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First Workshop on Nanomedicine for Infectious Diseases of Poverty, 2731 March 2011, Magaliesberg, South Africa

May/June 2011

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A Nanoformulation of Paediatric Efavirenz

Dr Alejandro Sosnik from the University of Buenos Aires discussed the potential applications of nanotechnology for paediatric formulations of HIV medicine.4

HIV in rich countries has become a largely manageable adult disease with more than 25 antiretroviral drugs and early diagnosis and access to HAART has reduced mother to child transmission to rates less than 1%. However, in most poorer countries HIV remains an acute disease with an estimated 1000 new paediatric infections globally each day, mostly in sub-Saharan Africa. Only 10% of children with HIV currently have access to treatment, and this drops to 2% in some regions.

Paediatric treatment in all countries is limited, with only 12 approved paediatric formulations. In particular, the lack of appropriate formulations, difficulties of dose adjustment, pill swallowing, and poor taste add to the challenges of enabling children to achieve the similar benefits from the advances seen in adult HIV care.

Dr Sosnik presented an example of a potential nanoformulation for efavirenz from his research group. Although a paediatric liquid formulation of efavirenz is produced by BMS this is not available globally and the indication is for children older than 3 years (and greater than 13 kg). The current oral formulation has lower bioavailability (by 40-45%) than capsule formulations and "tastes like liquid Vaseline" confirmed by associated weight-loss and diarrhoea. Interpatient and intrapatient bioavailability varies by 55-58% and 19-24% respectively.

The research goal and important unmet medical need is to develop a highly concentrated aqueous formulation with higher bioavailability, working with existing polymers like PEO-PPO polymeric micelles (poloxamers andoloamines) that are already commercially available in a broad spectrum of molecular weights and that already have a proven safety record (ie ethylendiamine).

So far, efavirenz-loaded micelles using surface aptamers to target CD4 cells have been produced in an oral solution and animal bioavailability data has been published.5-9 A micelle is an aggregate of compounds that lower the surface tension of a liquid and that are evenly dispersed.

In male rats the efavirenz-loaded micellar formulation was compared to that of a suspension prepared with the content of efavirenz capsules in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in a medium-chain triglyceride (Miglyol 812).

This formulation showed that the encapsulation of efavirenz, which is otherwise poorly water soluble, into polymeric micelles of different poly(ethylene oxide)–poly(propylene oxide) block copolymers significantly improves oral bioavailability and reduces the interindividual variability.

The solution has an improved taste, using only excipients approved by the FDA, and requiring less API has the potential to lower production costs.

A protocol has already been approved by an ethics committee in Buenos Aires for first in-human pharmacokinetic studies in HIV-negative volunteers, which if successful will progress to studies in HIV-positive adults and then HIV-positive children.

One of the discussion points after the presentation included the use of the formulation first in HIV-positive adults. This has been by the research group and not being linked to clinical HIV centres in Argentina. Expanding on this, Dr Soznik explained, "funding is difficult, industry studies are dominant. We need to now see if human exposure is similar to rats. Further animal studies might help but these are too expensive".

Other Antiretroviral Nanoformulations

Two other research groups at the workshop also presented data on formulations of antiretrovirals that are already approved, though none have yet been used in human studies.

Dr Lebogang Katata from CSIR in South Africa presented a poster on spray-dried efavirenz nanoparticles that was previously shown at the IAS conference in Vienna last year.10,11

In this process, efavirenz is encapsulated in a polycaprolactone (PCL) polymer by a double emulsion spray drying technique using two organic solvents. The nanoparticles have an average size of 220.6 ± 0.950 nm when using ethyl acetate and 372.1 ± 19.96 nm using dichloromethane. This formulation also overcomes the hydrophobic nature of efavirenz to improve bioavailability and it has met other manufacturing standards including encapsulation efficiency and a smooth particle surface. It also results in prolonged release compared to formulations of free drug (suggesting weekly dosing might be possible). The group have also produced formulations of other antiretrovirals including AZT and d4T and plan combination formulations. But the timeline for human studies that were due to start this year is likely to be several years away.

A poster from Dr Helanie van der Merwe and colleagues at the North-West University, Potchefstroom, South Africa presented results from a third technology for producing nanoparticles of antiretrovirals.12

This research group has encapsulated abacavir and lamivudine (3TC) in visicles using a technology called pheroid, that resulted in higher bioavailability in in vitro studies.

Professor Anne Grobler from North-West University explained pheroid technology in an oral presentation.13

This talk started with an example of South African drug development of Exorex. This is a coal tar preparation for psoriasis that was initially developed by an American individual for his personal treatment and was then developed by the University into a global treatment, with the advantage of greater efficacy from using a much lower percentage of coal tar (1% vs 5%).14

Pheroids use a form of colloidal transport (usually at 100 nm size but sometimes larger) using long chain fatty acids, modified in different ways, ie with pegylation to have with hydrophilic tails. The technology is apparently easy, and inexpensive but it was originally difficult to predict the type of pheroid because it was not designed working with the active compound. All fatty acids are currently being taken safely by humans and the technology allows packaging of more than one drug in each vesicle.

In addition to abacavir and lamivudine the group have produced Pheroid formulations of antimalarial15 and antituberculousis drugs16,17 that in preclinical development consisted of comparative in vitro and animal efficacy, bioavailability and pharmacokinetic studies and limited toxicology studies.

These studies reported enhanced rates of in vitro efficacy and in vivo bioavailability of first and second-line antimalarial compounds (including chloroquine, mefloquine, artemether and artesunate) and extended in vivo pharmackinetics and efficacy studies with formulation of tuberculosis drugs in mice.

Formulations of Anti-TB Medications

The CSIR research programme for formulations of TB medications is more advanced than that for HIV. Dr Rose Hayeshi, expanded on this programme.18

The group have encapsulated four first line anti-TB drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) with an encapsulation efficiency varying from 50-65% in particles of 250-400nm, using a multiple emulsion spray-drying technique.

The polymer used is poly(lactide-co- glycolide), (PLGA). The particles are taken up by macrophages in vitro indicating feasibility of intracellular drug delivery. Studies in mice using fluorescently-labelled PLGA nanoparticles indicated distribution to a broad diversity of tissues including macrophages of the peritoneum cell exudates that cross the blood brain barrier. Safety in mice after up to 10 days exposure was supported by histopathology on all major tissues including the spleen, lungs, kidney, liver, spleen, heart and the brain, which found no evidence of lesions.

Pharmocokinetic studies in mice showed that the drugs were released over a period of six days and the minimum inhibitory concentration for rifamicin and izoniazid was maintained over this period. Pharmacokinetic curves are similar to those of free drug, with an initial increase from drug on the outside of the molecule followed by slow release compared to free drug.

A study in six TB-infected mice dosed daily for four weeks showed a reduction in colony forming units in spleen, liver although there is a need to target actively to lungs. When repeated over nine weeks an improved pathology was observed in the lungs. The nanoformulation is a weekly dose compared to current requirement for strict daily dosing.

The research group are now looking at scale-up plans for all formulations, improved preclinical, dose formulation and design and then first clinical studies. Currently single formulations are used but combinations are planned and the group is working with compounds held by the TB Alliance.

The discussion after this presentation focused on the need to clarify the mechanism and route of administration for TB drugs. This included whether the controlled release is in blood, tissues, or the cells. Oral formulations are difficult to target to cells, and compounds often need IV administration, which is not practical in resource-limited settings.

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
See Also
More on HIV Medications
HIV Drugs in Development

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