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25 octubre 2016, 08:39

Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies

Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies - imagen 1


Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes.


Nanomedicine has made significant impact to patients globally across disparate disease conditions ranging from schizophrenia and hypercholesterinemia to macular degeneration and various cancers; existing therapies include Doxil/Caelyx and Myocet for breast cancer, paliperidone palmitate for 3 monthly long-acting schizophrenia treatment, Visudyne for macular degeneration and Tricor for cholesterol management1,2,3. The growing pipeline of candidate nanomedicines continues to have options at various development stages, moving towards the ranks of clinically proven medicines. Nanotherapies often utilize injectable nanocarriers that deliver drug cargoes directly to the bloodstream; however, daily injections are not practical in many clinical scenarios, such as chronic conditions requiring self-administration over a protracted period. Such conditions render many nanomedicine approaches inappropriate, especially if disease is not restricted to targetable organs, creating a prerequisite for oral administration and requiring consideration of inter-related factors such as pharmacokinetics, patient adherence and pill burden. Many of these issues are exacerbated during paediatric administration where there is much less understanding4.

Daily oral administration of modern antiretroviral (ARV) therapy has transformed HIV from a fatal disease to a manageable chronic condition. However, access to ARVs is not universal and paediatric treatment formats still require improvement. The global burden of HIV continues to grow, with 2014 World Health Organization (WHO) statistics estimating 36.9 million people living with HIV, 2.6 million of which were children <15 years. At the end of 2014, an estimated 14.9 million people were receiving ARVs including only 32% of infected children. The ability to moderate progression of HIV to AIDS, in addition to 2 million new annual infections, places increasing demand on ARVs. The 2015 WHO guidelines5 recommend therapy initiation for everyone living with HIV at any CD4 cell count in addition to daily oral pre-exposure prophylaxis for at-risk populations, exacerbating supply pressure and stimulating therapy optimization strategies. Although attrition processing of large drug particles down to smaller particle sizes, using techniques such as high-pressure homogenization or nanomilling2,6, has led to many Food and Drug Administration-approved oral nanomedicines utilizing solid drug nanoparticles (SDNs), there are currently no oral ARV nanotherapies available. In addition, it is not clear what chemical and physical parameters (for example, size, surface chemistry, charge, charge density and polydispersity) of SDNs will successfully achieve clinical target performance and attrition processing is labour and time intensive. While many nanotechnologies are being explored for HIV, the achievement of large-scale production, under clinical manufacturing conditions and at low cost, is often not addressed.

In new cases of paediatric HIV infection (<3 years), a ritonavir (RTV)-boosted lopinavir (LPV) oral liquid formulation is WHO-recommended as a 4:1 LPV:RTV combination. Both LPV and RTV have low bioavailability with poor water solubility (1.92 and 1.26 mg l−1, respectively) and substrate affinity for transporters and metabolic enzymes7. Despite its well-known side effects, RTV is required as a pharmacoenhancer to ‘boost’ the pharmacokinetics of other ARVs that are substrates for p-glycoprotein and/or cytochrome P450 3A4 (CYP3A4); a second drug, Cobicistat, is also approved as a booster for HIV therapies. For infants, the WHO-recommended twice-daily dose is 300 mg/75 mg LPV/RTV per m2 of body surface area, and a paediatric oral solution (80/20 mg ml−1) is available. Due to the poor water solubility of both drugs, the oral solution contains 42.4% (v/v) ethanol and 15.3% (w/v) propylene glycol. Administration may commence as early as 14 days after birth for prevention of mother-to-child transmission in HIV-positive mothers. Clearly, it would be preferential to avoid regular dosing of alcoholic mixtures, and viable strategies to remove RTV and/or alcohol are urgently required. Nanomedicine strategies may have a critical role to play in the formation of aqueous orally dosed paediatric therapies, but any strategy must allow rapid formation and evaluation of multiple SDN options and have cost and scalability at its core. We recently reported emulsion-templated freeze-drying (ETFD)8, a non-attrition approach to the production of aqueous re-dispersible SDNs, and its application to the ARV efavirenz9. The prototype nanomedicine exhibited higher pharmacokinetic exposure than a conventional preclinical formulation in rats after oral dosing.

Herein, we describe the extension of this strategy to the accelerated discovery and translation of LPV and LPV/RTV combination SDNs with high drug loading relative to excipients (≥50 wt%) through a unique iterative cycle of materials chemistry and pharmacology, utilizing a novel high-throughput ETFD screening process, with scale of production subsequently achieved by clinically compliant spray-drying. Reduction to lead candidates with optimized drug loading, larger pilot-scale production and stability testing has enabled formation of a candidate LPV nanomedicine for imminent human clinical trials (EudraCT number 2013-004913-41). By generating a formulation library with variability in size, surface charge and surface chemistry during screening stages, the identification of optimal nanoparticle properties as they relate to the pharmacology is possible. This process is highly translatable and offers the rapid production, evaluation and optimization of cost-effective orally dosed drug nanoparticles to address unmet clinical needs across various diseases.

Autor: Olga Moiseeva

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