Method of drug formulation based on increasing the affinity of active agents for 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: modifying the chemical potential of the active agent in the suspension by modifying the structure, flexibility, rigidity, solubility or stability of the active agent to allow for an energetically favorable interaction between the active agent and the preformed crystalline diketopiperazine microparticle independent of removal of solvent; wherein said modifying step 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, said preformed crystalline diketopiperazine microparticle does not comprise an active agent, and said active agent comprises an antibody or fragment thereof.
2. The method of claim 1 wherein the antibody or fragment thereof is humanized or chimeric.
3. The method of claim 1 wherein the antibody or fragment thereof comprises F(ab), F(ab)2, or a single-chain antibody.
4. The method of claim 3 wherein the antibody or fragment thereof is fused to a polypeptide.
5. The method of claim 1 wherein the antibody or fragment thereof can recognize a disease-associated antigen.
6. The method of claim 5 wherein the disease-associated antigen is a tumor-associated antigen or an infectious pathogen-related antigen.
7. The method of claim 5 wherein the disease-associated antigen is one of cancer antigens, cytokines, infectious agents, inflammatory mediators, hormones, and cell surface antigens.
8. The method of claim 7 wherein the antibody or fragment thereof is one of anti-SSX-2 41-49 (synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumor associated antigen), anti-PRAME (preferentially expressed antigen of melanoma), anti-PSMA (prostate-specific membrane antigen), anti-Melan-A (melanoma tumor associated antigen), anti-tyrosinase (melanoma tumor associated antigen), and anti-MOPC-21 (myeloma plasma-cell protein).
9. 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.
10. The method of claim 9 wherein said active agent modifier is sodium chloride.
11. The method of claim 1 wherein said modifying the chemical potential of the active agent 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.
12. The method of claim 9 wherein the active agent modifier improves the structural stability of the active agent.
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 adsorption has occurred.