Among the technologies that can make their contribution to micro- and nanomedicine and to pharmaceutical production there are also those that come from the digital world. As highlighted by the dedicated session of the AFI 2021 Symposium, organized in collaboration with CRS (Controlled Release Society), many techniques can be borrowed from other industrial sectors with a wide range of possible applications in hi-tech pharma.

From microelectronics to pharmaceuticals

A technique borrowed from precision electronics and called PRINT, for example, has revealed amazing potential at the pharmaceutical level. Thanks to this technology, in fact, it is possible to design and replicate in series biocompatible particles of nanometric or micrometric dimensions with specific shapes and chemical properties at a low cost. In this way, the PRINT methodology combines the uniformity and precision typical of electronic production with the specificity required by the pharmaceutical sector.

The approach is based on the principles of lithography. A mold with some cavities of the chosen shape is coupled to a layer of liquid polymer with the desired characteristics, which fills the cavities. After drying, the mold adheres to a base in water-soluble material which binds the polymer contained in the cavities. Once the mold has been removed, the particles remain anchored to the base, but immersion in water is sufficient to dissolve the water-soluble material and collect them.

Thanks to its flexibility, the PRINT technology allows to obtain particles suitable for many uses. For example, it is possible to produce hydrogel particles that mimic the characteristics of red blood cells and are therefore able to remain in circulation for a long time. Or biocompatible particles capable of penetrating into cells and degrading in a controlled manner in acidic conditions, which can be used in various fields including surgery and drug delivery. But this technology can also find application in development of vaccines and in improving the effectiveness of pharmaceutical preparations.

CLIP printing

3D printing also offers many applications in the pharmaceutical context, in particular in the field of micro- and nanomedicine. The 3D printing technique called CLIP (Continuous liquid interface production) represents a particularly interesting novelty since it allows to obtain very small and detailed products with high printing speeds.

Among the products that can be obtained with CLIP are microneedles, which pierce the skin without causing pain, opening up a range of opportunities compared to classic injections. Thanks to the CLIP technology it is possible, in fact, to produce microneedles of only 20 micrometers and of various shapes, as well as in different materials. Using microneedles allows you to overcome the stratum corneum that lines the epidermis in a very precise way. The types of existing microneedles are numerous, as well as their possible applications.

The most immediate is their use to apply drugs otherwise difficult to administer, such as when the target of a treatment is a particularly delicate organ, such as the eye.

On the other hand, one of the most interesting applications is offered by the possibility of making biocompatible microneedles that dissolve in the body after injection.

Microneedles in the patches

Making patches coupled with microneedles capable of dissolving after injection – as illustrated by Mark Prausnitz, professor at the Georgia Institute of technology in Atlanta – is in fact an innovative method of administration that has several advantages. The use of these devices is very easy and painless, and therefore increases compliance with the treatment. But there is more. The patches with microneedles also open interesting perspectives of control of the release kinetics, possible by modifying the composition of the microneedles themselves. The patch can in fact release the drug immediately or slowly, remaining attached to the skin for up to a month.

Another sector that can successfully exploit the opportunities offered by this technology is vaccines. The effectiveness of a vaccination administered in this way, in fact, appears to be completely comparable to that of traditional injection methods. According to a study presented by Prausnitz, in fact, the induction of the immune response of administration with microneedles would seem similar if not greater than that of an intramuscular injection.

Advanced applications of hi-tech pharma

For treating large areas of the body, however, patches offer limited help. Much more suitable, however, are microneedles which appear as single microscopic particles with sharp edges, which can be easily incorporated into creams and ointments. The principle is the same as for many cosmetic products already on the market. Once the preparation has been applied, in fact, the friction allows micro-abrasion by the particles which increases skin permeability to the active ingredient of the formulation. The increase in absorption can be considerable, when compared to the application of gel, and the discomfort caused to the patient is minimal.

Microneedles can also prove useful for ocular administration, challenging for the particularities of this organ. The most suitable area for the action of drugs is in fact on the back of the eye and to reach it, the entire organ is generally filled with preparation through ocular injections. This can cause problems in parts of the eye that are not intended for treatment but that still come into contact with the drug. Using devices equipped with needles of the order of microns, on the other hand, would allow to act effectively and with extreme precision.

The realm of nanotechnology

If we increase resolution by 1,000 times, from microscopic applications we’ll enter the world of nanomedicine. Working on a millionth of a millimeter scale allows different disciplines – such as biology, chemistry, medicine and physics – to collaborate on a wide variety of possible research projects. Applications of hi-tech pharma in this area can range from the development of pharmaceuticals and diagnostic technologies to the production of biomaterials for medical devices and smart prostheses, to regenerative medicine. This is why the attention towards nanotechnologies applied to health is very high. Especially in times of a pandemic. In fact, several lines of research aim at developing increasingly effective vaccines against Covid-19.

There are many pathologies and debilitating conditions for which nanomedicine can be a valid help:

  • degenerative diseases such as Parkinson’s and Alzheimer’s;
  • chronic diseases such as diabetes;
  • complex diseases such as cancer, organ failure or serious injuries.

The social and economic costs of these conditions are huge, which is why the contribution of nanotechnologies is important not only for patients, but also for healthcare systems.

Nanoparticles and stroke

Patrick Couvreur, honorary president of the French National Academy of Pharmacy, described an innovative treatment for ischemic stroke based on peripherally acting nanoparticles.

When developing treatments for brain-related disorders, we are confronted with the blood-brain barrier. Protective filter for our brain, this structure prevents the passage – and therefore the action – of many drugs. Rather than trying to overcome the barrier, a technique studies the use of peripherally acting drugs.

By choosing adenosine as a therapeutic agent against the damage caused by ischemia, the Couvreur team decided to bind it to a squalene molecule, to avoid its rapid denaturation in the blood. The nanoparticle that is formed is able to remain in circulation in the bloodstream for a long time, thanks to the ability to integrate with LDL lipoproteins, thus becoming a reservoir of adenosine, which is released in a prolonged way. By binding to the receptors on the endothelial cells of the blood vessels, the nanoparticle allows their relaxation and the decrease of blocked capillaries. The consequence is improved blood circulation and a protective effect at the neuronal level in experimental models.

Nanomedicine in pain therapy

Another application of nanoparticles concerns pain management. The abuse of morphine and other opiates and the related addiction cause significant social and economic problems. Replacing these compounds with enkephalins would be an excellent alternative. Although they have a less powerful analgesic effect than that of opiates, they have the great advantage of not causing addiction. However, these molecules are metabolized extremely quickly.

Once again, the use of squalene to form nanoparticles has allowed researchers to overcome the problem. The duration of the analgesic effect in experimental models is greater not only than that of free encephalin, but also that of morphine itself. Furthermore, there is no insensitivity to the painful stimulus that typically follows the administration of morphine. Finally, since they don’t cross the blood-brain barrier, the nanoparticles have local action, thus completely eliminating the risk of addiction.

From photovoltaics to the eye

A technology that could find application in the treatment of the consequences caused by degenerative eye diseases, such as retinitis pigmentosa, is based on a polymer from the world of photovoltaics called P3HT-poly (3-hexylthiophene). As Massimo Pedrani, member of AFI and director of Mogon Pharmaceuticals explains, this treatment would even allow the recovery of lost visual function. This material is able to absorb visible light in a similar way to cones and rods, and to transform it into electrical impulses. A colloidal suspension containing P3HT nanoparticles was tested in animal models with photoreceptor degeneration, demonstrating a real efficacy in the recovery of visual function.

Compared to other methodologies, this technique offers the additional advantage of not requiring external devices and of being potentially applicable to all those affected.