[Ester prodrug of scutellarin: synthesis, physicochemical property and degradation].
OBJECTIVE
To establish the fundamentals for the design of scutellarin prodrug and formulation with feasible physicochemical and biopharmaceutical properties by esterifying scutellarin, an active component with poor absorption extracted from Erigeron breviscapus of Chinese medicine.


METHODS
With the method of salifying followed by esterifying, ethyl and benzyl ester of scutellarin were synthesized. Glycolamide ester of scutellarin was also synthesized with an improved method. Their structures were confirmed by MS and 1H NMR. The solubility and partition coefficient of the prodrugs were determined and their degradations were investigated in various buffers and in human plasma. The emulsion and cyclodextrin complex of glycolamide ester were prepared and the protection of the ester from degradation was compared in the intestinal tract contents. Furthermore, the degradation of glycolamide ester in the homogenates of various intestinal segments was studied. Results Three prodrugs were synthesized successfully and their structures were confirmed. Glycolamide ester of scutellarin showed better stability in the aqueous solution (t(1/2) approximately =16 d, pH 4.2) and the shortest half-life in the human serum (t(1/2) approximately =7 min). Compared with scutellarin, the solubility of glycolamide ester was increased about ten times in pH 4.0 buffer, and about thirty five times in water. Partition coefficient of the glycolamide ester increased significantly from -2.56 to 1.48. However, the ester degradation in the homogenates of intestinal mucus would be an obstacle for its absorption. The degradation rates were in the order duodenum > ileum > or = jejunum > colon. The emulsion showed a better protection of glycolamide ester from the degradation than cyclodextrin complex.


CONCLUSIONS
Glycolamide ester of scutellarin shows better physicochemical properties than ethyl and benzyl eater of scutellarin, but its stability in intestinal tract needs to be improved. The emulsion or / and colon-targeted delivery may be selected as one of strategies to decrease the presystemic degradation.
Cao
Feng
F
Department of Pharmaceutics, China Pharmaceutical University, Nanjing.
Guo
Jian-xin
JX
Ping
Qi-neng
QN
Shao
Yun
Y
Liang
Jing
J
D000818:Animals; D047310:Apigenin / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics*; D004655:Emulsions; D049919:Erigeron / Q000737:chemistry; D004952:Esters; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D005965:Glucuronates / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics*; D020719:Glucuronides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D010946:Plants, Medicinal / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004655:Emulsions; D004952:Esters; D047309:Flavones; D005965:Glucuronates; D020719:Glucuronides; C517532:N,N-diethylglycolamide-4',5,6-trihydroxyflavone-7-glucuronide ester; D011355:Prodrugs; C517530:benzyl scutellarin; C517531:ethyl scutellarin; C484876:scutellarin; D047310:Apigenin