Increasing drug affinity for crystalline microparticle surfaces

1. A method of promoting binding of an active agent to a preformed crystalline diketopiperazine microparticle in suspension comprising the steps in the sequence set forth of:

(i) modifying the chemical potential of a protein, polypeptide or peptide active agent wherein said modifying allows for an energetically favorable interaction between the active agent and the preformed crystalline diketopiperazine microparticle independent of removal of solvent; followed by

(ii) allowing adsorption of the active agent onto the surface of the preformed crystalline diketopiperazine microparticle;

wherein said modifying step causes said absorbing of said active agent onto a surface of said preformed crystalline diketopiperazine microparticle to provide a coating of said active agent on said preformed crystalline diketopiperazine microparticle; and

wherein said preformed crystalline diketopiperazine microparticle does not comprise an active agent.

2. The method of claim 1 , wherein modifying the chemical potential comprises modifying the structure, flexibility, rigidity, solubility or stability of the active agent.

3. The method of claim 2 , wherein modifying the chemical potential of the active agent comprises altering solution conditions.

4. The method of claim 3 , wherein said altering solution conditions comprises adding an active agent modifier to the solution and wherein said active agent modifier is selected from the group consisting of sodium chloride, hexylene-glycol (Hex-Gly), trehalose, glycine, polyethylene glycol, trimethylamine N-oxide, mannitol, proline, methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, NaSCN, (CH 3 ) 3 N—HCl, Na 2 NO 3 , NaClO 4 , cesium chloride, sodium citrate, and sodium sulfate.

5. The method of claim 4 , wherein said active agent modifier is sodium chloride.

6. The method of claim 1 , wherein said modifying step comprises dissolving the active agent in a fluid phase of the suspension of preformed crystalline diketopiperazine microparticles and changing the pH of the fluid phase.

7. The method of claim 4 , wherein the active agent modifier improves the structural stability or pharmacodynamics of the active agent.

8. The method of claim 1 , wherein the active agent is selected from the group consisting of insulin, an insulin analog, ghrelin, growth hormone, and parathyroid hormone (PTH).

9. The method of claim 2 , wherein modifying the chemical potential of the active agent comprises modulating one or more energetically favorable interactions with the crystalline diketopiperazine microparticle surface.

10. The method of claim 9 , wherein the one or more energetically favorable interactions between the active agent and the crystalline diketopiperazine microparticle comprises an electrostatic interaction.

11. The method of claim 9 , wherein the one or more energetically favorable interactions between the active agent and microparticle comprises a hydrophobic interaction.

12. The method of claim 9 , wherein the one or more energetically favorable interactions between the active agent and microparticle comprises a hydrogen bonding interaction.

13. The method of claim 1 , wherein the diketopiperazine is fumaryl diketopiperazine.

14. The method of claim 1 , further comprising a step for removing the solvent after the allowing step.

15. The method of claim 1 , wherein the active agent comprises human insulin.

16. The method of claim 1 , wherein the active agent is insulin or an insulin analog and wherein the method comprises the steps of:

(i) obtaining a crystalline diketopiperazine microparticle wherein the crystalline diketopiperazine microparticle comprises fumaryl diketopiperazine and does not comprise an active agent;

(ii) forming a suspension comprising the crystalline diketopiperazine microparticle and an aqueous solvent;

(iii) dissolving the insulin or insulin analog in the fluid phase of the suspension;

(iv) changing the pH of the fluid phase from a low pH to about between 4.0 and 5.0;

(v) absorbing of the insulin or insulin analog onto a surface of the diketopiperazine microparticle to provide a coating of the insulin or insulin analog on the crystalline diketopiperazine microparticle;

(vi) removing or exchanging the solvent after step (v).