Combining Nanocrystals With Microneedles For Long-Acting Delivery With Alejandro Paredes

For treatment of chronic diseases, microneedle patches hold great promise for bolstering patient adherence and therapeutic efficacy over time. In this episode of Sit and Deliver, videocast host Tom von Gunden talks with Alejandro Paredes, senior lecturer in pharmaceutical sciences at Queen’s University Belfast, about getting long-acting formulations into combination products leveraging nanocrystals and microneedles as delivery platforms.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, chief editor at Drug Delivery Leader and your host for the series. Today I am joined by Alejandro Paredes, who is senior lecturer in pharmaceutical sciences at Queen’s University Belfast. And we're here today to talk about the combination of nanocrystals and microneedles in delivering long-acting formulations to patients.

Welcome, Alejandro.

Alejandro Paredes, Senior Lecturer, Queen’s University Belfast:

Thanks, Tom. Thanks for the invitation and great to be here.

Well, it's my pleasure to have you here. So, let's just go ahead and dive in. I like to start by looking out over the patient and therapeutic target landscape. So, before we get into the specific sciences and technologies that you'll be describing for us, who's out there in the patient landscape? What are those needs that are guiding the focus of your work? And, by the way, I should mention that part of my interest in your topic today is that I noticed that you present at the American Association of Pharmaceutical Scientists [AAPS] on this topic in symposia. Hence, the nature of the questions. So, again, who’s out there, what do they need, and why the focus of the work around these things?

Yeah, so I guess one of the best ways to enter the topic is to speak about long-acting therapies. So, in this space currently, there are a few fields where there is a lot of action, products already on the market that have been [in] patients, even for decades. One of them, a good example, would be schizophrenia, for example. So, in schizophrenia, patients often lack awareness of the disease. So, they could be taking medications orally every day and then they will start to feel better. They will think, okay, I am already better; I don't need the medication anymore. So, the medication then is discontinued. And then symptoms appear again, and patients need to go to hospital. This creates a lot of stress for them, for the families, [and] cost for healthcare systems. So, in these kinds of disorders, long-acting is really interesting and can help substantially.

So, what do we see in the landscape? We have some injectable suspensions in the form of oil suspension or PLGA [poly lactic-co-glycolic acid] particles. They're injected into the muscle, and they can release the drug maybe for a month. So, here we have a few hurdles, like PLGA particles will have a limited capacity, same for oil formulations because some of these drugs sometimes are so insoluble that you will even struggle to make them dissolve in an oil to form an emulsion, for example. So, this opened the way there for a more advanced delivery system, which are long-acting nanosuspensions.

And we have a few products on the market of the line Invega. They include paliperidone palmitate. This is a prodrug of paliperidone. This is really hydrophobic. And then there are products that can be applied once a month, once every three months, for example, allowing for treatment for just one injection and then more constant plasma concentrations.

Another area of a lot of interest is HIV pre-exposure prophylaxis. So here, users that have risk of getting the infection, probably because their partners are positive or because they are in a riskier population, they might need to take antiretrovirals. So far, this has been achieved by — and still today it's achieved by — oral treatments. But, more recently, since 2021 with the approval of Cabenuva is a long-acting nanosuspension, again, a new alternative appears. So, now you're looking at an injection that is applied every two months and then protects patients against transmission of the virus after just one single injection. So again, quite promising. And this also comes with certain social aspects because taking medications when in areas where this is might be socially a problem. And, if you offer patients something better, this can also bring benefits from that perspective as well.

Great, great. Thanks for painting the landscape of what's been currently available and some of the advances that have been made. So, let's take a deeper dive down into the formulation science and the delivery technology, separately and then together. Tell us a little bit about nanocrystals as a platform and then about microneedles as a delivery vehicle and then leveraging those things in combination.

Yeah, exactly. So, this is a good question. So, nanocrystals came to the game probably early ‘90s. So, as you know, particle size reduction has been around for many, many years. Micronized prodrugs are still today heavily used. But in the early ‘90s, people were using milling technologies that were applied to the dyes and paints industry — media milling — to mill drugs. And they discovered that the particle size could be reduced to the nanoscale.

So, you can now have crystals of the drug of a particle size of 700 nanometers, maybe 800 nanometers, even lower. So, [the] first products came to the market very quickly. After 10 years of development, first patents. There were products coming to the market mostly for oral administration. So, in most cases, media milling is applied to prepare nanocrystals. So, this is a specific kind of mill that is milling drugs in the presence of a solution of a surfactant. And then these suspensions can be dried, and the powders incorporated into maybe a tablet.

So, the first products [that] came into the market were products for the management of lipids in the blood. So fenofibrate was one of them. So, this is about nanocrystals [in the] early stages: oral products just to enhance the bioavailability of very poorly soluble drugs. And more recently, as I mentioned before, now going into more advanced drug delivery systems like long-acting nanosuspensions.

And then, from an academic perspective, we are applying nanocrystals for many other administration routes, including intranasal drug delivery, and, of course, tablet drug delivery as well. So, there's a lot of action in the space.

And then you were asking about microneedles. Again, this is an interesting platform. So, microneedles are made of very tiny micro projections. These needles can be applied in the skin without touching the nociceptors, the nerves, and the blood vessels.

So, they are able to deliver drug cargos in the viable layers of the skin without creating pain or bleeding. So, now they become really interesting to deliver literally any time, any type of drug. Even particles, gene therapies, can be delivered because now you don't depend on the properties of the drug to cross the skin barrier. Now you are creating very tiny holes in a minimally invasive way, to put the drug inside the skin.

