Polymer-agent conjugates, particles, compositions, and related methods of use

A particle, comprising:

• a) a plurality of hydrophobic polymer-pharmaceutically active agent represented by Formula (A) conjugates, wherein
• i) each hydrophobic polymer-pharmaceutically active agent represented by Formula (A) conjugate of said plurality comprises a hydrophobic polymer attached to a pharmaceutically active agent represented by Formula (A):
• or a pharmaceutically acceptable salts thereof, wherein:
• P is hydrogen or an amino-group-protecting moiety;
• B1, at each occurrence, is independently one of N or CH;
• X1, at each occurrence, is independently one of —C(O)—NH—, —CH2—NH—, —CH(OH)—CH2—, —CH(OH)—CH(OH)—, —CH(OH)—CH2—NH—, —CH═CH—, —C(O)CH2—, —SO2—NH—, —SO2—CH2— or —CH(OH)—CH2—C(O)—NH—, provided that when B1 is N, then the X1 attached to said B1 is —C(O)—NH—;
• X1 is one of —C(O)—NH—, —CH(OH)—CH2—, —CH(OH)—CH(OH)—, —C(O)—CH2—, —SO2—NH—, —SO2—, —CH2— or —CH(OH)—CH2—C(O)—NH—;
• R′ is hydrogen or alkyl, or R forms together with the adjacent R1, or when A is zero, forms together with the adjacent R2, a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
• R1, at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH2—R5, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
• R2 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH—R5, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
• R3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH2—R5, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
• R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R6, where W is a chalcogen and R6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
• Z1 and Z2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O;
• and
• A is 0, 1, or 2,
• ii) said hydrophobic polymer attached to said pharmaceutically active agent represented by Formula (A) can be a homopolymer or a polymer made up of more than one kind of monomeric subunit,
• iii) said hydrophobic polymer attached to said pharmaceutically active agent of Formula (A) has a weight average molecular weight of about 4-15 kD,
• iv) said pharmaceutically active agent of Formula (A) is about 1-30 weight % of said particle and
• v) said plurality of hydrophobic polymer-pharmaceutically active agent represented by Formula (A) conjugate is about 25-80 weight % of said particle;
• b) a plurality of hydrophilic-hydrophobic polymers, wherein
• i) each of said hydrophilic-hydrophobic polymers of said plurality comprises a hydrophilic portion attached to a hydrophobic portion,
• ii) said hydrophilic portion has a weight average molecular weight of about 1-6 kD, and
• iii) said plurality of hydrophilic-hydrophobic polymers is about 5-30 weight % of said particle;
• and
• c) a surfactant, wherein said surfactant is about 15-35 weight % of said particle;
• and
• wherein:
• the diameter of said particle is less than about 200 nm.