# US 2014/0193510 A1 · Polymer-Agent Conjugates, Particles, Compositions, and Related Methods of Use

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- Number: US 2014/0193510 A1
- Document ID: US20140193510A1
- Status: Published application
- Kind: A1
- Application number: 14/180,101
- Filed: 2014-02-13
- Published: 2014-07-10
- Earliest claimed: 2009-03-30
- Assignees: Cerulean Pharma Inc.
- Applicants: Cerulean Pharma Inc.
- Inventors: Scott Eliasof; Thomas C Crawford; Geeti Gangal; Lawrence Alan Reiter; Pei-Sze Ng
- Web page: https://patentgrep.com/patent/US20140193510A1

## CPC

- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/69: Boron compounds
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/765: Polymers containing oxygen
- A61K 31/80: Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Described herein are polymer-agent conjugates and particles, which can be used, for example, in the treatment of cancer. Also described herein are mixtures, compositions and dosage forms containing the particles, methods of using the particles (e.g., to treat a disorder), kits including the polymer-agent conjugates and particles, methods of making the polymer-agent conjugates and particles, methods of storing the particles and methods of analyzing the particles.

## Claims

### Claim at position 1

-121. (canceled)

### Claim 122

A particle comprising:
a) a plurality of hydrophobic polymer-therapeutic agent conjugates, wherein
i) each hydrophobic polymer-therapeutic agent conjugate of said plurality comprises a hydrophobic polymer covalently bonded to a therapeutic agent,
ii) said hydrophobic polymer covalently bonded to said therapeutic agent is a homopolymer or a polymer made up of more than one kind of monomeric subunit,
iii) said hydrophobic polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of hydrophobic polymer-therapeutic agent conjugates 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 covalently bonded 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.

### Claim 123 (depends on 122)

The particle of claim 122, comprising:
a) a plurality of hydrophobic polymer-therapeutic agent conjugates, wherein
i) each hydrophobic polymer-therapeutic agent conjugate of said plurality comprises a hydrophobic polymer covalently bonded to a therapeutic agent,
ii) said hydrophobic polymer covalently bonded to the therapeutic agent is a homopolymer or a polymer made up of more than one kind of monomeric subunit,
iii) said hydrophobic polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of hydrophobic polymer-therapeutic agent conjugates 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 covalently bonded to a hydrophobic portion,
ii) said hydrophilic portion has a weight average molecular weight of about 1-6 kD, wherein
if the weight average molecular weight of said hydrophilic portion is about 1-3 kD, the ratio of the weight average molecular weight of said hydrophilic portion to the weight average molecular weight of said hydrophobic portion is between 1:3-1:7, and if the weight average molecular weight of said hydrophilic portion is about 4-6 kD, the ratio of the weight average molecular weight of said hydrophilic portion to the weight average molecular weight of said hydrophobic portion is between 1:1-1:4, 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.

### Claim 124 (depends on 122)

The particle of claim 122, comprising:
a) a plurality of hydrophobic polymer-therapeutic agent conjugates, wherein
i) each hydrophobic polymer-therapeutic agent conjugate of said plurality comprises a hydrophobic polymer covalently bonded to a therapeutic agent,
ii) said hydrophobic polymer covalently bonded to said therapeutic agent is a homopolymer or a polymer made up of more than one kind of monomeric subunit,
iii) said hydrophobic polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of hydrophobic polymer-therapeutic agent conjugates is about 35-80 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 covalently bonded to a hydrophobic portion,
ii) said hydrophilic portion has a weight average molecular weight of about 2-6 kD and said hydrophobic portion has a weight average molecular weight of between about 8-13 kD,
iii) said plurality of hydrophilic-hydrophobic polymers is about 10-25 weight % of said particle, and
iv) said hydrophilic portion of said hydrophilic-hydrophobic polymer terminates in an OMe; and
c) a surfactant, wherein said surfactant is about 15-35 weight % of said particle; wherein
said particle further comprises a hydrophobic polymer having a terminal acyl moiety.

