Water soluble cyclosporine monomethoxy poly(ethyleneglycol) conjugates as potential prodrugs

Abstract

The highly water-soluble monomethoxypoly(ethyleneglycol) (mPEG) prodrugs of cyclosporin A (CsA) were synthesized. These prodrugs were prepared by initially preparing intermediate in the form of carbonate at the 3'-positions of CsA with chloromethyl chloroformate, in the presence of a base to provide a 3'-carbonated CsA intermediate. Reaction of the CsA intermediate with mPEG derivative in the presence of a base provides the desired water-soluble prodrugs. As a model, we chose molecular weight 5 kDa mPEG in the reaction with CsA to give water soluble prodrugs. To prove that the prodrug is decomposed in the body to produce CsA, the enzymatic hydrolysis test was conducted using human liver homogenate at 37 degrees C. The prodrug was decomposed in human liver homogenate to produce the active material, CsA, and the hydrolysis half-life (t(1/2)) of the prodrug, KI-306 was 2.2 minutes at 37 degrees C. However, a demonstration of non-enzymatic conversion in pH 7.4 phosphate buffer was provided by the fact that the half-life (t(1/2)) is 21 hours at 37 degrees C. The hydrolysis test in rat whole blood was also conducted. The hydrolysis was seen with half-life (t(1/2)) of about 9.9, 65.0, 14.2, 3.4, 2.1 9.5, and 1.6 minutes for KI-306, 309, 312, 313, 315, 316, and 317, respectively. This is the ideal for CsA prodrug. The pharmacokinetic study of the prodrug, KI-306, in comparison to the commercial product (Sandimmune Neoral Solution) was also carried out after single oral dose. Each rat received 7 mg/kg of CsA equivalent dose. Especially, the prodrug KI-306 exhibits higher AUC and Cmax than the conventional Neoral. The AUC and Cmax were increased nearly 1.5 fold. The kinetic value was also seen with Tmax of about 1.43 and 2.44 hours for KI-306 and Neoral, respectively.

Orally Absorbed Cyclic Peptides

“…: AUC = 32.8 μg/mL·h, C max = 1.8 μg/mL, T max = 1.43 h) had higher bioavailability than CSA (Sandimmune Neoral, 7 mg/kg p.o. : AUC = 21.4 μg/mL·h, C max = 1.1 μg/mL, T max = 2.6 h) …”

Water‐soluble prodrugs of cyclosporine A with tailored conversion rates

“…In finalizing the present manuscript, a publication by Cho and Chung (30) reports on the design of water‐soluble prodrugs of CsA featuring polyethylene glycol as solubilizing, enzymatically cleavable group. The t 1/2 ‐values obtained in rate whole blood confirm our data on a fast release of the parent drug.…”

Facile synthesis of polymer-peptide conjugates via direct amino acid coupling chemistry

“…However, this approach often has side reactions, including degradation of the polymer . Also, the reaction of the polymer hydroxyl group with chloroformates, namely, p ‐nitrophenyl chloroformate, 2,4,5‐trichlorophenyl chloroformate, and chloromethyl chloroformate yields amine‐reactive carbonated derivatives. Klok et al synthesized polymer brushes via surface‐initiated ATRP, then modified the hydroxyl end groups with p ‐nitrophenyl chloroformate before reaction with the amine groups of a benzylguanine derivative in the presence of dimethylformamide and 4‐dimethylaminopyridine (DMAP) .…”

“…Chung and coworkers conjugated cyclosporine A to monomethoxy‐PEO (mPEO) to afford a water‐soluble prodrug. The hydroxyl group of the peptide was activated by chloromethyl chloroformate before ligation to succinate‐functionalized mPEO in the presence of base . Using chloroformates directly with terminal hydroxyl groups to PEGylate proteins and peptides in this manner has the distinct advantage that the polymer can be directly ligated without prior functionalization.…”

“…The hydroxyl group of the peptide was activated by chloromethyl chloroformate before ligation to succinate-functionalized mPEO in the presence of base. 33 Using chloroformates directly with terminal hydroxyl groups to PEGylate proteins and peptides in this manner has the distinct advantage that the polymer can be directly ligated without prior functionalization. However, the activated intermediate in this approach is markedly less reactive and, moreover, a urethane connection is created, rather than the natural-based amide linkage.…”