Carbon-substituted diketopiperazine delivery systems

A pharmacological composition comprising:

• (a) at least one pharmacologically active agent;
• and
• (b) at least one diketopiperazine having the formula:
• wherein R1 and R2 are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl (C1-C10 alkenyl), naphthyl (C1-C10 alkyl), and naphthyl (C1-C10 alkenyl);
• both R1 and R2, optionally, are substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, —OH, —SH, and —CO2R3 or any combination thereof;
• wherein R3 is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl;
• R1 and R2, optionally, are interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are substituted by C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, —OH, —SH, or CO2R4 wherein R4 is hydrogen, C1-C6 alkyl, or C1-C6 alkenyl;
• and
• R1 and R2 are not both hydrogen.

A method for preparing microspheres containing an active agent, said method comprising:

• (A) solubilizing, in a solvent, at least one diketopiperazine having the formula:
• wherein R1 and R2 are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl (C1-C10 alkenyl), naphthyl (C1-C10 alkyl), and naphthyl (C1-C10 alkenyl);
• both R1 and R2, optionally, are substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, —OH, —SH, and —CO2R3 or any combination thereof;
• wherein R3 is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl;
• R1 and R2, optionally, are interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are substituted by C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, —OH, —SH, or CO2R4 wherein R4 is hydrogen, C1-C6 alkyl, or C1-C6 alkenyl;
• and
• R1 and R2 are not both hydrogen, to yield a diketopiperazine solution;
• and
• B) contacting said diketopiperazine solution with said active agent and a precipitator solution in which said diketopiperazine is insoluble.

A delivery composition consisting essentially of:

• (a) an active agent;
• and
• (b) at least one diketopiperazine having the formula:
• wherein R1 and R2 are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl (C1-C10 alkenyl), naphthyl (C1-C10 alkyl), or naphthyl (C1-C10 alkenyl);
• both R1 and R2, optionally, are substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, —OH, —SH, and —CO2R3 or any combination thereof;
• wherein R3 is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl;
• R1 and R2, optionally, are interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are substituted by C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, —OH, —SH, or CO2R4 wherein R4 is hydrogen, C1-C6 alkyl, or C1-C6 alkenyl;
• and
• R1 and R2 are not both hydrogen.

A delivery composition consisting of:

• (a) an active agent;
• and
• (b) at least one diketopiperazine having the formula:
• wherein R1 and R2 are hydrogen, C1-C24 alkyl, C1-C24 alkenyl, phenyl, naphthyl, (C1-C10 alkyl)phenyl, (C1-C10 alkenyl)phenyl, (C1-C10 alkyl)naphthyl, (C1-C10 alkenyl)naphthyl, phenyl (C1-C10 alkyl), phenyl (C1-C10 alkenyl), naphthyl (C1-C10 alkyl), or naphthyl (C1-C10 alkenyl);
• both R1 and R2, optionally, are substituted with C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy, —OH, —SH, and —CO2R3 or any combination thereof;
• wherein R3 is hydrogen, C1-C4 alkyl, or C1-C4 alkenyl;
• R1 and R2, optionally, are interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are substituted by C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, —OH, —SH, or CO2R4 wherein R4 is hydrogen, C1-C6 alkyl, or C1-C6 alkenyl;
• and
• R1 and R2 are not both hydrogen.