyl, alkaryl, alkenyl, alkynyl, heteroalkyl, heterocyclic, alkyl-heterocyclic, or heterocyclic-alkyl;

T is --C(O)O, --OC(O), --C(O)NH, --NH, --NQ, --OQO, --O, --NHC(O), --OP(O), --P(O)O, --OP(O)₂, --P(O)₂ O, --OS(O)₂, or --S(O)₃ ;

U is an acid group, a basic group or a zwitterionic C_1-20 chain containing at least one acidic group and at least one basic group, wherein the side chains can be further functionalized with an alkene or alkyne group at any position, one or more of the carbons on the side chain can be replaced with an oxygen, one or more of the carbons can be functionalized with an acidic or basic group, and wherein the ring atoms X at positions 1 and 4 are either O or N.

11. The method of claim 10 wherein the diketopiperazine is formed from amino acids selected from the group consisting of glutamic acid, aspartic acid, lysine, ornithine and diaminopropionic acid, cyclized by

(i) protecting side chain amino groups,

(ii) heating the amino acids in a solvent to dimerize the amino acids, and

(iii) removing the protecting groups.

12. The method of claim 11 further comprising acylating the ring nitrogens of the diketopiperazine.

14. The method of claim 10 further comprising adding to the diketopiperazine solution a biologically active agent selected from the group consisting of proteins, peptides, polysaccharides, lipids, lipopolysaccharides, nucleic acids and other biologically active organic molecules, imaging agents, and cell specific targeting agents prior to forming the microparticles.

15. The method of claim 14 wherein the biological agent is selected from the group consisting of insulin, calcitonin, felbamate, heparin, parathyroid hormone and fragments thereof, growth hormone, erythropoietin, AZT, DDI, G CSF, lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β

-galactosidase and Argatroban.

16. The method of claim 10 further comprising coupling a targeting molecule to the diketopiperazine.

23. The method of claim 10 wherein Q is selected from the group consisting of cis and trans --CH═

CH--CO₂ H, --CH(CH₃)═

CH(CH₃)--CO₂ H, --(CH₂)₃ --CO₂ H, --CH₂ CH(CH₃)--CO₂ H, --CH(CH₂ CO₂ H)═

CH₂, -(tetrafluoro)benzoic acid and -benzoic acid.

24. The method of claim 10 wherein Q is selected from the group consisting of -aniline, -phenyl-C(NH)NH₂, -phenyl-C(NH)NH(alkyl), -phenyl-C(NH)N(alkyl)₂ and --(CH₂)₄ NHC(O)CH(NH₂)CH(NH₂)CO₂ H.

25. The method of claim 10 wherein Q is selected from the group consisting of --CH(NHC(O)CF₃)--CH₂ --CO₂ H, --CH(NH₂)--CH₂ --CO₂ H and --NH(CH₂)_1-20 CO₂ H.

17. A method for administering a biologically active agent to a patient comprising providing the agent selected from the group consisting of proteins, peptides, polysaccharides, lipids, lipopolysaccharides, nucleic acids and other biologically active organic molecules, imaging agents, and cell specific targeting agents, in combination with microparticles formed of diketopiperazines, wherein the microparticles are stable at a first defined pH due to association and precipitation of the diketopiperazines and unstable at a second defined pH due to dissociation of the diketopiperazines.

18. The method of claim 17 wherein the microparticles further comprise compounds selected from the group consisting of stabilizers of the biologically active agents and non-encapsulated biologically active compounds.

19. The method of claim 17 wherein the microparticles are further encapsulated within an enteric coating.

20. The method of claim 17 wherein the microparticles are stable at acidic pH and unstable at a more basic pH.

21. The method of claim 17 wherein the microparticles are unstable at acidic pH and stable at a more basic pH.

22. The method of claim 17 wherein the microparticles are stable at neutral pH and unstable at acidic and basic pH.

26. The method of claim 17 wherein the biologically active agent is selected from the group consisting of hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, vasoactive agents, neuroactive agents, anaesthetics or sedatives, steroids, decongestants, antivirals, antisense, antigens, and antibodies.

27. The method of claim 17 wherein the biologically active agent is selected from the group consisting of insulin, calcitonin, felbamate, heparin, parathyroid hormone and fragments thereof, growth hormone, erythropoietin, AZT, DDI, G CSF, lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β

-galactosidase and Argatroban.

28. The method of claim 17 wherein the biologically active agent is not bioavailable when administered unencapsulated, and bioavailable when administered encapsulated, when administered to a patient via the same route of administration.