Pharmaceutical compositions suitable for parenteral administration comprising aqueous suspensions of benzylamine derivatives having low solubilities

An aqueous pharmaceutical suspension composition suitable for parenteral administration in a mammalian patient comprising a very slightly soluble, practically insoluble or insoluble active ingredient that is a compound of formula I:

• wherein:
• R1 is H, alkyl, —COalkyl, —COaryl, —COheteroaryl, —CO2alkyl, —(CH2)aOH, —(CH2)bCOOR10, —(CH2)cCONH2, —SO2alkyl, or —SO2aryl;
• R2 is H or alkyl;
• R3 is H, alkyl, —(CH2)daryl, —(CH2)eheteroaryl, —(CH2)fcycloalkyl, —(CH2)gheterocycloalkyl, —CH(cycloalkyl)2, or —CH(heterocycloalkyl)2;
• R4 and R6 are independently H or alkyl;
• R5 is H, alkyl, alkoxy, or OH;
• or R4 and R5, together with the atoms to which they are attached, form a 5- or 6-membered azacycloalkyl structure;
• R7 and R8 are independently H, alkyl, alkoxy, CN, or halo;
• R9 is aryl or heteroaryl;
• R10 is H or alkyl;
• a, b, c, d, e, f and g are independently 1, 2 or 3;
• *1 and *2 denote chiral centres;
• alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10);
• wherein the alkyl may optionally be substituted with 1 or 2 substituents that are independently (C3-C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR11, fluoro, or NR11R12;
• cycloalkyl is a mono- or bi-cyclic saturated hydrocarbon of between 3 and 10 carbon atoms;
• wherein the cycloalkyl may optionally be fused to an aryl group;
• heterocycloalkyl is a C-linked or N-linked 3 to 10 membered saturated, mono- or bi-cyclic ring, wherein said heterocycloalkyl ring contains, where possible, 1, 2 or 3 heteroatoms that are independently N, NR11, or O;
• alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6);
• wherein the alkoxy may optionally be substituted with 1 or 2 substituents that are independently (C3-C10)cycloalkyl, OH, CN, CF3, COOR11, fluoro, or NR11R12;
• aryl is phenyl, biphenyl or naphthyl;
• wherein the aryl may be optionally substituted with up to 5 substituents that are independently alkyl, alkoxy, OH, halo, CN, COOR11, CF3, or NR11R12;
• heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members that are independently N, NR11, S and O;
• heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3, or NR11R12;
• R11 and R12 are H or alkyl;
• or a tautomer, isomer, stereoisomer, pharmaceutically acceptable salt, and/or solvate thereof;
• and one or more stabilising agents, present in an amount of less than about 0.1% by weight of the composition, including polyoxyethylene (20) sorbitan monooleate or polyoxyethylene (20) sorbitan monolaurate or a combination thereof, and
• the one or more tonicity agents including dextrose or trehalose or a combination thereof;
• wherein the D50 particle size of the active ingredient changes by less than 30% after storage of the suspension at 5° C. for 5 weeks.