How Nanomedicine is Tackling HIV

This month we got the opportunity to talk to Dr Marco Giardiello about his work on Solid Drug Nanoparticles through Emulsion-Templated Freeze Drying (ETFD), the process he developed at the University of Liverpool. ETFD was the core technology behind the launching of Tandem Nano, a University of Liverpool spinout company to produce Solid Drug Nanoparticle versions of typically hydrophobic drug candidates.

Why should we care about nano-formulating drugs that already exist?

In medicine, oral dosing of drugs (taking a pill or capsule) is the main patient-acceptable form of drug administration. If every time you had a headache, your only analgesic recourse was to administer paracetamol by injection, you would probably seek relief this way much less frequently. No one likes injections.

This problem might not be too pressing if the health concern is a headache as this can be ignored, but what if the medicine was required to suppress the negative effects of more serious diseases like diabetes or HIV. Most diabetic patients are content to reliably administer insulin because the consequences of missing an injection are immediate and severe. For HIV, missing an injection doesn't mean you drop dead the next day, so the negative consequence is easier to rationalise. If however, the patient drops out of the therapeutic window for treatment (when the concentration of drug remaining in the body becomes too low) the body can develop resistance to the treatment, and future treatments can become ineffective resulting in HIV progressing to AIDS.

Pill forms of drugs also have a major logistical advantage over injection, they can be disseminated and administered without training, and don't require -80C storage as is the case for the Pfizer COVID-19 vaccine. Imagine if the government could simply ship "pill-form" vaccines to every house in the nation, rather than setting up vaccination clinics.

The issue is that most drugs, as well as pipeline drug candidates, have low water-solubility, meaning they do not dissolve or mix well in water (like oil). As a consequence, these drugs may have low bioavailability; the body may struggle to absorb them. This means that to administer them orally, very high doses are required to have any hope of dosing to within the therapeutic window. This means the drug candidate becomes expensive and most of the active components are wasted; unabsorbed by the body.

The solution to increase uptake of drugs with low-solubility and low bio-availability is to increase their surface area; usually by grinding the solid into fine particles. This has an analogous effect to the difference between dropping a sugar cube into a cup of tea, which slowly absorbs the tea changing its colour, before fragmenting and slowly dissolving vs adding a spoon full of sugar which dissolves almost instantly.

So what is the problem?

The problem here is that most common manufacturing approaches such as nanomilling (grinding repeatedly) or high pressure homogenisation (forcing the mix through a small gap) don't work unless the drug is crystalline with a “high” melting point, else the drug reaggregates. They may also introduce impurities from milling agents and require repeated cycles.

Here is where Dr Giardiello's work (ETFD) comes into its own. Rather than the top-down approach of powdering large particles into smaller, ETFD grows nanometer sized particles of drug from the bottom-up and captures them in excipients (polymers and surfactants) to keep the particles stable and separated so they cannot reaggregate.

The end result as Dr Giardiello describes is essentially a blueberry muffin for drug delivery. Active pharmaceutical ingredients (APIs) are captured in a water-soluble, solid excipient matrix, which on contact with water can dissolve to deliver nanometer-sized capsules of API straight into the lining of the stomach or gut wall allowing for significantly higher bioavailability and uptake of the medication.

Results of clinical trials of this manufacturing approach on Lopinavir and Efavirenz, two common treatments for HIV showed matching of the desired therapeutic response by Dr Giardiello's approach which requires half the amount of API. This result not only reduces the cost of treatment, but also makes dissemination and administering the drug significantly easier. These parameters are essential in the fight against HIV which affected a reported 7 million adult patients in 2014 increasing to 16 million in 2020.