Who really likes needles? A brand-new episode of our Tech Briefs podcast series Here’s an Idea™ explores the emergence of micro-ones.
Learn all about how an array of microneedles can deliver drugs in a more precise way than the needle and syringes that we're used to. The Velcro-like micro option is less painful – and more effective, it turns out.
And the devices are especially valuable during a pandemic. (Listen to the brand-new episode below.)
Subscribe or listen via your preferred podcast provider here.
Episode Highlights:
- (0:54) Professor Ryan F. Donnelly, from Queen's University Belfast, sets the stage and explains what a microneedle is exactly, and how microneedles are being used today.
- (11:05) Stanford Professor Joseph DeSimone details his team's 3D-printed vaccine patch that provides greater protection than a typical vaccine shot.
- (18:48) Sandia researcher Ronen Polsky discusses efforts to use microneedles to draw out interstitial fluid, which can offer early detection of diseases.
Additional Resources:
Ryan Donnelly talks about microarray patches and their role in precise, effective drug delivery. Watch the presentation below:
Watch a Tech Talk from Ronen Polsky:
We want to hear from you. Share your comments below.
Transcript
00:00:00 hello everybody i'm ryan donnelly i'm professor of pharmaceutical technology at the school of pharmacy here at queen's university in belfast the school is a leading international center for education and research in pharmacy and pharmaceutical sciences my presentation today i will give you a snapshot of some of the work my group are doing on microarray or micronatal
00:00:26 patches in that i will have a look at some of the work that we're doing on high-dose drug delivery and how that can be used to target global healthcare challenges i'm going to talk about conventional microneedle strategies first to set the scene i'll then move on to talk about how if we can change our mindset to consider
00:00:51 delivery of high doses of purely water soluble drugs how we can open up a number of possibilities i will talk about the design and manufacture considerations associated with high-dose drug delivery using microneedles and then look in particular at various dissolving microneedle strategies that can achieve this
00:01:11 and finally i'll finish on some important patient and translational considerations so microneedles as the name suggests are arrays of tiny projections on a solid patch and it can be in all sorts of shapes and sizes and can be made from numerous materials including metal elemental silicon glass but most commonly polymeric
00:01:38 materials and what these microneedles tend to have in common is that they tend to be shorter than one millimeter in height and they tend to be on arranged on small patches around about one square centimeter so because the patches are small we tend to only really be able to deliver potent substances with
00:01:59 conventional microneedles so intradermal vaccine administration would be the most common use alternatively we could do systemic administration of a very potent drug like insulin for example or we could do local drug delivery we want to target a disease or infection off the skin microneedles don't cause pain and they
00:02:23 don't cause bleeding because they don't penetrate deep enough into the skin what they do is to breach the skin stratum cranium barrier and that means that we can deliver a range of different types of substances microneedles have been considered in the news and throughout the covid19 crisis and i think what what this has shown is that there is an increasing need for
00:02:48 microneedle products and i don't necessarily think that is all going to be around code 19 vaccines or even the use of conventional vaccines and through microneedle delivery i think that there is a big benefit obviously in developing countries to have a heat stable vaccine that could be administered without risk of needlestick injury by
00:03:12 somebody who isn't necessarily a skilled healthcare professional but i think where microneedles are really going to come to the fore in the post covid19 world will be an administration of medicines that ordinarily require injections so this could be long-acting contraceptives or antipsychotics it could be hiv drugs or therapeutic
00:03:35 antibodies so these are our medicines that normally the person has to come to a healthcare setting to have administered by injection by a skilled healthcare professional i think healthcare professionals are going to be spending a lot of time in the coming years catching up with a backlog in normal treatment and diagnosis and also in routine
00:03:56 administration of covid19 vaccines so if we can take the administration of conventional injected drugs out of the doctor's office and put them into the hands of patients in their own homes then there would be a lot of benefits in terms of reducing health care costs but also reducing inconvenience for patients and the likelihood that a patient could bring
00:04:18 covid19 into a healthcare setting or could catch it while they're there and so this opens a range of possibilities but we will have to innovate in terms of our micro needles to make this possible so for considering delivery of high-dose drugs and hydrophobic drugs in particular and remember that about sixty percent of new chemical entities tend to
00:04:41 be very hydrophobic in nature then there are a few things we need to consider first of all microneedles create aqueous pores in the skin and secondly for most drugs we need tens or hundreds of milligrams per day not the micrograms that we're talking about for a vaccine so we need to think about what implications this might have for the
