Disclosed herein are controlled-release oral pharmaceutical dosage forms comprising MGBG, and their application for the improved treatment of diseases with reduced side effects and/or longer time at maximum concentration.

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure

##STR00001##

wherein R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30alkyl, optionally substituted C.sub.10-C.sub.30alkenyl, optionally substituted C.sub.10-C.sub.30alkynyl, optionally substituted C.sub.10-C.sub.30acyl, or -linker-ligand; R3 is H, optionally substituted C.sub.1-C.sub.10alkyl, optionally substituted C.sub.2-C.sub.10alkenyl, optionally substituted C.sub.2-C.sub.10alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O).sub.2N(Q), S(O).sub.2, N(Q)S(O).sub.2, SS, ON, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, -aminoalkyl, -(substituted)aminoalky, -phosphoalkyl or -thiophosphoalkyl.

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure

##STR00001##

wherein R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30alkyl, optionally substituted C.sub.10-C.sub.30alkenyl, optionally substituted C.sub.10-C.sub.30alkynyl, optionally substituted C.sub.10-C.sub.30acyl, or -linker-ligand; R3 is H, optionally substituted C.sub.1-C.sub.10alkyl, optionally substituted C.sub.2-C.sub.10alkenyl, optionally substituted C.sub.2-C.sub.10alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O).sub.2N(Q), S(O).sub.2, N(Q)S(O).sub.2, SS, ON, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, -aminoalkyl, -(substituted)aminoalky, -phosphoalkyl or -thiophosphoalkyl.

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure

##STR00001##

wherein: R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure

##STR00001##

wherein: R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structures: ##STR00001##

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure ##STR00001##
wherein:
R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40 K), optionally substituted mPEG (mw 120-40 K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure ##STR00001##
wherein:
R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40 K), optionally substituted mPEG (mw 120-40 K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure ##STR00001##
wherein R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40 K), optionally substituted mPEG (mw 120-40 K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O).sub.2N(Q), S(O).sub.2, N(Q)S(O).sub.2, SS, ON, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, -aminoalkyl, -(substituted)aminoalky, -phosphoalkyl or -thiophosphoalkyl.

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure ##STR00001##
wherein R.sub.1 and R.sub.2 are each independently for each occurrence optionally substituted C.sub.10-C.sub.30 alkyl, optionally substituted C.sub.10-C.sub.30 alkenyl, optionally substituted C.sub.10-C.sub.30 alkynyl, optionally substituted C.sub.10-C.sub.30 acyl, or -linker-ligand; R.sub.3 is H, optionally substituted C.sub.1-C.sub.10 alkyl, optionally substituted C.sub.2-C.sub.10 alkenyl, optionally substituted C.sub.2-C.sub.10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, -aminoalkyls, -(substituted)aminoalkyls, -phosphoalkyls, -thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40 K), optionally substituted mPEG (mw 120-40 K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O).sub.2N(Q), S(O).sub.2, N(Q)S(O).sub.2, SS, ON, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, -aminoalkyl, -(substituted)aminoalky, -phosphoalkyl or -thiophosphoalkyl.