Design of an i.v. formulation of an unstable prodrug candidate for prostate cancer treatment: solution chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin.
The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between pH 5 and 6. The dependence of log k(obsd) on pH in acidic medium is characteristic of specific acid-catalysis of the sugar hemiaminal of 1 (as in the case of doxorubicin). Isolation of degradates and structural determination shows that the degradation at lower pH values yields the water-insoluble aglycone doxorubicinone, supporting the mechanism of acid-catalyzed loss of the amino sugar. At pH higher than 5, a more complicated degradation pattern is observed, including the loss of the amino sugar and the aromatization of the saturated ring to give 7,8-dehydro-9,10-desacetyldoxorubicinone as one of the major products. Around the pH of maximum stability in solution, the rate of degradation of 1 is significantly greater than that for doxorubicin, which rules out the formulation of a room temperature solution product with a sufficiently long shelflife for market use. Design of a stable lyophilized formulation for sterile reconstitution based on the physicochemical properties of 1 is described.
Pharmaceutical Research and Development, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania, USA. skarki@prdus.jnj.com
Shyam B
SB
Karki
Varaporn
V
Treemaneekarn
Drazen
D
Ostovic
Maneesh
M
Nerurkar
Orn
O
Almarsson
D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000737:chemistry* / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy*
D000903:Antibiotics, Antineoplastic; D009842:Oligopeptides; D011355:Prodrugs; C440619:glutaryl-hydroxyprolyl-alanyl-seryl-cyclohexylglycyl-glutaminyl-seryl-leucyl-doxorubicin; D004317:Doxorubicin