00:05:03 patch size of our microneedle system and how easy it might be for patients to actually apply these because these aren't going to be a system that's only applied once or twice like a vaccine we need to think about what might happen if we repeatedly apply microneedles to people's skin i do think and i'll show in the talk that all of these considerations can be
00:05:26 overcome and i think this will give a range of different and cost reduction and implications for health care providers and competitive benefits for industry but really as a pharmacist what i want to see are considerable benefits for patients and i think microneedles can deliver that so if we consider first then how to make
00:05:48 high loading dissolving microneedles so what we really need to do because microneedles are quite small and they might only weigh 10 or 12 milligrams in terms of the needles per square centimeter then we need to get a high drug loading in there greater than 50 percent weight per weight in the needles and we should use a biodegradable or low
00:06:09 molecular weight polymer because remember we're not only depositing the drug in the person's skin we're depositing polymer in there as well so if we're going to use a typical pharma polymer that's biocompatible but not biodegradable then we need to have a molecular weight that's less than 60 kilodaltons so the kidneys can clear it the alternative is to use a
00:06:28 biodegradable polymer something like hyaluronic acid or dextran for example the polymer should be a good film former and have a low glass transition temperature so what this means is that the micro needles will be hard and sharp enough to penetrate the skin without bending we should dry the microneedle slowly to promote physical stability the last
00:06:52 thing we want to do is trap the drug in the amorphous state and then have it slowly recrystallize upon storage because that will influence the behavior of the ultimate so the height of the microneedles and the number of needles that we have on each array and the actual patch size will all influence the deliverable dose and if we're depositing the drug as
00:07:13 hydrophobic particles in the skin then that will of course influence the duration of the delivery after we remove the patch because remember the micro needles might dissolve in less than an hour for a hydrophobic drug particularly one in particular form we're not going to deliver anything in the base plate so we have to load the
00:07:35 drug into the needles and get most of it as close to the tips as we can because the needles may not insert 100 off their length we also need to make sure that when the microneedlings are removed we don't leave a sticky residue on the person's skin for aesthetic reasons and we don't want to waste drug if we can avoid it so the first disease that we want to
00:07:58 consider in terms of high-dose long-acting drug delivery with microneedles is hiv aids and since the beginning of the current epidemic more than 33 million people have died due to hiv infection and in 2019 there were about 38 million people worldwide living with hiv aids and 150 000 new infections in children
00:08:23 the vast majority of people living with hiv are in low and middle income countries and in 2019 21.7 million people um were living with hiv and accessing antiretroviral therapies this is 67 of the total number of infected patients are actually getting antiretroviral
00:08:46 therapy between 2000 and 2019 then new hiv infections fell by 39 and hiv-related deaths fell by 51 with 15.3 million lives saved due to empty retroviral therapy but there is a considerable pill burden so people are taking tablets every day and um either for treatment or pre-exposure prophylaxis in high-risk
00:09:10 individuals and this can then lead to what's known as pill fatigue where people will not be so compliant with their medication and this can lead to resistance long acting injections of poorly soluble or hydrophobic drugs is an alternative um method so in this case the person gets a monthly or every two months
00:09:31 injection of the hiv drug as a crystalline nano suspension and more than one drug can be administered if we're treating as opposed to trying to prevent disease now microneedles could be particularly advantageous over hypodermic injections particularly in developing countries because they could be self-applied by the person and they wouldn't need to go
00:09:51 to a healthcare setting and then they also won't need to dispose of a hypodermic needle so if we want to then formulate long-acting anti-retroviral drugs into microneedle patches then we take the nano-formulated drugs at high concentration and load them into aqueous gels we then cast them into a microneedling
00:10:13 mold and we dry and add a border adhesive and an occlusive backing layer to form the patch the base plate should readily detach upon microneedle dissolution in the skin and then the nano-formulated drug will be deposited in the viable skin layers for sustained release and absorption by the rich derma micro circulation so this is the first study that we did
00:10:37 and thanks to path in usaid for funding the work and johnson for providing recovery cereal pivoting is a long-acting antiretroviral drug normally given by injection we took the recovering crystalline drug nano suspension we loaded it into the microneedles and we applied that to the skin of rats as a control we administered the same
