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.

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.

An alkoxide compound is represented by General Formula (I) below:

##STR00001##

wherein R.sup.1 to R.sup.3 each independently represent hydrogen, a C.sub.1-12 hydrocarbon group, etc.; R.sup.4 represents a C.sub.1-12 hydrocarbon group, etc.; L represents hydrogen, halogen, a hydroxyl group, an amino group, an azi group, a phosphido group, a nitrile group, a carbonyl group, a C.sub.1-12 hydrocarbon group, etc.; and M represents a metal atom or a silicon atom, n represents an integer of 1 or more, m represents an integer of 0 or more, and n+m represents the valence of the metal atom or silicon atom.

Certain embodiments of the invention provide ionizable lipids having optimized clearance properties. Certain embodiments of the invention also provide nucleic acid-lipid particles comprising ionizable lipids, methods of making the lipid particles, and methods of delivering and/or administering the lipid particles.

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).

Processes for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone ##STR00001##
are described, which are useful for commercial manufacturing. Said compound is an orexin receptor modulator and may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia and depression.

Processes for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone ##STR00001##
are described, which are useful for commercial manufacturing. Said compound is an orexin receptor modulator and may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia and depression.