### Claim 125 (depends on 122)

A method of making the particle of claim 122, comprising:
providing an organic solution comprising:
a) a plurality of hydrophobic polymer-therapeutic agent conjugates, wherein
i) each hydrophobic polymer-therapeutic agent conjugate of said plurality comprises a hydrophobic polymer covalently bonded to a therapeutic agent,
ii) said hydrophobic polymer covalently bonded to said therapeutic agent is a homopolymer or a polymer made up of more than one kind of monomeric subunit,
iii) said hydrophobic polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of hydrophobic polymer-therapeutic agent conjugates 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 covalently bonded 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
combining said organic solution with an aqueous solution comprising a solvent to provide said particles.

### Claim 126 (depends on 122)

A pharmaceutically acceptable composition comprising a plurality of particles of claim 122.

### Claim 127 (depends on 122)

A kit comprising a plurality of particles of claim 122.

### Claim 128 (depends on 122)

A dosage unit comprising a plurality of particles of claim 122.

### Claim 129 (depends on 122)

The particle of claim 122, comprising:
a) a plurality of hydrophobic polymer-therapeutic agent conjugates, wherein
i) each hydrophobic polymer-therapeutic agent conjugate of said plurality comprises a hydrophobic polymer covalently bonded to a therapeutic agent,
ii) said hydrophobic polymer covalently bonded to said therapeutic agent is a homopolymer or a polymer made up of more than one kind of monomeric subunit,
iii) said hydrophobic polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of hydrophobic polymer-therapeutic agent conjugates is about 25-80 weight % of said particle;
b) a plurality of polyethylene glycol (“PEG”)-hydrophobic polymers, wherein
i) each of said PEG-hydrophobic polymers of said plurality comprises a PEG portion covalently bonded to a hydrophobic portion,
ii) said PEG portion has a weight average molecular weight of about 1-6 kD, and
iii) said plurality of PEG-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.

### Claim 130 (depends on 129)

The particle of claim 129, comprising:
a) a plurality of hydrophobic polymer-therapeutic agent conjugates, wherein
i) each hydrophobic polymer-therapeutic agent conjugate of said plurality comprises a hydrophobic polymer covalently bonded to a therapeutic agent,
ii) the hydrophobic polymer is made up of a first and a second type of monomeric subunit, and the ratio of the first to second type of monomeric subunit is said hydrophobic polymer covalently bonded to said therapeutic agent is from about 25:75 to about 75:25,
iii) said hydrophobic polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of hydrophobic polymer-therapeutic agent conjugates is about 25-80 weight % of said particle;
b) a plurality of PEG-hydrophobic polymers, wherein
i) each of said PEG-hydrophobic polymers of said plurality comprises a PEG portion covalently bonded to a hydrophobic portion,
ii) said PEG portion has a weight average molecular weight of about 1-6 kD, wherein
if the weight average molecular weight of said PEG portion is about 1-3 kD, the ratio of the weight average molecular weight of said PEG portion to the weight average molecular weight of said hydrophobic portion is between 1:3-1:7, and if the weight average molecular weight of said PEG portion is about 4-6 kD, the ratio of the weight average molecular weight of said PEG portion to the weight average molecular weight of said hydrophobic portion is between 1:1-1:4, and
iii) said plurality of PEG-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.

