Hydrophobic ion pairing of isoniazid using a prodrug approach.
Inhalation therapy for infectious lung diseases, such as tuberculosis, is currently being explored, with microspheres being used to target alveolar macrophages. One method of drug encapsulation into polymeric microspheres to form hydrophobic ion-paired (HIP) complexes, and then coprecipitate the complex and polymer using supercritical fluid methodology. For the potent antituberculosis drug, isoniazid (isonicotinic acid hydrazide, INH), to be used in this fashion, it was modified into an ionizable form suitable for HIP. The charged prodrug, sodium isoniazid methanesulfonate (Na-INHMS), was then ion paired with hydrophobic cations, such as alkyltrimethylammonium or tetraalkylammonium. The logarithms of the apparent partition coefficients (log P') of various HIP complexes of INHMS display a roughly linear relationship with the numbers of carbon atoms in the organic counterions. The water solubility of the tetraheptylammonium-INHMS complex is about 220-fold lower than that of Na-INHMS, while the solubility in dichloromethane exceeds 10 mg/mL, which is sufficient for microencapsulation of the drug into poly(lactide) microspheres. The actual logarithm of the dichloromethane/water partition coefficient (log P) for tetraheptylammonium-INHMS is 1.55, compared to a value of - 1.8 for the sodium salt of INHMS. The dissolution kinetics of the tetraheptylammonium-INHMS complex in 0.9% aqueous solutions of NaCl was also investigated. Dissolution of tetraheptylammonium-INHMS exhibited a first-order time constant of about 0.28 min(-1), followed by a slower reverse ion exchange process to form Na-INHMS. The half-life of this HIP complex is on the order of 30 min, making the enhanced transport of the drug across biological barriers possible. This work represents the first use of a prodrug approach to introduce functionality that would allow HIP complex formation for a neutral molecule.
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Campus Box C238, 4200 E. Ninth St., Denver, USA.
Huiyu
H
Zhou
Corinne
C
Lengsfeld
David J
DJ
Claffey
James A
JA
Ruth
Brooks
B
Hybertson
Theodore W
TW
Randolph
Ka-Yun
KY
Ng
Mark C
MC
Manning
D000280:Administration, Inhalation; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions; D007538:Isoniazid / Q000008:administration & dosage / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
D000995:Antitubercular Agents; D007477:Ions; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; C055292:tetrahexylammonium; D007538:Isoniazid