Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-09-03
2001-12-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S426000, C424S443000, C424S484000
Reexamination Certificate
active
06331309
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to formulations for the controlled delivery of growth factors. In specific embodiments, the invention relates to controlled release delivery of angiogenic growth factors for the treatment of ischemic tissue and/or for wound healing.
Polypeptide growth factors regulate the growth and proliferation of cells. A number of human growth factors have been identified and characterized. Merely by way of example, these include basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial cell growth factor (VEGF), platelet derived growth factor (PDGF), insulin-like growth factors (IGF-I and IGF-II), nerve growth factor (NGF), epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HBEGF). Because of their ability to stimulate cell growth and proliferation, growth factors have been used as wound healing agents. Some growth factors, such as bFGF and VEGF exhibit potent angiogenic effects, i.e. they stimulate the growth of new capillary vessels. These angiogenic growth factors have been used to treat conditions associated with ischemia, such as coronary artery disease and peripheral vascular disease. By treating ischemic tissue with an angiogenic growth factor, new blood vessels are generated which are capable of bypassing occluded segments of arteries, thereby reestablishing blood flow to the affected tissue (a procedure sometimes referred to as a “bio-bypass”). Angiogenic growth factors have also been used to promote wound healing.
A major challenge in the use of growth factors is the development of a delivery vehicle which will provide the appropriate level of bioavailability of the drug to the affected area to achieve a desired clinical result. Hence, U.S. Pat. No. 5,457,093 discloses the use of various agents to produce relatively high viscosity hydrogels containing growth factors. We have found, however, that the use of a hydrogel containing bFGF and hydroxyethyl cellulose failed to produce a desired result in a human clinical trial directed at topical wound healing despite the fact that bFGF is a potent angiogenic agent and possesses other biological activities that are desirable in a wound healing agent. Additionally, we have found that the use of a hydrogel containing bFGF and a polyoxyethylene-polyoxypropylene block copolymer (Pluronic) in an animal model of angiogenesis failed to produce a desired angiogenic response.
Another problem that has been encountered in the preparation of controlled release formulations of polypeptide growth factors is that the excipients employed to impart controlled release characteristics may make it difficult to prepare an homogeneous dispersion of the growth factor by simple mixing techniques. For example, a topical formulation of PDGF has been produced commercially using greater than 1% carboxymethylcellulose. At such concentrations, obtainment of an homogeneous dispersion of the polypeptide is difficult.
It is an object of the invention to provide a formulation for the controlled release delivery of polypeptide growth factors which releases the growth factor at a rate which promotes angiogenesis and/or wound healing.
It is another object of the invention to provide methods for administering growth factors at controlled rates capable of promoting wound healing and/or angiogenesis in a subject in need of such treatment.
It is a further object of the invention to provide controlled release for formulations of polypeptide growth factors that can be prepared as homogeneous compositions by simple mixing techniques.
Other objects of the invention will be apparent from the description which follows.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a hydrogel composition for the controlled release delivery of a polypeptide growth factor comprising:
(a) a therapeutically effective amount of a polypeptide growth factor having at least one region of positive charge;
(b) a physiologically acceptable water-miscible anionic polymer;
(c) a physiologically acceptable water-miscible non-ionic polymeric viscosity controlling agent; and
(d) water.
We have discovered that the use of an anionic polymer in combination with a non-ionic polymeric viscosity controlling agent allows one to control independently the drug release characteristics and the physical characteristics, i.e. viscosity, of the formulation. In particular, we have discovered that the water-miscible anionic polymer can be used to impart a therapeutically efficacious release rate when used at low concentrations. Preferably, the water-miscible anionic polymer is selected from sodium carboxymethylcellulose and poly(acrylic acid). Poly(acrylic acid) imparts a therapeutically efficacious release rate when it constitutes as little as 0.001% to 0.01% by weight of the total hydrogel composition. At this low concentration, poly(acrylic acid) does not contribute significantly to an increase in viscosity of the formulation. Thus, one can use the poly(acrylic acid) to optimize the release rate of the growth factor in order to obtain a desired biological effect while employing the physiologically acceptable non-ionic polymer to obtain a desired viscosity for use in a particular application. While one may produce a highly viscous hydrogel in accordance with the invention, we have found that high viscosity is not necessary in order to obtain a desired biological effect in wound healing or angiogenesis.
In one embodiment of the invention, there is provided a method for treating a condition characterized by ischemia wherein the composition of the invention is employed to administer a controlled release dosage of an angiogenic growth factor such as bFGF or VEGF to the ischemic tissue. This method can be used, for example, to treat coronary artery disease or peripheral vascular disease.
In another embodiment of the invention, there is provided a method for promoting wound healing wherein the composition of the invention is employed to administer a controlled release dosage of a growth factor to the wound site.
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Jennings, Jr. Robert N.
Protter Andrew A.
Wang Yu-Chang John
Yang Bing
Howard S.
Knobbe Martens Olson & Bear LLP
Page Thurman K.
Scios Inc.
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