### Claim 131 (depends on 129)

The particle of claim 129, comprising:
a) a plurality of hydrophobic polymer-therapeutic agent conjugates, wherein
i) each hydrophobic polymer-therapeutic agent conjugate of said plurality comprises a hydrophobic polymer covalently bonded to a therapeutic agent,
ii) the hydrophobic polymer is made up of a first and a second type of monomeric subunit, and the ratio of the first to the second type of monomeric subunit in said hydrophobic polymer covalently bonded to said therapeutic agent is from about 25:75 to about 75:25,
iii) said hydrophobic polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of hydrophobic polymer-therapeutic agent conjugates is about 35-80 weight % of said particle;
b) a plurality of PEG-hydrophobic polymers, wherein
i) each of said PEG-hydrophobic polymers of said plurality comprises a PEG portion covalently bonded to a hydrophobic portion,
ii) said PEG portion has a weight average molecular weight of about 2-6 kD and said hydrophobic portion has a weight average molecular weight of between about 8-13 kD,
iii) said plurality of PEG-hydrophobic polymers is about 10-25 weight % of said particle, and
iv) said PEG portion of said PEG-hydrophilic polymer terminates in an OMe; and
c) a surfactant, wherein said surfactant is about 15-35 weight % of said particle.

### Claim 132 (depends on 122)

The particle of claim 122 comprising:
a) a plurality of poly(lactic-co-glycolic acid) (“PLGA”)-therapeutic agent conjugates, wherein
i) each PLGA-therapeutic agent conjugate of said plurality comprises a PLGA polymer covalently bonded to a therapeutic agent,
ii) the ratio of lactic acid to glycolic acid in said PLGA polymer covalently bonded to said therapeutic agent is from about 25:75 to about 75:25,
iii) said PLGA polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of PLGA-therapeutic agent conjugates is about 25-80 weight % of said particle;
b) a plurality of PEG-PLGA polymers, wherein
i) each of said PEG-PLGA polymers of said plurality comprises a PEG portion covalently bonded to a PLGA portion,
ii) said PEG portion has a weight average molecular weight of about 1-6 kD, and
iii) said plurality of PEG-PLGA polymers is about 5-30 weight % of said particle; and
c) a surfactant, wherein said surfactant is about 15-35 weight % of said particle.

### Claim 133 (depends on 132)

The particle of claim 132, comprising:
a) a plurality of PLGA-therapeutic agent conjugates, wherein
i) each PLGA-therapeutic agent conjugate of said plurality comprises a PLGA polymer covalently bonded to a therapeutic agent,
ii) the ratio of lactic acid to glycolic acid in said PLGA polymer covalently bonded to said therapeutic agent is from about 25:75 to about 75:25,
iii) said PLGA polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of PLGA-therapeutic agent conjugates is about 25-80 weight % of said particle;
b) a plurality of PEG-PLGA polymers, wherein
i) each of said PEG-PLGA polymers of said plurality comprises a PEG portion covalently bonded to a PLGA portion,
ii) said PEG portion has a weight average molecular weight of about 1-6 kD, wherein
if the weight average molecular weight of said PEG portion is about 1-3 kD, the ratio of the weight average molecular weight of said PEG portion to the weight average molecular weight of said PLGA portion is between 1:3-1:7, and if the weight average molecular weight of said PEG portion is about 4-6 kD, the ratio of the weight average molecular weight of said PEG portion to the weight average molecular weight of said PLGA portion is between 1:1-1:4, and
iii) said plurality of PEG-PLGA polymers is about 5-30 weight % of said particle; and
c) a surfactant, wherein said surfactant is about 15-35 weight % of said particle.

### Claim 134 (depends on 132)

The particle of claim 132, comprising:
a) a plurality of PLGA-therapeutic agent conjugates, wherein
i) each PLGA-therapeutic agent conjugate of said plurality comprises a PLGA polymer covalently bonded to a therapeutic agent,
ii) the ratio of lactic acid to glycolic acid in said PLGA polymer covalently bonded to said therapeutic agent is from about 25:75 to about 75:25,
iii) said PLGA polymer covalently bonded to said therapeutic agent has a weight average molecular weight of about 4-15 kD,
iv) said therapeutic agent is about 1-30 weight % of said particle, and
v) said plurality of PLGA-therapeutic agent conjugates is about 35-80 weight % of said particle;
b) a plurality of PEG-PLGA polymers, wherein
i) each of said PEG-PLGA polymers of said plurality comprises a PEG portion covalently bonded to a PLGA portion,
ii) said PEG portion has a weight average molecular weight of about 2-6 kD and said PLGA portion has a weight average molecular weight of between about 8-13 kD,
iii) said plurality of PEG-PLGA polymers is about 10-25 weight % of said particle, and
iv) said PEG portion of said PEG-PLGA polymer terminates in an OMe; and
c) a surfactant, wherein said surfactant is about 15-35 weight % of said particle; wherein
said particle further comprises PLGA having a terminal acyl moiety.

