Biocompatible hydrogel polymer formulations for the controlled delivery of biomolecules

• US 10,111,985 B2
• Filed: 08/09/2012
• Issued: 10/30/2018
• Est. Priority Date: 08/10/2011
• Status: Active Grant

• Current Assignee: Theragenics Corporation (Juniper Investment Co. LLC)
• Original Assignee: Medicus Biosciences, LLC
• Inventors: Askari, Syed H., Choi, Yeon S., Horng, George
• Primary Examiner(s): Barham, Bethany P
• Assistant Examiner(s): Lazaro, Dominic
• Application Number:
  US13/571,116
• Publication Number:
  US 20140302051A1
• Time in Patent Office: 2,273 Days
• Field of Search: None
• 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 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence

Abstract

Provided herein are biocompatible hydrogel polymers capable of gelling in vivo comprising a therapeutic agent such as a protein or other biomolecule and kits comprising at least one nucleophilic compound or monomer unit, at least one electrophilic compound or monomer unit, and at least one therapeutic agent. The biocompatible hydrogel polymer is bioabsorbable and releases the therapeutic agent at a target site, avoiding systemic exposure and achieving a controlled delivery.

Claims

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

(a) one or more multi-ARM nucleophilic PEG monomers, wherein the multi-ARM PEG nucleophilic monomers comprise a polyol core, wherein the polyol core is selected from the group consisting of

2. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the molecular weight of the multi-ARM PEG nucleophilic monomers and/or the multi-ARM PEG electrophilic monomers is about 15000 to about 40000.

3. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the pharmaceutically active biomolecule is released from the biocompatible hydrogel polymer within 14 days.

4. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the biocompatible hydrogel polymer has a pore size, wherein the pore size is small enough to essentially inhibit the release of the pharmaceutically active biomolecule before the time that the biocompatible hydrogel polymer starts to degrade, and wherein the ratio of the pore size of the biocompatible hydrogel polymer to the size of the pharmaceutically active biomolecule is less than 8.

5. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the biocompatible hydrogel polymer has a pore size, wherein the pore size is large enough to allow at least a partial release of the pharmaceutically active biomolecule before the time that the biocompatible hydrogel polymer starts to degrade, and wherein the ratio of the pore size of the biocompatible hydrogel polymer to the size of the pharmaceutically active biomolecule is more than 8 and less than 12.

6. The biocompatible hydrogel polymer of claim 1.

7. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the polyol core of the multi-ARM PEG nucleophilic monomer is:

8. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the polyol core of the multi-ARM PEG nucleophilic monomer is:

9. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the polyol core of the multi-ARM PEG nucleophilic monomer is:

10. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the polyol core of the multi-ARM PEG nucleophilic monomer is:

11. The in vivo gelling pharmaceutical pre-formulation of claim 1, wherein the antibody is an anti-CD20 antibody.

12. A biocompatible hydrogel polymer made by mixing:

(a) one or more multi-ARM nucleophilic PEG monomers, wherein the multi-ARM PEG nucleophilic monomers comprise a polyol core, wherein the polyol core is selected from the group consisting of

13. The biocompatible hydrogel polymer of claim 12, wherein the mixing is performed outside a human body and the biocompatible hydrogel polymer gels at least in part inside the human body.

14. The biocompatible hydrogel polymer of claim 12, wherein the mixing is performed outside a human body, and the biocompatible hydrogel polymer gels outside the human body before delivery to a target site.

15. The biocompatible hydrogel polymer of claim 12, wherein the molecular weight of the multi-ARM PEG nucleophilic monomers and/or the multi-ARM PEG electrophilic monomers is about 15000 to about 40000.

16. The biocompatible hydrogel polymer of claim 12, wherein the pharmaceutically active biomolecule is released from the biocompatible hydrogel polymer within 14 days.

17. The biocompatible hydrogel polymer of claim 12, wherein the biocompatible hydrogel polymer has a pore size, wherein the pore size is small enough to essentially inhibit the release of the pharmaceutically active biomolecule before the time that the biocompatible hydrogel polymer starts to degrade, and wherein the ratio of the pore size of the biocompatible hydrogel polymer to the size of the pharmaceutically active biomolecule is less than 8.

18. The biocompatible hydrogel polymer of claim 12, wherein the biocompatible hydrogel polymer has a pore size, wherein the pore size is large enough to allow at least a partial release of the pharmaceutically active biomolecule before the time that the biocompatible hydrogel polymer starts to degrade, and wherein the ratio of the pore size of the biocompatible hydrogel polymer to the size of the pharmaceutically active biomolecule is more than 8 and less than 12.