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Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages
Huiyu Zhou1, Yanling Zhang, Danielle L Biggs
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Campus Box C238, Denver, CO 80262, USA.
Abstract:
Microparticles prepared by the precipitation with a compressed antisolvent (PCA) process were evaluated for their potential in targeting an ionizable prodrug of isoniazid (INH), isoniazid methanesulfonate (INHMS), for sustained delivery of INH to alveolar macrophages (AMs). The charged prodrug was ion-paired with two different hydrophobic cations (tetrapentylammonium (TPA)- and tetraheptylammonium (THA)-bromide), and loaded separately into the poly(l-lactide) (PLA) microparticles. The drug/polymer particles were spherical in shape and between 1 and 3 mum in diameter. The choice of hydrophobic cations did not affect drug incorporation efficiencies or the release kinetics of INH from the microparticles. Using a sensitive liquid chromatographic tandem mass spectrometric (LC-MS/MS) assay developed for INH, high level of INH was detected in NR8383, a rat AM cell line, following exposure of these cells to drug-loaded microparticles. To confirm the microparticles can target AMs in vivo, we compared the INH levels in lavaged bronchoalveolar macrophages by LC-MS/MS after the Sprague-Dawley rats were administered either INHMS in PLA microparticles by intra-tracheal instillation or INH solution by gavage or intra-tracheal instillation. As expected, only microparticles provided sustained and targeted delivery of INH to AMs. Most importantly, this method of delivery led to substantial reduction in the blood levels of acetylisoniazid (AcINH), a major and potential toxic metabolite of INH.
Insights
Poly(l-lactide) microparticles effectively deliver isoniazid methanesulfonate to alveolar macrophages, enhancing drug targeting and reducing toxic metabolite levels.
Area of Science:
- Drug Delivery Systems
- Nanotechnology in Medicine
- Pharmacology
Background:
- Isoniazid (INH) is a primary drug for tuberculosis treatment.
- Targeted delivery of INH to alveolar macrophages (AMs) can improve efficacy and reduce toxicity.
- Developing effective delivery systems for ionizable drugs like INH is challenging.
Purpose of the Study:
- To develop and evaluate poly(l-lactide) (PLA) microparticles for sustained and targeted delivery of isoniazid methanesulfonate (INHMS) to AMs.
- To assess the in vitro and in vivo efficacy of these microparticles in delivering INH to AMs.
- To investigate the impact of this delivery method on the formation of toxic INH metabolites.
Main Methods:
- Microparticles were prepared using the precipitation with a compressed antisolvent (PCA) process.
- INHMS was ion-paired with hydrophobic cations and loaded into PLA microparticles.
- Drug loading, release kinetics, and INH levels in AMs were analyzed using LC-MS/MS.
- In vivo studies involved intra-tracheal instillation and gavage in rats, with subsequent analysis of INH in bronchoalveolar macrophages.
Main Results:
- PLA microparticles were spherical, 1-3 µm in diameter, and efficiently loaded with INHMS.
- Hydrophobic cation choice did not impact drug incorporation or release kinetics.
- High INH levels were detected in rat AM cell line (NR8383) exposed to microparticles.
- In vivo studies confirmed sustained and targeted delivery of INH to AMs via microparticles.
- Microparticle delivery significantly reduced blood levels of the toxic metabolite acetylisoniazid (AcINH).
Conclusions:
- PCA-prepared PLA microparticles provide a viable system for sustained and targeted delivery of INH to AMs.
- This targeted delivery approach enhances therapeutic potential by concentrating the drug at the site of infection.
- Reducing toxic metabolite formation through targeted delivery offers a safer therapeutic strategy for tuberculosis treatment.
