Efavirenz-loaded Polymeric Micelles for Pediatric anti-HIV Pharmacotherapy with Significantly Higher Oral Bioavailaibility

Diego A Chiappetta; Christian Hocht; Carlos Taira; Alejandro Sosnik


Nanomedicine. 2010;5(1):11-23. 

In This Article

Abstract and Introduction


Children constitute the most challenging population in anti-HIV/AIDS pharmacotherapy. Efavirenz (EFV; aqueous solubility 4 µg/ml, bioavailability 40–45%) is a first-line agent in the pediatric therapeutic cocktail. The liquid formulation of EFV is not available worldwide, preventing appropriate dose adjustment and more convenient administration. The bioavailability of liquid EFV is lower than that of the solid formulation. Improving the bioavailability of the drug would reduce the cost of treatment and enable less affluent patients to access this drug.
Aim: To encapsulate EFV in polymeric micelles to improve the aqueous solubility and the the oral bioavailability of the drug.
Methods: EFV was incorporated into the core of linear and branched poly(ethylene oxide)–poly(propylene oxide) block copolymer micelles. The size and size distribution of the drug-loaded aggregates were characterized by dynamic light scattering and the morphology by transmission electron microscopy. The bioavailability of the EFV-loaded micellar system (20 mg/ml) was assessed in male Wistar rats (40 mg/kg) and compared to that of a suspension prepared with the content of EFV capsules in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in a medium-chain triglyceride (Miglyol® 812).
Results: This work demonstrates that the encapsulation of EFV, which is poorly water soluble, into polymeric micelles of different poly(ethylene oxide)–poly(propylene oxide) block copolymers significantly improves the oral bioavailability of the drug, and reduces the interindividual variability.
Conclusion: This strategy appears a very promising one towards the development of a liquid aqueous EFV formulation for the improved pediatric HIV pharmacotherapy.


A recent report on the global situation of HIV/AIDS indicates that approximately 40 million infected people live worldwide.[101] Approximately 2.5 million patients are children (<15 years). Children show especially high mortality rates and represent a high-risk population.[101] HAART combines at least three different antiretroviral (ARV) drugs.[1,2,102] ARV doses are high and complicated regimens compromise the patient's lifestyle. According to epidemiological investigations, adherence levels below 95% dramatically reduce the chances of therapeutic success to approximately 50%.[3]

Pediatric HIV has been almost eliminated in developed countries by limiting maternal-to-fetus and breastfeeding transmission.[103] By contrast, the situation in developing countries is dramatically different, where approximately 90% of infected children do not have access to medication. Pediatric HAART implementation is challenging owing to the reduced number of drugs approved for pediatric use;[4] pharmaceutical companies have only recently been compelled to conduct clinical trials in children by the US FDA and EMEA.[104] Adult-approved ARV drugs are available only in solid form.[5] To make adult medicines appropriate for children and enable dose adjustment and easy swallowing, solid forms are often processed to prepare magistral formulations.[6] Approximately 40 million children are administered unlicensed medicines every year in Europe.[7,105] There are serious quality, safety and effectiveness concerns over the use of these medicines.[8–10] However, when a liquid formulation is not commercially available, they remain the only alternative to treat HIV-infected neonates and infants.[11]

The last World Health Assembly (WHA) recognized the right of pediatric patients to access safe, effective and proven medicines, approving the resolution 'Better medicines for children'[106] and launching the global campaign 'Make medicines child size'.[106]

Efavirenz (EFV; Sustiva®) is a highly lipophilic non-nucleoside reverse transcriptase inhibitor classified in class II of the Biopharmaceutic Classification System.[12] EFV is a first-choice ARV in adult[13] and pediatric pharmacotherapy.[14,15] The low solubility of the EFV in aqueous medium hinders the absorption and biodistribution of the drug from the GI tract.[16,17] The oral bioavailability of the drug is around 40–45% and the interindividual variability observed demands therapeutic drug monitoring.[18,19] In general, a good correlation has been established between solubility improvement and higher bioavailability for most of the class II drugs.[20,21] For example, amprenavir, a poorly water-soluble protease inhibitor ARV, shows a dramatically low oral bioavailability.[22] To enhance the gastrointestinal absorption of the drug, two approaches were pursued: the chemical modification to the water-soluble phosphate ester prodrug, fosamprenavir, which is converted into the active molecule in vivo;[22] and solubilization in 23% D-α-tocopheryl polyethylene glycol 1000 succinate.[23] To make EFV more soluble and palatable, the drug was solubilized in a series of water-insoluble triglycerides;[24,25] however, this 30 mg/ml oily solution showed lower bioavailability than the solid formulation. Moreover, the intake of large oil volumes are expected to produce profuse diarrhea and affect patient compliance. To improve drug solubility and dissolution, Dutta et al. prepared EFV–dendrimer complexes.[26,27] However, the design of a drug-delivery system based on a non-approved carrier (e.g., dendrimer) constitutes, from a pharmaceutical perspective, a drawback by itself. Others have investigated the solubilization of EFV in different cyclodextrins (CD) and CD-containing polymers.[28,29] For instance, Sathigar et al. investigated the preparation of inclusion complexes of EFV with β-CD, hydroxypropyl β-CD and randomly methylated β-CD. Dissolution extents were between six- and 20-fold higher than the intrinsic solubility in water.[28] However, this solubilization improvement still appears to be insufficient for the development of a highly concentrated aqueous solution; a 200 mg dose of EFV would demand approximately 1 l of formulation.

Prevalence of the disease is extremely high in resource-constrained countries,[30] where the development of scalable and cost-effective ARV medicines is a crucial access to enable patients to receive the appropriate medication;[31,32] owing to lower production costs, the administration of lower doses that are absorbed more efficiently after oral administration would represent a substantial improvement in the accessibility of more patients to EFV. In this framework, nanotechnologies can provide unique tools to improve the effectiveness of anti-HIV pharmacotherapy.

Inclusion into the hydrophobic core of polymeric micelles represents a very versatile nanotechnology approach to enhance the aqueous solubility of highly hydrophobic drugs.[33] The most broadly investigated polymeric micelle-forming materials are the poly(ethylene oxide)–poly(propylene oxide) (PEO–PPO) block copolymers.[34] Two families are commercially available: the linear PEO–PPO–PEO triblocks or poloxamers (Pluronic®) and the branched poloxamines (Tetronic®). Most works focused on the linear derivatives, although the four-arm counterparts have attracted increasing attention over the past few last years owing to their dually responsive behavior (temperature and pH).[35,36] A remarkable advantage of the PEO–PPO-based systems over other experimental polymeric amphiphiles is the approval of some of the derivatives by the FDA and EMEA for use in pharmaceuticals and medical devices.[37–39]

Our research group has embraced the spirit of the WHA resolution, Better Medicines for Children, and investigates different nanotechnological approaches to optimize the biopharmaceutical properties of anti-HIV drugs in the pediatric pharmacotherapy. In an attempt to improve the solubility and oral bioavailability of EFV, the present study explored the inclusion of the drug into polymeric micelles of linear and branched PEO–PPO copolymers. The solubilization profiles and properties of the drug-loaded micelles were thoroughly characterized. Pharmacokinetic studies in rats showed a significant increase in the bioavailability of EFV and supports the use of this strategy toward the development of a concentrated, stable and cost-efffective EFV aqueous formulation for the management of pediatric HIV/AIDS.


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