Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Skin burn or open wound treatment
Reexamination Certificate
1996-05-20
2003-02-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Skin burn or open wound treatment
C424S078170, C424S078080, C424S078270
Reexamination Certificate
active
06517824
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the treatment of fibrotic conditions, and to the use of antifibrotic agents for the amelioration and modification of such diseases. The present invention is also concerned with therapeutic compositions in which antifibrotic agents are chemically combined with carriers such as polymers in order to enhance the pharmacokinetic profile of the antifibrotic agents.
BACKGROUND OF THE INVENTION
The fibrotic conditions which the present invention is intended to treat include changes in the structure and function of various organs in connection with the metabolism of collagen and other biomolecules. One of the long-term sequelae of hypertension is the deposition of connective tissue in walls of blood vessels. In hypertensive rats, collagen biosynthesis and deposition are increased in the aorta, and these effects are reversed when blood pressure is lowered by antihypertensive drugs. Treatment of animals with experimental hypertension with agents that selectively inhibit collagen formation and reduce vascular collagen content, suggesting that increased collagen contributes to the maintenance of hypertension. Although the use of antifibrotic agents has increased the understanding of the role of collagen in hypertension and vascular disease, their application as potential therapeutic agents for chronic conditions has been limited.
Collagen is the most abundant protein in vertebrates. The biosynthesis of collagen involves unique post-translational modification of pro-alpha chains. Hydroxylation of prolyl and lysyl residues, a key part of collagen formation, is vital for normal triple-helix formation and intermolecular cross-linking. When post-translational processing is inhibited, non-helical procollagen forms, and it is then degraded by intracellular proteases and is secreted into the extracellular matrix at a slower rate as a nonfunctional protein. The incorporation of proline analogues, e.g., cis-4-hydroxy-L-proline (cHyp), into nascent pro-alpha chains reduces the extracellular accumulation of collagen. The agents described herein are believed to act more generally by inhibiting collagen synthesis and thereby averting certain of the pathophysiological sequelae of fibrosis, such as atherosclerosis and hypertension. Through the distortion of bond angles and from steric hindrance among polypeptide chains; cHyp inhibits the folding of pro-alpha chains into a stable triple helix. Other proline analogues such as cis-4-fluoroproline, cis-4-bromoproline, and 3,4-dehydroproline have similar effects, but can also inhibit other post-translational steps. The compound 3,4-dehydroproline is an example of a proline analogue which can also inhibit other post-translational steps; for example, 3,4-dehydroproline inhibits prolyl hydroxylase activity. This proline analogue has been administered to humans with pulmonary fibrosis in the condition referred to as adult respiratory distress.
The antifibrotic agents described herein are most effective in tissues undergoing rapid rates of collagen synthesis. For example, collagen comprises about one-third of the dry weight of pulmonary arteries in which synthesis increases rapidly following induction of hypertension. Exposure to hypoxia causes constriction of small pulmonary arteries and hypertension develops form sustained vasoconstriction and structural changes in the vascular wall. Proliferation of vascular smooth muscle cells and connective tissue accumulation thicken the vessel walls and narrow the lumen of pulmonary arteries. These structural changes cause or contribute to hypertension.
Collagen metabolism has been implicated as a negative factor in other diseases and conditions. For example, scar tissue is comprised largely of collagen. While some scar tissue is normal as a result of the closure and healing of wounds, excess scar tissue and collagen based adhesions are often undesirable and unhealthy. It is important to note, accordingly, that several proline analogues have been shown to be effective in inhibiting scar formation.
The present invention in particular relates to polymers which contain the antifibrotic compounds described herein, pharmaceutical compositions containing such polymers and various methods of preparation and use. In such polymers, cis-hydroxyproline (cHyp) or another antifibrotic agent is the pharmacologically active agent, useful in controlling the proliferation of collagen or the other changes in tissue as described herein in detail. This is particularly important in diseases and conditions where collagen is deposited or synthesized in abnormally high levels, or where collagen is not properly broken down or removed, contributing to the pathology of the particular disease or condition. In the past it has been recognized that cHyp is active in reducing the abnormal proliferation of collagen. More particularly, the pharmacological effectiveness of cHyp has been demonstrated in treating pulmonary fibrosis. Unfortunately, it is also recognized that cHyp can be potentially toxic if used improperly, particularly in chronic use, and thus has had limited clinical utility.
In recent efforts to provide a stable carrier for cHyp, poly tethylene glycol-co-lysine) (PEG-Lys) functioned as such a carrier for the antifibrotic agent; Poiani et al.,
Bioconjugate Chemistry;
1994; 5(6):621-630. It was demonstrated that a hydrolytically stable amide-linkage between cHyp and the polymeric backbone is needed to maximize the antifibrotic activity both in vitro and in vivo; Poiani, G. J., et al., supra. Typically, the cHyp is coupled to the free acid carrier via the dicyclohexylcarbodiimide, 4-dimethylaminopyridine (DCC/DMAP) system. However, the primary disadvantage of this system is the significant variability in cHyp attachment. The maximum degree of attachment via this coupling scheme for the amide-linked cHyp is approximately 65%, requiring a three-fold excess of the appropriately protected cHyp. In order to alleviate this variability and low degree of drug incorporation, the present invention uses the dipeptide of L-Lys and cHyp as the drug-containing chain extender. Thus, controlled dosage forms, i.e., mg/ml of a carrier matrix for which a specific drug content is maintained, can be readily obtained and administered.
The present invention thus provides an improved synthetic scheme that has been developed in order to optimize the capacity of cHyp that can be conjugated to the poly(PEG-Lys) carrier, and a detailed hydrolytic stability profile has been developed. In a further extension of the present invention, aimed at combining the high bioactivity of poly(PEG-Lys-cHyp) which has been observed with further extensions of existing treatments into fibrotic lung disorders, there is also provided intravenous liposomal delivery of drug conjugates using non-immunogenic polysaccharide-coated vesicles. Organ distribution and biological stability were investigated using radiolabeled drug conjugates of the present invention.
The controlled release and targeting of drugs to specific cells and organs has become increasingly important. Accordingly, the present invention provides a hybrid drug delivery system comprising a non-specific, non-cytotoxic, polymeric carrier containing a covalently bound, low molecular weight, water soluble, polar drug delivered by means of a liposomal vehicle containing target-specific ligands. Data has been gathered and is presented below in order to demonstrate the efficacy of this drug delivery system, as well as to illuminate the general principles on which it operates. The targeting of such sustained release antifibrotic treatment compositions to tissues with increased collagen production is an approach which can be taken in order to prevent organ fibrosis. Broader applications are found in treating scar for mnation, adhesions, and fibrosing disorders of other visceral organs.
Accordingly, the present invention seeks to overcome the disadvantages of past approaches to treatment of fibrotic diseases. Thus, one object of the present invention is to facilitate the use
Kemnitzer, III John E.
Kohn Joachim
Poiani George J.
Riley David J.
Page Thurman K.
Perkins Coie
University of Medicine & Denistry of New Jersey
Ware T.
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