Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2002-04-29
2004-07-06
Nashed, Nashaat T. (Department: 1652)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06759432
ABSTRACT:
The present invention relates to matrix metalloproteinase (MMP) inhibitors, especially collagenase inhibitors, and to their use in the manufacture of medicaments.
There are many different types of collagen found in the body and they, together with other extracellular matrix components, for example, elastin, gelatin, proteoglycan and fibronectin, make up a large proportion of the body's extracellular tissue. Matrix metalloproteinases (MMPs) are enzymes that are involved in the degradation and denaturation of extracellular matrix components. Collagenases, for example, are matrix metalloproteinases that degrade or denature collagen.
A large number of different collagenases are known to exist. These include interstitial collagenases, type IV-specific collagenases and collagenolytic proteinases. Collagenases are generally specific for collagens which, in their full triple helix structure, are extremely resistant to other enzymes.
Other MMPs are involved in the degradation and denaturing of different extracellular matrix components, for example, elastin, gelatin and proteoglycan. Some MMPs are able to degrade or denature several different types of collagen and also other extracellular matrix components. For example, stromelysin degrades type IV collagen, which is found in basement membrane, and also has an effect on other extracellular matrix components such as elastin, fibronectin and cartilage proteoglycans.
There is a classification system for MMPs, see Nagase et al 1992. For example, MMP1 is a collagenase that is sometimes called “collagenase”, MMP2 is a 72kD gelatinase, MMP3 is stromelysin and MMP9 is a 92kD gelatinase. The official designations are used herein.
Collagenases have been implicated in a number of diseases, for example, rheumatoid arthritis [Mullins, D. E. et al 1983], periodontal disease and epidermolysis bullosa, and it has been proposed to use MMP inhibitors in the treatment of such conditions.
U.S. Pat. Nos. 5,183,900, 5,189,178 and 5,114,953 describe the synthesis of N-[2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide, also known as GM6001, Galardin or Galardin-MPI (trade names), and other MMP inhibitors, and their use in the prevention and treatment of corneal ulceration. Treatment of corneal ulcers with peptide hydroxamic acid inhibitors has been found to assist in the healing of those ulcers. Further details of such uses are given in Schultz et al 1992.
Also described in the above-mentioned U.S. patent specifications is the use of collagenase inhibitors in situations where bacterial enzymes may be detrimental to tissue, for example, in bacterial ulceration.
Other collagenase inhibitors based on hydroxamic acid are disclosed in WO 90/05716, WO 90/05719 and WO 92/13831. Such collagenase inhibitors are disclosed as being used in the management of disease involving tissue degradation, particularly disease involving collagen breakdown, and/or the promotion of wound healing.
Other synthetic MMP inhibitors and, in particular, collagenase inhibitors that have been developed include those described in EP-A-126, 974 and EP-A-159, 396 and in U.S. Pat. Nos. 4,599,361 and 4,743,587.
One inhibitor undergoing clinical trials is BB-94 also known as Batimastat (British Bio-technology Ltd.). Potential uses of BB-94 for the control of cancer metatasis are described in EP-A-276436. It has been proposed to use an oral formulation of BB-94 in the treatment of bone cancer.
The present invention is concerned with the contraction of tissues, for example, scars. Contraction of tissues comprising extracellular matrix components, especially of collagen-comprising tissues, may occur in connection with many different pathological conditions and with surgical or cosmetic procedures. Contracture, for example, of scars, may cause physical problems, which may lead to the need for medical treatment, or it may cause problems of a purely cosmetic nature.
It has been proposed that contraction is cell-mediated and a number of studies have suggested possible mechanisms for cell mediated collagen contraction [Gabbiani et al. 1972, Ehrlich & Rajaratnam 1990]. Investigations have been made into the role, if any, played by MMPs in the process of contracture. However, according to one proposition, MMPs are not produced during contraction [Schor et al. 1980]. According to another proposition, MMPs are produced during lattice contraction but are not implicated in the contractile process [Nakagawa et al. 1989, Mauch et al. 1989, Lambert 1992]. Instead, it has been proposed that contraction is dependent upon the extracellular lattice cell number, upon there being an intact actin cytoskeleton, and upon attachment of the cells to the extracellular matrix.
The present invention is based on the surprising observation that, during experiments on in vitro models of scar contraction, collagen (the main component of scar tissue) appears to be invaded and permanently remodelled by fibroblasts and that such invasion and remodelling is inhibited by collagenase inhibitors. The remodelling generally appears as contraction of the collagen, which contraction is inhibited by inhibition of collagenase. Furthermore, inhibition of other MMPs also results in inhibition of contraction. The observation that contraction of the tissue involves MMPs is particularly surprising since previous investigations have shown that MMPs are not produced during contraction while other investigations have indicated that MMPs are produced but are not involved in the contractile process (see above).
The present invention provides the use of an MMP inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a natural or artificial tissue comprising extracellular matrix components to inhibit, i.e. restrict, hinder or prevent, contraction of the tissue, especially contraction resulting from a pathological condition or from surgical or cosmetic treatment.
The present invention also provides a method for the inhibition in vivo or in vitro of contraction of a natural or artificial tissue comprising extracellular matrix components, which comprises administering an MMP inhibitor to the tissue during and/or after its formation. Under in vivo conditions, a therapeutically effective amount of the MMP inhibitor should be administered.
The present invention especially provides the use of a collagenase inhibitor in the manufacture of a medicament for the treatment or prophylaxis of tissue comprising collagen to inhibit contraction of the tissue resulting from contraction of the collagen.
Further, the present invention especially provides a method for the inhibition of contraction of tissue comprising collagen, resulting from contraction of the collagen, which comprises administering a therapeutically effective amount of a collagenase inhibitor to the tissue.
The methods of the present invention may be used for medical or cosmetic treatment.
The invention provides a method for the inhibition, for cosmetic reasons, of disfigurement caused by contraction of tissue comprising extracellular matrix components, which method comprises administering a matrix metalloproteinase inhibitor to the tissue.
Cosmetic treatments, such as chemical or physical dermal abrasion, used as anti-ageing treatments, cause trauma to the skin. Use of MMP inhibitors during the healing process which occurs after the initial abrasion is a cosmetic use of MMP inhibitors according to the present invention.
The present invention also provides the use of an MMP inhibitor to inhibit, i.e. restrict, hinder or prevent, invasion by cells, especially fibroblasts, into tissue comprising an extracellular matrix and/or migration by cells, especially fibroblasts, in or through tissue comprising an extracellular matrix.
The term “MMP inhibitor” is used herein to denote any substance that is capable of inhibiting, i.e. restricting, hindering or preventing, the action of an MMP. The term “collagenase inhibitor” is used herein to denote any substance that is capable of inhibiting, i.e. restricting, hin
Khaw Peng Tee
Schultz Gregory S.
Greenlee Winner and Sullivan P.C.
Nashed Nashaat T.
University of Florida Research Foundation
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