00:11:01 nanosuspension as an intramuscular injection and we followed the plasma levels over a 56 day period and we found that the microneedles performed extremely well relative to the intramuscular injection including in terms of drug content in vaginal tissue because remember heterosexual transmission is the most common route of hiv transmission
00:11:25 it's very difficult to do allometric scaling for long-acting drugs because they exhibit flip-flop pharmacokinetics where overall plasma exposure is dictated by the dissolution phase rather than the elimination phase of the drug and so it's very difficult to work out a patch size for a person based on rat data we have had a go with this
00:11:51 and we estimate that for seven days human treatment in other words to maintain the drug above therapeutic plasma levels we might need a patch between 25 and 30 square centimeters which is extremely um possible in terms of manufacturing in terms of what microneedle patch that size as we will see later on
00:12:15 the next compound we considered was etra firing and we realized that nano suspensions can be quite expensive to produce so we looked at just including the plain powder and out of the bottle into the gel to make the micro needles and then we also then made a nano suspension and we applied both micro needles independently to the skin of rats and then we looked at
00:12:36 an intravenous injection because there is no um intramuscular injection product for etrovirene and as expected with the intramuscular injection or the intravenous injection we got a rapid um peak of plasma levels of heterovariant and then they declined over a 10 day period or so what we did see for both the micro needles containing the powder form
00:13:02 of the drug and the nano suspension was sustained plasma levels above the therapeutic plasma level for around about a month and we think then that this shows that microneedles can be used in long-acting delivery of etrafirine as another hiv compound the next compound we looked at was
00:13:25 cabategravir so again used in long-acting um prevention and when combined with recovering treatment of hiv when given by injection and what we did here was we loaded in either the proprietary vave nano suspension and thanks to vave path and usaid for supporting this work
00:13:47 we took the nano suspension we loaded it into dissolving micro needles and we also took the free acid powder form off the drug and also the sodium salt and powder form and loaded those into the micro needles and we compared that to intramuscular and intradermal injections of the proprietary wave nanosuspension after 28 days all of the microneedles and still had um therapeutic plasma
00:14:12 levels in the rats what was very notable was after seven days the free acid um was similar to the nano suspension but the sodium salt had plasma levels very similar to the intramuscular injection and the um intradermal injection so what this suggests is that microneedles are quite a viable delivery system for
00:14:37 long-acting administration of hiv compounds again predicting patch size can be a challenge but we think that for around about seven days human treatment the patch size could be in and around about 20 square centimeters for cabot aggregate so again a reasonable patch size we then moved on and we considered
00:14:59 administration of both relpeverine and cabategravir because this is this combination can be used for long-acting treatment and what we found was that for the recovery the microneedle needles actually performed better over a 70-day period than the injection in terms of plasma levels for a pivoting we um for kabategravir we saw a similar
00:15:24 pattern to what we we have seen before and again over a 28 day period the microneedles look extremely promising we then wanted to simulate a repeated application because we we think that microneedles um would need to be applied every week and or possibly every month and we looked at a loading dose of repairing and cabot agrovir in the rats and we also then um
00:15:53 did that by intramuscular loading dose with each of the top up doses administered by microneedles so we had either a micronatal and loading dose or an intra intramuscular loading dose and then we basically followed the the plasma levels after we applied the patches every 14 days and essentially by applying micronatal patches for both recovering and kabategravir we were
00:16:19 actually able and to top up the drug that was being cleared from the body so repeat dosing and does look promising and what was notable was that we didn't see any adverse effects um on the rats with repeat dosing either systemically or locally at the actual site the second disease we want to consider is lymphatic filariasis this is a disease where over
00:16:44 120 million people are infected with about 40 million people disfigured and incapacitated by the disease so basically what happens is the person gets an infection of microfilaria in the bloodstream and they end up then with adult and worms in their lymph node and this causes damage to the lymphatic system which can impair drainage of fluid
00:17:09 from the limbs in particular and this causes this elephant um syndrome in patients where their limbs swell whenever drugs and to treat lymphatic filariasis or administer orally they penetrate poorly into the lymphatic system however it is known that if you can deliver particles of less than 100
00:17:31 nanometers into the intradermal space or intramuscular space you can target the lymphatic system so loading and anti-filler ion and drugs and both anthem ethnics and antibiotics and that actually target not only the worm but also the bacteria and that symbiotically lives in the belly of the worm then you could potentially have much better treatment of lymphatic
