Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-07-07
2001-01-16
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S021800, C514S054000, C514S055000, C514S802000, C530S380000, C530S382000
Reexamination Certificate
active
06174855
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the use of known pharmaceutically-active compounds in the manufacture of a product for use in the control of wound healing processes within the body, in particular in the prevention of adhesions, and/or the formation of scar tissue, resulting from physical trauma, including injury, surgery and burns, as well as from inflammation; and further to pharmaceutical products for use in the control of wound healing processes within the body.
BACKGROUND TO THE INVENTION
The relative mobility of many organs of the human body is a prerequisite of optimal function. In this respect, it is important that such organs are able to move and slide in relation to adjacent organs and/or in relation to the body cavities within which they are enclosed. For example, if the oesophagus, the stomach, the intestines, the liver and the urogenital organs were not at least partially mobile in relation to adjacent organs and the abdominal wall and the diaphragm, functional disturbances would occur, such as the restriction of respiratory movement, hampered movement of intra-abdominal structures, intestinal obstruction and/or infertility.
If an organ receives a physical trauma, such as an injury, surgery, a burn or an electric shock, or experiences inflammation as a result of a pathogenic cause, one of the inevitable consequences of the healing and inflammatory processes which follow is the formation of adhesions and scar tissue, which may naturally restrict the aforementioned organ mobility.
Adhesions and scar tissue are formed as a result of the formation of a fibrin-platelet network following physical trauma or pathogenic inflammation, and the subsequent rebuilding and replacement of this network by granulation tissue.
The complex and typically highly irregular structure of the fibrin-platelet network, formed at an early stage after the trauma or as a result of inflammation, is of key importance in the fate of any wound healing process. Any physical structure, particularly filaments and membranes, whether diffusely or distinctly outlined, acts as a guide for the invading granulation tissue. This newly formed tissue is, in accordance with the mechanism described above, eventually rebuilt as scar tissue, organised as fibrous strands or membranes. The invading granulation tissue cells can practically never fully substitute for the original cells and, as a result, the tissue is never regenerated, but merely repaired. This is true for both the skin and for mucosal membranes, including those lining the body cavities, as well as other structures including muscles, tendons and nerves. Moreover, the scar tissue so formed may, in time, contract and remain contracted, deforming and disorganising the injured area.
The proliferation and invasion of fibrin threads by even a few granulation tissue cells (including angiogenic cells) is usually sufficient to induce the formation of adhesions. The direction, density and organization of the individual fibrin threads in the fibrin-platelet network of the clot provides information, and determines the track to be taken by the invading granulation tissue cells, as well as by specific cells such as Schwann cells. Extracellular fibrin may deposit, stick to and establish abnormal bridges between adjacent structures.
Thus, the structure of the fibrin-platelet network is of key importance in guiding the invading granulation tissue and thus in the formation of adhesions and scar tissue.
PRIOR ART
European Patent Application EP 0 051 354 describes a polymeric substrate coated with the polysaccharide chitosan, to which is appended the antithrombotic agent heparin.
U.S. Pat. No. 5,116,824 describes a composite material comprising an N-acylchitosan and collagen which is suitable for wound dressings. Heparin may be incorporated as an antithrombotic agent.
Neither of these prior art documents disclose the use of the devices described therein in the prevention of the formation of adhesions and/or scar tissue following physical trauma, such as injury or surgery or pathogenic inflammation. Moreover, the use of thrombin inhibitors, and in particular low molecular weight thrombin inhibitors, is not mentioned.
Further, the combined use of fibrinolytic agents and polysaccharides has been neither disclosed nor suggested to be of potential in the prevention of formation of adhesions and/or scar tissue.
DISCLOSURE OF THE INVENTION
We have now found, surprisingly, that thrombin inhibitors significantly inhibit or prevent the formation of adhesions and/or scar tissue following physical trauma or pathogenic inflammation, and may thus be used in the control of wound healing processes within the body.
According to a first aspect of the invention there is provided the use of a thrombin inhibitor in the manufacture of a product for use in the control of wound healing processes within the body.
In particular, we have found that thrombin inhibitors may be used to inhibit or prevent fibrin-related adhesion and/or scar tissue formation as a result of physical trauma or pathogenic inflammation.
By “fibrin-related adhesion” we mean adhesion resulting from the establishment of a fibrin-platelet network (i.e. a network of fibrin and cells including platelets) following a physical trauma or pathogenic inflammation, as described hereinbefore.
We have found that thrombin inhibitors may be used to inhibit or prevent the formation of fibrin-related adhesion and/or scar tissue following physical trauma, including physical injury to the skin or the internal organs, including accidental injury; surgery, including laparoscopic surgery, “open” conventional gastrointestinal and gynaecological surgery, oncological surgery, orthopaedic surgery (e.g. treatment of fractures, implantation of a prosthesis, surgery on tendons, muscles and ligaments), neurosurgery, heart and chest surgery or trauma surgery and the insertion of catheters; thermal trauma, including burns; chemical trauma, including exposure to corrosive, acidic or alkaline substances; and electrical shock.
Moreover, we have found that thrombin inhibitors may be used to inhibit or prevent the formation of fibrin-related adhesion and/or scar tissue resulting from pathogenic inflammation, including inflammation produced as a result of medical conditions, such as rheumatoid diseases, systemic inflammatory reactions and autoimmune diseases.
According to a further aspect of the invention, there is provided a method of inhibition or prevention of fibrin-related adhesion and/or scar tissue formation, which method comprises administration of a thrombin inhibitor to a patient in need of such inhibition or prevention.
In the case of surgery, or pathogenic inflammation, “administration” may take place before, after or during the surgical event or the onset of the medical condition as appropriate.
The thrombin inhibitor may be administered either locally or systemically, in the form of pharmaceutical preparations comprising the thrombin inhibitor in a pharmaceutically acceptable dosage form. Dosage forms which may be employed for local and systemic administration include those which are well known to those skilled in the art, for example as described in Lachman et al, “
Theory and Practice of Industrial Pharmacy
”, Lea & Febiger (1986).
By “pharmaceutically acceptable dosage form” we mean a dosage form which is sterile and, preferably, non-pyrogenic.
In particular, we have found that the co-administration of a polysaccharide and a thrombin inhibitor results in the inhibition or prevention of fibrin-related adhesion and/or scar tissue formation when compared to administration of the polysaccharide alone.
Thus, according to a further aspect of the invention there is provided a method of inhibition or prevention of fibrin-related adhesion and/or scar tissue formation, which method comprises the co-administration of a polysaccharide and a thrombin inhibitor to a patient in need of such inhibition or prevention.
The thrombin inhibitor may be co-administered with the polysaccharide either locally or systemically. Moreover co-administration
Astrazeneca AB
Low Christopher S. F.
Mohamed Abdel A.
White & Case LLP
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