Bisphosphonate Prodrugs: Synthesis and in Vitro Evaluation of Novel Clodronic Acid Dianhydrides as Bioreversible Prodrugs of Clodronate

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Abstract
P,P‘-Diacetyl, P,P‘-dibutyroyl, P,P‘-dipivaloyl, and P,P‘-dibenzoyl (dichloromethylene)bisphosphonic acid dianhydride disodium salts (2a−d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding acid anhydride. The dianhydrides 2a − d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between 1-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 °C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 °C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to formation of poorly water-soluble chelates, which may also hinder the oral absorption of clodronate. However, Ca2+ ions did not have an effect on the aqueous solubility of clodronic acid dianhydrides, and therefore, these prodrugs may improve oral absorption of the parent drug. In conclusion, these novel dianhydride derivatives may be potentially useful prodrugs of clodronate which, due to their lipophilicity and lack of Ca2+ chelating, increase its bioavailability after oral administration.