### Claim 135 (depends on 122, 123, 124, 129, 130, 131, 132, 133)

The particle of any one of claim 122, 123, 124, 129, 130, 131, 132, 133, or 134, wherein the therapeutic agent is a compound of Formula (A):
or a pharmaceutically acceptable salt 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 is —C(O)—NH—;
X2 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 is 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 is optionally substituted;
R2 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 is 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 is 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 is 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, one or more heteroatoms independently selected from N, S, and O; and
A is 0, 1, or 2.

### Claim 136 (depends on 135)

The particle of claim 135, wherein:
P is R7—C(O)—, where R7 is heteroaryl or heteroarylalkyl;
X2 is —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 is optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R2 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 is 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 is 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;
R6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle is 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, one or more heteroatoms independently selected from N, S, and O; and
A is zero.

### Claim 137 (depends on 135)

The particle of claim 135, wherein:
P is hydrogen or an amino group protecting moiety;
A is zero;
X2 is —C(O)—NH—;
R′ is hydrogen or C1-8 alkyl;
R2 is —CH2—R5;
R3 is C4 alkyl;
R5 is aryl, wherein R5 is optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkyl(C3-8)cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, cyano, amino, C1-6 alkylamino, di(C1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-6)alkoxy, trifluoromethyl, halogen, C1-6 alkoxy, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C6-10 aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10 arylsulfinyl, C6-10 arylsulfonyl, C1-6 alkyl(C6-10)aryl, and halo(C6-10)aryl;
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, one or more heteroatoms independently selected from N, S, and O; and
A is zero.

### Claim 138 (depends on 135)

The particle of claim 135, wherein:
P is hydrogen or an amino-group protecting moiety;
R′ is hydrogen or alkyl;
A is 0, 1, or 2;
R1, R2, and R3 are each independently hydrogen, alkyl, cycloalkyl, aryl, or —CH2—R5;
R5, in each instance, is aryl, aralkyl, alkaryl, cycloalkyl, 5 to 10 membered saturated, partially unsaturated or aromatic heterocycle, or —W—R6, where W is a chalcogen and R6 is alkyl;
wherein the ring portion of any of said aryl, aralkyl, alkaryl, or heterocycle in R1, R2, R3, or R5 is optionally substituted; and
Z1 and Z2 together form a moiety derived from a sugar, wherein the atom covalently bonded to boron in each case is an oxygen atom.

### Claim 139 (depends on 135)

The particle of claim 135, wherein:
P is R′ or R7—C(O)— or R7—SO2—, wherein R7 selected from the group consisting of
or P is
X2 is selected from the group consisting of
R′ is hydrogen or alkyl;
R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle and —CH2—R5, where R5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or —Y—R6,
where Y is a chalcogen, and R6 is alkyl; and
Z1 and Z2 are independently one of 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, one or more heteroatoms independently selected from N, S, and O.

### Claim 140 (depends on 135)

The particle of claim 135, wherein the compound of formula (A) is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 141 (depends on 122, 123, 124, 129, 130, 131, 132, 133)

The particle of any one of claim 122, 123, 124, 129, 130, 131, 132, 133, or 134, wherein the diameter of said particle is less than about 200 nm.

### Claim 142 (depends on 126)

The pharmaceutically acceptable composition of claim 126, wherein the pharmaceutical composition further comprises a lyoprotectant.

