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Biomaterials. 2015 Jan;37:383-94. doi: 10.1016/j.biomaterials.2014.10.026. Epub 2014 Oct 25.

Novel protease inhibitor-loaded Nanoparticle-in-Microparticle Delivery System leads to a dramatic improvement of the oral pharmacokinetics in dogs.

Author information

1
Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
2
Small Animal Teaching Hospital, Faculty of Veterinary Sciences, National University of Central Buenos Aires, Tandil, Argentina.
3
Small Animal Teaching Hospital, Faculty of Veterinary Sciences, National University of Central Buenos Aires, Tandil, Argentina; National Science Research Council (CONICET), Buenos Aires, Argentina.
4
Group of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, Technion City, Haifa, Israel. Electronic address: alesosnik@gmail.com.

Abstract

With the advent of the Highly Active Antiretroviral Therapy, the morbidity and the mortality associated to HIV have been considerably reduced. However, 35-40 million people bear the infection worldwide. One of the main causes of therapeutic failure is the frequent administration of several antiretrovirals that results in low patient compliance and treatment cessation. In this work, we have developed an innovative Nanoparticle-in-Microparticle Delivery System (NiMDS) comprised of pure drug nanocrystals of the potent protease inhibitor indinavir free base (used as poorly water-soluble model protease inhibitor) produced by nanoprecipitation that were encapsulated within mucoadhesive polymeric microparticles. Pure drug nanoparticles and microparticles were thoroughly characterized by diverse complementary techniques. NiMDSs displayed an encapsulation efficiency of approximately 100% and a drug loading capacity of up to 43% w/w. In addition, mucoadhesiveness assays ex vivo conducted with bovine gut showed that film-coated microparticles were retained for more than 6 h. Finally, pharmacokinetics studies in mongrel dogs showed a dramatic 47- and 95-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the free unprocessed drug. These results support the outstanding performance of this platform to reduce the dose and the frequency of administration of protease inhibitors, a crucial step to overcome the current patient-incompliant therapy.

KEYWORDS:

HIV infection; Indinavir free base; Mucoadhesion; Oral bioavailability; Protease inhibitors; Pure drug Nanoparticle-in-Microparticle Delivery System (NiMDS)

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