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Building a Better HIV Drug: Nano-Formulated Medicines

By Warren Tong

December 18, 2013

Building a Better HIV Drug: Nano-Formulated Medicines

Antiretrovirals have turned HIV infection from a deadly disease into a manageable chronic condition. However, current treatment does have downsides, including the need for daily dosing (at minimum) and the risk for drug resistance to emerge when doses are missed.

One of the keys to the future of HIV treatment may be nano-formulations of drugs that help deliver medications in a more potent and efficient manner with a lower frequency of doses. Andrew Owen, Ph.D., from the University of Liverpool, gave a mini-lecture at EACS 2013 providing an overview and update on the topic.

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Types of Nanomedicine

Types of Nanomedicine

There are two types of nanomedicines, Owen said: nanoscale-containing drugs and solid drug nanoparticles (SDNs).

Nanoscale-containing drugs are often called "drug-delivery vehicles" because they are carriers that can either be loaded with antiretrovirals or surface-functional groups with antiretrovirals. They can be diverse, ranging from inorganic, insoluble nanoparticle carriers (such as gold nanoparticles) to lipid-based nanoparticles (such as liposomes) to organic polymeric nanoparticles (such as dendrimers).

SDNs, often called "nanosuspensions," are very small particles of the solid drugs themselves. Each of these particles is about one millionth the size of a human hair. They can be made either by milling, in which a solid chunk of a drug is ground down until it's nano-sized, or via the precipitation of solutions to form nano-sized versions of the drug.

Drivers for Developing Nanomedicine

Drivers for Developing Nanomedicine

There are different drivers for and against researching and developing nanomedicines, but the pros outweigh the cons, Owen asserted. On the downside, there can be issues with insolubility of active pharmaceutical ingredients, and the difficulty and cost of formulation during development can be high. However, the pros that nanomedicines could offer include a modified delivery profile, a solution to fed/fasted variability, an improvement in patient adherence, a reduction in pill burden and decreased adverse drug reactions.

Pre-clinical research has shown that nano-formulations have greater potency at lower dosage levels than conventional formulations. Furthermore, with intramuscular or intravenous delivery, there could be a sustained release of the drug and better targeting of the virus.

Benefits for Sustained Release of Antiretrovirals

Benefits for Sustained Release of Antiretrovirals

Since some nanomedicines can act as depots, releasing the active drug over an extended period of time, this can be beneficial for long-acting formulations of antiretrovirals, Owen said. For patients, this has the potential for drugs to be taken only once a month or longer. It also could result in formulations of PrEP (pre-exposure prophylaxis) that are easier to take and more practical as an extended means of HIV prevention.

However, currently only two such drugs are in development: long-acting rilpivirine, a monthly intramuscular injection, and an injectable formulation of the integrase inhibitor GSK744. Another current downside is that these drugs require an oral "lead-in" to mitigate adverse drug reactions.

Limitations of Long-Acting Formulations

Limitations of Long-Acting Formulations

While having long-acting drugs will reduce the frequency of doses, there are some limitations, Owen noted.

For one thing, treatment interruptions won't be possible, which is particularly a concern when the need arises to manage an acute event (such as surgery or coinfection), pregnancy or the patient's desire to take a drug holiday.

There also are no strategies yet for how to manage drug-drug interactions between long-acting antiretrovirals. Furthermore, we don't yet know how appropriate long-acting drugs would be for patients with high viral loads. But hopefully with more research and trials, these concerns can be addressed.

Passive and Active Targeting Opportunities in HIV

Passive and Active Targeting Opportunities in HIV

Because of the smaller particle size of nanomedicines, they can better penetrate and target HIV where it lives, as opposed to the systemic approach that current conventional, oral formulations take, Owen said. With passive targeting, particularly at cellular and tissue sites, there can be size-influenced penetration of nanoparticles into lymph nodes where HIV can be hard to reach.

Additionally, there are active targeting opportunities: For instance, nanomedicines could be armed with special receptors, such as a range of cell-specific protein receptors that target HIV replication-competent cells, or tissue-specific protein receptors that may improve distribution into HIV reservoir sites.

What the Patients Want

What the Patients Want

According to a recent survey, more than 73% of patients indicated they would definitely or probably try injectable antiretroviral therapy. In terms of dose frequency, 61% were interested in weekly, 72% every two weeks and 84% monthly.

Therefore, there is overwhelming support from the patients themselves, particularly if nano-formulations can improve adherence, lower pill burden and cost, and ultimately improve quality of life.




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