Water soluble paclitaxel derivatives

Abstract

Disclosed are water soluble compositions of paclitaxel and docetaxel formed by conjugating the paclitaxel or docetaxel to a water soluble polymer such as poly-glutamic acid, poly-aspartic acid or poly-lysine. Also disclosed are methods of using the compositions for treatment of tumors, auto-immune disorders such as rheumatoid arthritis. Other embodiments include the coating of implantable stents for prevention of restenosis.

1 . A composition comprising (i) a conjugate of a therapeutic agent, contrast agent or drug and (ii) a water-soluble amino acid polymer in which there is more than one different type of amino acid residue and in which greater than 50% of the amino acid residues comprise glutamic acid and/or aspartic acid and/or lysine.  
     
     
         2 . A composition as claimed in  claim 1 , wherein the drug is a chemotherapeutic or antiangiogenic drug, preferably a taxoid, tamoxifen, etoposide, teniposide, fludarabine, doxorubicin, daunomycin, emodin, 5-fluorouracil, FUDR, estradiol, camptothecin, a retinoid, verapamil, an epothilone or a cyclosporine.  
     
     
         3 . A composition as claimed in  claim 1 , wherein the drug is a taxoid which is paclitaxel or taxotere.  
     
     
         4 . A composition as claimed in  claim 1 , which contains, in addition to glutamic acid and/or aspartic acid and/or lysine residues, residues derived from at least one of the other amino acids provided through the genetic code, and/or residues derived from at least one of 2-Aminoadipic acid, 3-Aminoadipic acid, beta-alanine, 2-Aminobutyric acid, 4-Aminobutyric, 6-Aminocaproic acid, 2-Aminoheptanoic acid, 2-Aminoisobutyric acid, 3-Aminoisobutyric acid, 2-Aminopimelic acid, 2-4-Diaminobutyric acid, Desmosine, 2,2′-Diaminopimelic acid, 2,3-Diaminopropionic acid, N-Ethylgylcine, N-Ethylasparagine, Hydroxylysine, allo-Hydroxylysine, 3-Hydroxyproline, 4-Hydroxyproline, Isodesmosine, allo-Isoleucine, N-Methylglycine, N-Methylisoleucine, 6-N-Methyllysine, N-Methylvaline, Norvaline, Norleucine, and Ornithine.  
     
     
         5 . A composition as claimed in  claim 1 , wherein said copolymer has a molecular weight of from about 5,000 to about 100,000 daltons, preferably from about 20,000 to about 80,000 daltons, more preferably from about 25,000 to about 50,000 daltons.  
     
     
         6 . A composition as claimed in  claim 1 , wherein the amount of the drug is at least 10% (w/w), preferably from about 10% to about 40% (w/w), based on the mass of said conjugate.  
     
     
         7 . A composition as claimed in  claim 1 , wherein said amino acid residues are in the I form.  
     
     
         8 . A composition as claimed in  claim 1  for use in a method of therapy.  
     
     
         9 . A composition as claimed in  claim 1  for use in the treatment of breast cancer, ovarian cancer, malignant melanoma, lung cancer, gastric cancer, prostate cancer, colon cancer, head and neck cancer, leukemia or Kaposi's sarcoma.  
     
     
         10 . Use of a composition as claimed in  claim 1  in the manufacture of a medicament for treating breast cancer, ovarian cancer, malignant melanoma, lung cancer, gastric cancer, prostate cancer, colon cancer, head and neck cancer, leukemia or Kaposi's sarcoma.  
     
     
         11 . A water soluble amino acid chain or polymer comprising a mixture of glutamic acid, aspartic acid, and/or lysine having about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, to about 50% or so of the glutamic acid, aspartic acid, or lysine residues, respectively, substituted by any of the naturally occurring amino acids such that the majority of residues comprise glutamic acid and/or aspartic acid and/or lysine.