IN-VIVO GELLING PHARMACEUTICAL PRE-FORMULATION

• US 20130116341A1
• Filed: 05/06/2011
• Published: 05/09/2013
• Est. Priority Date: 05/07/2010
• Status: Active Grant

• Current Assignee: Theragenics Corporation (Juniper Investment Co. LLC)
• Original Assignee: Medicus Biosciences, LLC
• Inventors: Askari, Syed H., Horng, George
• Granted Patent: US 10,189,773 B2
• Time in Patent Office: Days
• US Class Current: 514/772.3
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 229/24 having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
• CPC Class Codes: C08G 65/34 from hydroxy compounds or their metallic derivatives C08G65/26 takes precedence

Abstract

Provided herein are in vivo gelling pharmaceutical pre-formulations forming biocompatible hydrogel polymers that are polymerized in vivo and kits comprising at least one nucleophilic compound or monomer unit, at least one electrophilic compound or monomer unit, and optionally at least one therapeutic agent. The biocompatible hydrogel polymer is bioabsorbable and releases the therapeutic agent at a target site, avoiding systemic exposure.

Claims

1-83. -83. (canceled)

84. An in vivo gelling pharmaceutical pre-formulation, comprising:

(a) at least one water soluble first compound comprising more than one nucleophilic group selected from a thiol and an amino, wherein the first compound is a glycol, trimethylolpropane, pentaerythritol, hexaglycerol, or tripentaerythritol derivative, and wherein the first compound further comprises one or more polyethylene glycol sections;

(b) at least one water soluble second compound comprising more than one electrophilic group selected from an epoxide, N-succinimidyl succinate, N-succinimidyl glutarate, N-succinimidyl succinamide or N-succinimidyl glutaramide, wherein the second compound is a trimethylolpropane, glycerol, diglycerol, pentaerythritol, sorbitol, hexaglycerol, tripentaerythritol, or polyglycerol derivative, and wherein the second compound further comprises one or more polyethylene glycol sections;

(c) an aqueous buffer in the pH range of 5.0 to 9.0; and

(d) optionally, one or more therapeutic agents;

wherein mixing the first compound, the second compound, and the optional therapeutic agent in the aqueous buffer and delivering the mixture to a target site in the human body generates the in vivo gelling pharmaceutical pre-formulation such that the in vivo gelling pharmaceutical pre-formulation at least in part polymerizes and gels at the target site to form a biocompatible hydrogel polymer.

85. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the first compound is selected from the group consisting of ethoxylated pentaerythritol ethylamine ether, ethoxylated pentaerythritol propylamine ether, ethoxylated pentaerythritol amino acetate, ethoxylated hexaglycerol ethylamine ether, ethoxylated hexaglycerol propylamine ether, and ethoxylated hexaglycerol amino acetate.

86. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the first compound is selected from the group consisting of trimethylolpropane trimercaptoacetate, trimethylolpropane tri-3-mercaptopropionate, pentaerythritol tetramercaptoacetate, pentaerythritol tetra-3-mercaptopropionate, ethoxylated trimethylolpropane trimercaptoacetate, ethoxylated trimethylolpropane tri-3-mercaptopropionate, ethoxylated pentaerythritol tetramercaptoacetate, and ethoxylated trimethylolpropane tri-3-mercaptopropionate.

87. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the molecular weight of each of the first compound and the second compound is between about 500 and 40000.

88. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the second compound is selected from the group consisting of ethoxylated pentaerythritol succinimidyl succinate, ethoxylated pentaerythritol succinimidyl glutarate, ethoxylated pentaerythritol succinimidyl glutaramide, ethoxylated hexaglycerol succinimidyl succinate, ethoxylated hexaglycerol succinimidyl glutarate, and ethoxylated hexaglycerol succinimidyl glutaramide.

89. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the second compound is selected from the group consisting of sorbitol polyglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, and trimethylolpropane polyglycidyl ether.

90. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the therapeutic agent is independently selected from the group consisting of an anticancer agent, an antiviral agent, an antibacterial agent, antifungal agent, an immunosuppressant agent, an hemostasis agent, and an anti-inflammatory agent.

91. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the gelling time is between about 20 seconds and 5 minutes.

92. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the pH of the aqueous buffer is from about 6.9 to about 7.9.

93. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the biocompatible hydrogel polymer is bioabsorbed within about 1 to 70 days.

94. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the biocompatible hydrogel polymer is substantially non-bioabsorbable.

95. The in vivo gelling pharmaceutical pre-formulation of claim 84, further comprising a radiopaque material or a pharmaceutically acceptable dye.

96. The in vivo gelling pharmaceutical pre-formulation of claim 84, wherein the therapeutic agent is substantially released from the biocompatible hydrogel polymer within 180 days.

97. The biocompatible hydrogel polymer of claim 84.

98. A biocompatible hydrogel polymer made by mixing:

(a) at least one water soluble first compound comprising more than one nucleophilic group selected from a thiol and an amino, wherein the first compound is a glycol, trimethylolpropane, pentaerythritol, hexaglycerol, or tripentaerythritol derivative, and wherein the first compound further comprises one or more polyethylene glycol sections;

(b) at least one water soluble second compound comprising more than one electrophilic group selected from an epoxide, N-succinimidyl succinate, N-succinimidyl glutarate, N-succinimidyl succinamide or N-succinimidyl glutaramide, wherein the second compound is a trimethylolpropane, glycerol, diglycerol, pentaerythritol, sorbitol, hexaglycerol, tripentaerythritol, or polyglycerol derivative, and wherein the second compound further comprises one or more polyethylene glycol sections;

(c) an aqueous buffer in the pH range of 5.0 to 9.0; and

(d) optionally, one or more therapeutic agents;

wherein the mixing is performed outside a human body, and the biocompatible hydrogel polymer gels at least in part inside the human body.

99. The biocompatible hydrogel polymer of claim 98, wherein the first compound is selected from the group consisting of ethoxylated pentaerythritol ethylamine ether, ethoxylated pentaerythritol propylamine ether, ethoxylated pentaerythritol amino acetate, ethoxylated hexaglycerol ethylamine ether, ethoxylated hexaglycerol propylamine ether, ethoxylated trimethylolpropane tri-3-mercaptopropionate, and ethoxylated hexaglycerol amino acetate.

100. The biocompatible hydrogel polymer of claim 98, wherein the second compound is selected from the group consisting of ethoxylated pentaerythritol succinimidyl succinate, ethoxylated pentaerythritol succinimidyl glutarate, ethoxylated pentaerythritol succinimidyl glutaramide, ethoxylated hexaglycerol succinimidyl succinate, ethoxylated hexaglycerol succinimidyl glutarate, ethoxylated hexaglycerol succinimidyl glutaramide, and sorbitol polyglycidyl ether.

101. The biocompatible hydrogel polymer of claim 98, wherein the therapeutic agent is selected from the group consisting of an anticancer agent, an antiviral agent, an antibacterial agent, antifungal agent, an immunosuppressant agent, an hemostasis agent, and an anti-inflammatory agent.

102. An in vivo polymerized biocompatible hydrogel polymer comprising:

(a) at least one first monomeric unit bound through at least one amide, thioester, or thioether linkage to at least one second monomeric unit, wherein the first monomeric unit is a glycol, trimethylolpropane, pentaerythritol, hexaglycerol, or tripentaerythritol derivative, and wherein the first monomeric unit further comprises one or more polyethylene glycol sections;

(b) at least one second monomeric unit bound to at least one first monomeric unit, wherein the second monomeric unit is a trimethylolpropane, glycerol, diglycerol, pentaerythritol, sorbitol, hexaglycerol, tripentaerythritol, or polyglycerol derivative, and wherein the second monomeric unit comprises one or more polyethylene glycol sections; and

(c) optionally, one or more therapeutic agents;

wherein the in vivo polymerized biocompatible hydrogel polymer is polymerized at least in part at a target site in a human body.

103. The in vivo polymerized biocompatible hydrogel polymer of claim 102, wherein the therapeutic agent is selected from the group consisting of an anticancer agent, an antiviral agent, an antibacterial agent, antifungal agent, an immunosuppressant agent, an hemostasis agent, and an anti-inflammatory agent.