Method of drug formulation of compositions comprising crystalline microparticle surfaces
View Patent ↗Methods are provided for promoting the adsorption of an active agent to microparticles by modifying the structural properties of the active agent in order to facilitate favorable association to the microparticle.
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 the active agent wherein said modifying comprises modifying the structure, flexibility, rigidity, solubility or stability of the active agent and 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 adsorbing 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, said preformed crystalline diketopiperazine microparticle does not comprise an active agent, and said active agent is a small molecule.
2. The method of claim 1 wherein the small molecule is a hydrophobic molecule.
3. The method of claim 2 wherein the small molecule is cyclosporin A.
4. The method of claim 1 wherein the small molecule is an ionizable molecule.
5. The method of claim 1 wherein modifying the chemical potential of the active agent comprises altering solution conditions by adding an active agent modifier to the solution 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, sodium sulfate, and water.
6. The method of claim 5 wherein said active agent modifier is sodium chloride.
7. 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.
8. The method of claim 7 wherein the pH is changed prior to the addition of active agent.
9. The method of claim 7 wherein the pH is changed subsequent to the addition of active agent.
10. The method of claim 5 wherein the active agent modifier improves the structural stability or pharmacodynamics of the active agent.
11. The method of claim 1 wherein the diketopiperazine is fumaryl diketopiperazine.
12. The method of claim 1 further comprising a step for removing the solvent after the allowing step.
13. A process for preparing a drug delivery composition comprising an active agent and a crystalline diketopiperazine microparticle comprising the steps in the sequence set forth of: i) providing an active agent solution comprising an active agent molecule and providing a preformed crystalline diketopiperazine microparticle in a suspension or powder; next ii) combining said active agent solution with said preformed crystalline diketopiperazine microparticle suspension or powder to form a fluid phase; and iii) then modifying the chemical potential of the active agent in the fluid phase; wherein said modifying step comprises modifying the structure, flexibility, rigidity, solubility or stability of the active agent and causes adsorption 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 said active agent is a small molecule.
14. The process of claim 13 wherein the modifying step allows for interaction between the active agent and the preformed crystalline diketopiperazine microparticle.
15. The process of claim 13 wherein the modifying step comprises adding an active agent modifier to the fluid phase, 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, sodium sulfate, and water.
16. The process of claim 13 wherein the modifying step comprises the addition of water and wherein said modification decreases the solubility of the active agent.
17. The process of claim 13 wherein the modifying step comprises adding an active agent modifier to the fluid phase and the active agent modifier promotes association between the active agent and a preformed crystalline diketopiperazine microparticle, wherein said active agent modifier is selected from the group consisting of sodium chloride, NaSCN, (CH 3 ) 3 N—HCl, Na 2 NO 3 , NaClO 4 , cesium chloride, sodium citrate, sodium sulfate, methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, hexylene-glycol, trehalose, glycine, polyethylene glycol, trimethylamine N-oxide, mannitol, proline, and water.
18. The process of claim 13 wherein the modifying step comprises adding an active agent modifier to the fluid phase and the active agent modifier improves the structural stability of the active agent molecule, wherein said active agent modifier is selected from the group consisting of sodium chloride, NaSCN, (CH 3 ) 3 N—HCl, Na 2 NO 3 , NaClO 4 , cesium chloride, sodium citrate, sodium sulfate, methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, hexylene-glycol, trehalose, glycine, polyethylene glycol, trimethylamine N-oxide, mannitol, and proline.
19. The process of claim 13 wherein the diketopiperazine is fumaryl diketopiperazine.