Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-09-01
2003-04-01
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S350000, C530S399000, C530S388240, C435S069400, C424S400000, C424S581000
Reexamination Certificate
active
06541447
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to wound healing compositions and, particularly, to such a composition comprising of a growth hormone and growth factor in a balanced mixture that will deliver the maximum therapeutic results with non-healing wounds, burns, trauma, and certain dermatological disorders.
BACKGROUND OF THE INVENTION
1. Overview of the Invention
There have been recent dramatic strides with the discovery of growth factors as wound healing agents. Indeed, the discovery of growth factors has triggered great optimism into the possibility of mastering the art of wound healing and intense effort has been launched on the part of medical researchers and pharmaceutical companies to procure, characterize, and harvest these healing enhancement agents. Because it is believed that administering growth factors to patients with dermal and subdermal wounds enhances the speed by which wounds heal, as discussed in greater detail below, it is the object of this invention to provide a topical composition containing growth factors to increase the body's wound healing properties.
2. Background and Prior Art
Since their discovery almost 30 years ago, growth factors have been shown to stimulate neovascularization in vitro and in animal studies. In the past 10 years, knowledge of growth factors has grown immensely. Broadly defined, growth factors are multifunctional, locally acting, intercellular signaling polypeptides which, among other things, organize and coordinate cellular proliferation. Most growth factors are large peptides or glycoproteins secreted by many cells as a base function, or in response to a challenge, such as a wound or carcinogen. These peptides represent a system of signals that mediate physiologic and pathologic cellular growth and repair, including embryogenesis, wound healing and carcinogenesis.
Currently, there are two known classes of intercellular signaling proteins: (i) endocrine proteins which are long range signaling proteins released into the circulation or other body fluids, and (ii) paracrine proteins which are short range signaling proteins that act locally within tissues. Growth factors are generally considered as paracrine proteins since they are predominantly short range locally acting, intercellular signaling proteins.
There exist six known varieties of growth factors: platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), transforming growth factor beta (TGF&bgr;), and TGF&bgr; Superfamily. In addition to their local mode of action, the different varieties of growth factors share common biological properties. For example, growth factor action is mediated by association with specific, high affinity receptors expressed by the target cells, and growth factors are able to exert their biological effect at low concentrations (10
−9
to 10
−11
M).
Furthermore, on the cellular level, growth factors bind with ligands on the cell surface to generate an intracellular signal on the inside of the cell to modify cellular behavior. Growth factors function by binding to specific cell-surface receptors that are composed of three distinct regions or domains: an extracellular domain, which binds to the growth factor ligand; a transmembrane domain; and an intracellular domain. When the ligand binds to neighboring receptors, conformational changes occur that are transmitted to the intracellular domain and elicit a series of cytoplasmic changes leading to the initiation of the nucleic acid transcription. In many cases, these intracytoplasmic events are enacted through an enzyme, tyrosine kinase, that phosphorylates cytoplasmic proteins, some of which remain in the cytoplasm and some pass to the nucleus with a corresponding gene activation.
Studies have shown that fluid factors isolated from chronic wounds lack the presence of growth factors. Moreover, in vitro studies have shown that growth factors added to wound fluid extracted from postoperative or traumatic wounds have accelerated the wound healing cascade. These facts strongly suggest the important role of growth factors.
One in vitro study examined the effect of human wound fluid on the growth of human dermal fibroblasts and umbilical vein endothelial cells. Katz M H et al., J. Am. Acad. Dermatol.,
Human Wound Fluid from Acute Wounds Stimulates Fibroblast and Endothelial Cell Growth,
25:1054-1058 (December 1988). Katz et al. collected wound fluid from six patients undergoing split-thickness skin and wound fluid from postoperative patients. After seeding the wound fluid in optimal growth media (control) on day 0, cultures of human dermal fibroblasts and umbilical vein endothelial cells were supplemented with or without acute wound fluid on days 1 and 3. The study found that 2% acute wound fluid stimulated the growth of human dermal fibroblasts and umbilical vein endothelial cells when these cells were cultured in 2% fetal bovine serum and endothelial growth medium, respectively. Wound fluid from the postoperative patients caused the same level of stimulation. Furthermore, when anti-platelet-derived growth factor antibody was added to wound fluid, there was a 45% mean reduction in the stimulatory effect on fibroblast growth. This result further suggests that platelet-derived growth factor contributes to the fibroblast growth effect.
It has also been suggested that ulcer healing may be improved by the exogenous provision of specific growth factors. Research has shown that fibroblasts isolated from wound sites on patients proliferated at a slower rate and are morphologically distinct (larger and polyglonal in shape) from normal fibroblasts cells. Stanley A C et al., J. Vasc. Surg.,
Reduced Growth of Dermal Fibroblasts from Chronic Venous Ulcers can be Stimulated with Growth Factors,
26(6):994-999 (December 1997). It was also found that the decreased growth of wound fibroblasts were stimulated by growth factors FGF, EGF, IL-1.
A combination of growth factors produce a magnified effect in stimulating protein synthesis and decreasing protein degradation. They have also been shown to have additive effect in improving whole-body and muscle kinetics. For example, it has been shown that the addition of pure PDGF to a wound site involving the epidermis and dermis has little effect on the morphology or biochemistry of wound healing. Lynch S E et al., Proc. Nat'l. Acad. Sci. USA,
Role of Platelet
-
Derived Growth Factor in Wound Healing: Synergistic Effects with Other Growth Factors,
84(21):7696-7700 (November 1987). In contrast, the addition of partially purified PDGF results in significant dose-dependent increases in the width of the newly synthesized connective tissue and epidermal layers. Further, the addition of partially purified PDGF results in significant increases in the rate of protein and DNA synthesis and the total content of these components in biopsies taken from the wound site. Similar effects were obtained when IGF was added in combination with pure PDGF. Combining the growth factors caused a 2.4 fold increase in the width of newly formed connective tissue layer and a 95% increase in epidermal thickness compared with controls. Id. On the other hand, IGF applied alone did not cause similar morphological changes, thus indicating that the synergistic actions of other factors with PDGF are important in the modulation of the wound healing process. Therefore, a combination of growth factors and growth hormones have a potential amplified effect on accelerated non-healing of ulcers, open wound, osteomyelitis, skeletal muscle injuries such as sports and trauma, and bums and dermatological disorders.
Animal and clinical trials using growth factor therapy have produced outstanding results. Healing of a variety of wounds in animals and patients was enhanced by treatment with EGF or TGF-alpha. Several different studies of topically applied growth factors have shown to accelerate healing by stimulating granulation tissue formation and enhancing epithelialization. Epidermal regeneration of partial thickness b
B & M Healthcare Technologies, Inc.
Carlson Karen Cochrane
Kam Chih-Min
Mahoney Joseph A.
Mayer Brown Rowe & Maw
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