00:17:56 filariasis so what we did here was we loaded um the drugs into solid lipid nanoparticles and we placed those into microneedlings and we applied them to the skin of rats and then we did an oral control and we looked at the levels in the lymphatic system and what we found was that
00:18:18 microneedles led to about seven-fold improvement in lymphatic concentrations of the drugs apart from um albendazole sulfone where this drug is actually a metabolite of albendazole that is only formed during first pass through the liver so we would have been able in this case to target the drugs to the lymphatic system
00:18:48 and have a profound improvement in lymphatic levels of the key drug substances here so this means that we have a potential means of targeting lymphatic diseases using microneedles as well i've been mentioning how particularly with the hiv drugs in order to deliver the requisite dose the patch size is going to have to be relatively large
00:19:15 so what we did was we got 10 human volunteers and we got them to self-apply either a small one square centimeter a microneedle patch or a patch made up of 16 individual one square centimeter patches to their skin and we used optical coherence tomography which is the optical analog of ultrasound to study the depth of insertion and the
00:19:37 width of the pore created and we then compared in these individuals the depth of insertion of the multiple um patches and needles or the the um the width of pore with those created by the single one square centimeter patch and for the large patch we looked at various different areas on the sides in the middle and so on
00:20:03 so the main insertion depth was not any different for the larger patch and neither was the poor width created so what this suggests is if you give people appropriate instruction they can apply large patches by hand um just as effectively as they can a small patch so large patch application is viable and we have in the past made single piece micro needle patches up to 25 square
00:20:28 centimeters most of these medicines will have to be repeatedly dosed using microneedles so we took a series of nude but fully immunocompetent mice and we applied microneedles to their skin on a weekly basis for five weeks and we looked at skin appearance and at the end of the five-week period we found that that had not changed we couldn't see any evidence
00:20:52 of polymer deposition in the skin of the mice and when we measured trans epidermal water loss and to assess skin barrier function we found that that was also unchanged relative to control we then looked at immune response and in this case we had two microneedle designs so they either was 11 by 11 or 19 by 19 arrays of 600 micrometer needles
00:21:17 and we looked at three formulations so the acid polymer gantry is s97 the neutral polymer pvp and then swellable microneedles that didn't dissolve in the skin and would be neutral in nature we found that there was no immune response relative to control and needle density had no effect and there was no significant difference whether the
00:21:39 microneedles dissolved or swelled in the skin and this was measured by immunoglobulin g levels we then measured interleukin-1 alpha and again found no significant difference relative to control needle density had no effect and even the low ph of the gantry system had no significant impact we also looked at infection um as
00:22:02 indicated by c reactive protein body temperature and weight change and again there was no indication that repeat application of microneedles caused infection so i think that microneedle systems are very promising for high-dose delivery whether we're targeting specific compartments in the body or whether we're doing long-acting delivery of
00:22:24 hydrophobic drugs we can deliver more than one molecule at the same time and i think that such systems really do have the potential to address global healthcare challenges particularly in the postcovid era of course we still need to do some work on understanding pharmacokinetics and comparing between animals and humans particularly for long-acting drugs where
00:22:48 flip-flop pharmacokinetics are in operation we've recently been very fortunate to receive a large grant from the engineering and physical sciences research council to de-risk our delivery platforms in accordance with regulatory advice we basically will show that the delivery systems are safe and the polymer can be
00:23:07 cleared from the system readily and then develop a bridging program that we can offer to any industrial partner and that will be applicable to each drug that they may wish to be delivered where they only need to to show then the administration of their drug molecule doesn't cause any unusual effects the microneedles field has made considerable strides in terms of
00:23:30 manufacturing scale up and gmp production over recent years so we're now confident that a product can be manufactured for the market ultimately we will be involved in macaque studies infection models for hiv and also clinical trials to show um that the microneedles um will deliver the molecules effectively in humans and we're working towards both of
00:23:55 those at present ultimately we would expect to see microneedles commercialized within the coming years and that this will lead to considerable patient benefit so that concludes my presentation all that remains for me is to thank the many sponsors of our work and also to thank the members of my group for all of their hard work and innovation in bringing
00:24:18 this work to fruition thank you