### Claim 143 (depends on 122, 123, 124, 129, 130, 131, 132, 133)

The particle of any one of claim 122, 123, 124, 129, 130, 131, 132, 133, or 134, wherein the surfactant in c) is poly(vinyl alcohol) (“PVA”), wherein the PVA has a weight average molecular weight of about 5-45 kD.

### Claim 144 (depends on 123, 124)

The particle of either of claim 123 or 124, wherein the PEG-hydrophobic polymers in b) are PEG-PLGA polymers.

### Claim 145 (depends on 130, 131)

The particle of either of claim 130 or 131, wherein the PEG-hydrophobic polymers in b) are PEG-PLGA polymers.

### Claim 146 (depends on 122, 123, 124, 130, 131)

The particle of any of claim 122, 123, 124, 130 or 131, wherein the hydrophobic polymer of the hydrophobic polymer-therapeutic agent conjugates in a) is PLGA.

### Claim 147 (depends on 144)

The particle of claim 144, wherein the hydrophobic polymer of the hydrophobic polymer-therapeutic agent conjugates in a) is PLGA.

### Claim 148 (depends on 130, 131)

The particle of either of claim 130 or 131, wherein the hydrophobic polymer of the hydrophobic polymer-therapeutic agent conjugates in a) is PLGA.

### Claim 149 (depends on 122, 123, 124, 129, 130, 131, 132, 133, 134)

The particle of any one of claim 122, 123, 124, 129, 130, 131, 132, 133 or 134, wherein the therapeutic agent is an anti-cancer agent.

### Claim 150 (depends on 122, 123, 124, 129, 130, 131, 132, 133)

The particle of any one of claim 122, 123, 124, 129, 130, 131, 132, 133, or 134, wherein the therapeutic agent is an anti-inflammatory agent.

### Claim 151 (depends on 122, 123, 124, 129, 130, 131, 132, 133)

The particle of any one of claim 122, 123, 124, 129, 130, 131, 132, 133, or 134, wherein the therapeutic agent is an agent for the treatment of a cardiovascular disease.

### Claim 152 (depends on 151)

The particle of claim 151, wherein the agent for the treatment of a cardiovascular disease is efonidipine.

### Claim 153 (depends on 143)

The particle of claim 143, wherein the therapeutic agent is an anti-cancer agent.

### Claim 154 (depends on 143)

The particle of claim 143, wherein the therapeutic agent is an anti-inflammatory agent.

### Claim 155 (depends on 143)

The particle of claim 143, wherein the therapeutic agent is an agent for the treatment of a cardiovascular disease.

### Claim 156 (depends on 144)

The particle of claim 144, wherein the therapeutic agent is an anti-cancer agent.

### Claim 157 (depends on 144)

The particle of claim 144, wherein the therapeutic agent is an anti-inflammatory agent.

### Claim 158 (depends on 144)

The particle of claim 144, wherein the therapeutic agent is an agent for the treatment of a cardiovascular disease.

### Claim 159 (depends on 145)

The particle of claim 145, wherein the therapeutic agent is an anti-cancer agent.

### Claim 160 (depends on 145)

The particle of claim 145, wherein the therapeutic agent is an anti-inflammatory agent.

### Claim 161 (depends on 145)

The particle of claim 145, wherein the therapeutic agent is an agent for the treatment of a cardiovascular disease.

### Claim 162 (depends on 146)

The particle of claim 146, wherein the therapeutic agent is an anti-cancer agent.

### Claim 163 (depends on 146)

The particle of claim 146, wherein the therapeutic agent is an anti-inflammatory agent.

### Claim 164 (depends on 146)

The particle of claim 146, wherein the therapeutic agent is an agent for the treatment of a cardiovascular disease.

### Claim 165 (depends on 147)

The particle of claim 147, wherein the therapeutic agent is an anti-cancer agent.

### Claim 166 (depends on 147)

The particle of claim 147, wherein the therapeutic agent is an anti-inflammatory agent.

### Claim 167 (depends on 147)

The particle of claim 147, wherein the therapeutic agent is an agent for the treatment of a cardiovascular disease.