Biodegradable pH/thermosensitive hydrogels for sustained delivery of biologically active agents

• US 6,451,346 B1
• Filed: 12/23/1998
• Issued: 09/17/2002
• Est. Priority Date: 12/23/1998
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Dai, Weiguo, Shah, Subodh
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/221,178
• Time in Patent Office: 1,364 Days
• Field of Search: 424/78.08, 424/486, 424/78.18, 424/78.26, 424/426, 424/428, 514/772.3, 514/944
• US Class Current: 424/486
• 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: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00

Abstract

The present invention relates generally to the development of pharmaceutical compositions which provide for sustained release of biologically active polypeptides. More specifically, the invention relates to the use of pH/thermosensitive biodegradable hydrogels, consisting of a A-B di block or A-B-A tri block copolymer of poly(d,l- or l-lactic acid) (PLA) or poly(lactide-co-glycolide) (PLGA) (block A) and polyethylene glycol (PEG) (block B), with ionizable functional groups on one or both ends of the polymer chains, for the sustained delivery of biologically active agents.

Claims

1. A pharmaceutical composition for the sustained administration of an effective amount of a protein, comprising an injectable biodegradable polymeric matrix into which said protein has been incorporated, said polymeric matrix having reverse thermal gelation properties and pH-responsive gelation/de-gelation properties;

wherein said polymeric matrix is a biodegradable block copolymer comprising;

(a) 55% to 80% by weight of a hydrophobic A polymer block comprising poly lactide-co-glycolide (PLGA) having an average molecular weight of between 1000-20,000; and

(b) 20% to 45% by weight of a hydrophilic B polymer block comprising a polyethylene glycol having an average molecular weight of between 500-10,000; and

wherein said biodegradable block copolymer has ionizable functional groups on one or both ends of the polymer chains.

2. The composition of claim 1, wherein said ionizable functional groups have a pK_a in the range of 3-8.

3. The composition of claim 2, wherein said hydrophobic A polymer block is poly lactide-co-glycolide (PLGA).

4. The composition of claim 3, wherein said block copolymer is a tri block copolymer having a configuration selected from the group consisting of A-B-A and B-A-B block segments.

5. The composition of claim 4, wherein said hydrophobic A polymer block comprises 74% by weight of said block copolymer and said hydrophilic B polymer block comprises 26% by weight of said block copolymer.

6. The composition of claim 5 further comprising an excipient which will vary the lower critical solution temperature and increase the rate of gelation of said block copolymer.

7. The composition of claim 1, wherein said protein is selected from the group consisting of interferon consensus, interleukins, erythropoietins, granulocyte-colony stimulating factor (GCSF), stem cell factor (SCF), leptin (OB protein), interferons (alpha, beta, gamma), tumor necrosis factor (TNF), tumor necrosis factor-binding protein (TNF-bp), interleukin-1 receptor antagonist (IL-1ra), brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), neurotrophic factor 3 (NT3), fibroblast growth factors (FGF), neurotrophic growth factor (NGF), bone growth factors such as osteoprotegerin (OPG), granulocyte macrophage colony stimulating factor (GM-CSF), megakaryocyte derived growth factor (MGDF), keratinocyte growth factor (KGF), thrombopoietin, platelet-derived growth factor (PGDF), novel erythropoiesis stimulating protein (NESP), tissue plasminogen activator (TPA), urokinase, streptokinase and kallikrein.