Polymer-Agent Conjugates, Particles, Compositions, and Related Methods of Use

• US 20140193510A1
• Filed: 02/13/2014
• Published: 07/10/2014
• Est. Priority Date: 03/30/2009
• Status: Abandoned Application

• Current Assignee: Cerulean Pharma Inc. (Daré Bioscience, Inc.)
• Original Assignee: Cerulean Pharma Inc. (Daré Bioscience, Inc.)
• Inventors: Eliasof, Scott, Gangal, Geeti, Reiter, Lawrence Alan, Ng, Pei-Sze, Crawford, Thomas C
• Application Number:
  US14/180,101
• Publication Number:
  US 20140193510A1
• Time in Patent Office: Days
• US Class Current: 424/501
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: A61K 31/80 Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

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

1-121. -121. (canceled)

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.

123. 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.

124. 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.

125. 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.

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

127. A kit comprising a plurality of particles of claim 122.

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

129. 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.

130. 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.

131. 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.

132. 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.

133. 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.

134. 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.

135. 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):

136. 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.

137. 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 C_1-8 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 C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6 alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, C_6-10 arylsulfonyl, C_1-6 alkyl(C_6-10)aryl, and halo(C_6-10)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.

138. 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.

139. The particle of claim 135, wherein:

P is R′

or R⁷—

C(O)—

or R⁷—

SO₂—

, wherein R⁷ selected from the group consisting of

140. The particle of claim 135, wherein the compound of formula (A) is represented by the following structural formula:

141. 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.

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

143. 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.

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

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

146. 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.

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

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

149. 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.

150. 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.

151. 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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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