So, what is happening there is that, depending on the system that you are using, drugs will dissolve very slowly in the fluids of the skin. We have a lot of fluids there. And then drugs that are dissolved will diffuse through less concentrated areas to reach the microvasculature of the skin. And now drugs will be picked up in the systemic circulation.

So, the two technologies, though microneedles are not yet in the market for drug products — they exist for cosmetics, though — they are still in development, and they have proved to be useful for the delivery of a variety of systems and drugs into the skin in a minimally invasive way. So, there are two interesting technologies that combine together.

Great. So, as you look to advance those technologies in combination, what are some of the additional problems to be solved or questions to be answered or challenges to be overcome as the work proceeds?

So, from both sides, we'll have challenges. Maybe from a regulatory perspective, nanocrystals are easier in the sense that they already exist in the clinic and they can be produced at very large scale using specific mills. They can be sterilized as well. So, this is a good difference in comparison with other nanoparticle types.

So, I guess, a problem with nanocrystals is that some drugs might dissolve too quickly. So, whenever you put them in the skin or in the muscle, they will essentially be washed out very quickly. So, the solution for that, as they did, for example, with paliperidone, is to create a prodrug that is less soluble. So now, you, on purpose, are making a drug less soluble. And then you can engineer particle size to achieve the long-acting components. So, there are a few challenges there.

On the microneedle side of the game, there could be some other challenges that are still in early development. So, regulators are still unsure of these devices. Will they be a drug dosage form? Will they be a device? So, FDA is already providing some preliminary guidance in this space.

Other questions could come, for example, around sterility. Are we speaking about the formulation that needs to be fully sterile? Or maybe just a low bioburden would be enough. So. from that perspective, normal needles for the administration of insulin, for example, are applied on the skin with minimal cleaning. And we know that this doesn't create a systemic infection. So, with microneedles, it would be more or less the same: [Infection] would be rare. And there is literature in the field showing that even infected microneedles, in [use], were not creating an infection in the skin. But questions like that will be around. So, one of them would be regulatory; another would be sterility.

And then one question that is already being addressed by some Big Pharma companies is large-scale manufacturing of microneedles. How do we make sure that drugs are contained within the patches and within each of the microneedles in a uniform manner? So, challenges like that would come into play.

Another aspect that would be important is the need for applicators or not. Would just the pressure of the thumb be enough to apply the microneedles in a uniform way? Would we need an applicator? If yes, what kind of system? How do we make sure that the microneedles are inserted correctly in the skin? So, from a formulation science perspective, the topic is really interesting, and there are many questions around where we are going with a lot of progress. So, this is really interesting.

Yeah, great. And as the work continues and some of those challenges are overcome, problems solved, questions answered, assuming everything moves forward at pace, eventually and over time: What do you envision as a potential and hoped for future state in the patient experience, both terms of cures or symptom reduction and in the receiving-of-treatments experience itself?

Yeah, so one key point here is that these long-acting treatments that we were speaking of at the beginning are challenging to the liver. So, applying an injection brings a lot of challenges. You first need a patient that is able to get an injection. This is a new product. Many patients will probably struggle with the fact that the needle will come to their house. So, there's pain, and this sometimes leads to low adherence to treatment.

And then from a healthcare perspective, you need people that are qualified to apply injections. And then these needles need to be disposed of in the right way. And if you think of treatments, for example, for pre-exposure prophylaxis where the highest prevalence of the disease happens in low and middle income countries where the healthcare system is not really well-developed, all these problems can essentially impair the deployment of these technologies there.

So, from a patient perspective, we would like to have ways to deliver the long-acting treatments in a minimally invasive way. Here is where microneedles will come to play because they would enable the application of these long-acting nanosuspensions in a way that would be more feasible for patients to do themselves with a little bit of instruction. And then without creating pain, without creating bleeding. And because these patches are in most cases self-disabled, you apply them to the skin, the microneedles will dissolve in the skin, and then you can just peel off the patch, no microneedles. So, you would be simplifying the approach quite a lot.

So, we will be achieving long-acting for patients in minimally invasive ways. And then we'll be saving money and resources from the healthcare system because now these systems could be applied much more easily. So, this is where I think we have a lot of evidence now in the literature, but I think where the industry could be interesting to go in the coming years.

Great. Well, it all sounds very promising. I'd like to step back a little bit and maybe conclude with this question, and that is: From your seat, as a senior lecturer at Queen's University Belfast in a pharmaceutical sciences program, how do you see the role and the contributions of programs like that — academic and university-oriented lab work — in the broader ecosystem of drug development and drug delivery development?

Yeah, well, I have a personal component here because I truly believe that interaction between academia and industry is the key to this. So, innovation created in universities can very often complement innovation created in industry. So, there is a synergistic approach here. We have collaborated with pharma companies. Sometimes they come to the lab with a drug that is fully soluble or maybe with some patent [about to] expire, and they want to explore new administration routes. And we have the know-how for that. So, the approach here would be to try to synergize as much as possible in order to facilitate the delivery of these drugs to make a better option for patients or sometimes even to solve formulation problems that they might be having on their side. So, here the key point is interaction between the two parties.

Gotcha. Well, Alejandro, I want to thank you for sharing your perspectives with our audience —and, obviously, for sharing your work with audiences like AAPS — but specifically here for our Drug Delivery Leader audience. And to that audience, I want to say thank you for joining us for another episode of Sit and Deliver. And we'll see you next time.