An Intradermal Platform Built for Industry and Patients

Early Insight

AN INTRADERMAL PLATFORM BUILT FOR INDUSTRY AND PATIENTS

In this article, Moe Wehbe, PhD, Drug Delivery Strategist, Iman Mansoor, PhD, Co-Founder and Vice-President of Engineering, and Sahan Ranamukha, PhD, Co-Founder and Vice-President of R&D, all of Microdermics, discuss the potential of intradermal injection for modern medicines and its advantages over the subcutaneous route. The authors go on to discuss the design considerations for a novel intradermal device and introduce Microdermics' intradermal platform.

WHY INTRADERMAL? WHY NOW? “As medicine advances and products

Intradermal (ID) injections shift from small molecules to large have long been known Dr Moe Wehbe biologics, the ability to administer Drug Delivery Strategist to possess efficacy and drugs easily and reliably must improve.” T: +1 778 985 4544 drug bioavailability E: [email protected] advantages over their subcutaneous (SC) and intramuscular approximately 1 mm deep.² If performed (IM) counterparts. ID injections are less correctly, a bleb is formed, showing the invasive and enable access to the dermal distribution of the liquid beneath the skin layer, which is rich in antigen-presenting skin, which disappears minutes after. cells that are ideal for vaccination.1 Yet, Whilst this technique has been vital in the to date, there are few vaccines or drug understanding and evaluation of intradermal products approved for ID use. In fact, the therapeutics, it is difficult to master and skin is rarely used as a drug delivery route, limits the use to healthcare professionals.³ typically only used for topical administration The difficulty of the Mantoux method Dr Iman Mansoor for local treatment. This begs the question – limits ID delivery to the hospital setting, Co-Founder and Vice-President of Engineering why aren’t ID injections being used to deterring its adoption as a common method T: +1 604 992 0321 deliver drugs? of drug administration. E: [email protected] The current approved method for As medicine advances and products shift ID injection is known as the Mantoux from small molecules to large biologics, technique, developed by Charles Mantoux the ability to administer drugs easily and in the early 20th century. The Mantoux reliably must improve. Many biologics technique entails a needle being inserted are given to patients to self-administer into the skin at a 10-15o angle, at home, typically by SC injection. While this method has been successful, a high burden on patients’ lifestyles and needle- “There are four distinct phobia (the extreme fear of injections) has led to challenges with patient compliance, Dr Sahan Ranamukha types of microneedle resulting in discontinuation of therapy and Co-Founder and designs that have been increased costs. These costs and hurdles are Vice-President of R&D compounded by the poor bioavailability T: +1 604 446 0793 created – solid, coated, E: [email protected] of biologics when administered orally dissolvable and hollow or by SC injection.4 Low bioavailability – of which hollow requires higher doses in order to reach microneedles have highest therapeutic plasma concentrations and, due to the high cost of these biologics, this applicability for a wide leads to increased costs for patients and Microdermics Inc. range of drugs, since healthcare systems. Thus, the ideal medical 045 – 2366 Main Mall device would allow for simple, reproducible Vancouver BC liquid drug formulations V6T1Z7 injections or infusions of the drug into Canada can pass through them.” the skin with minimal or no burden on a patient’s lifestyle. www.microdermics.com

MICRONEEDLES ARE IDEAL FOR REPRODUCIBLE “The ability to produce drugs and medical devices at relevant INTRADERMAL INJECTIONS quantities for patient use is a fundamental, and sometimes The concept and development of overlooked, requirement in the pharmaceutical industry.” microneedles has been discussed in scientific literature for more than 25 years. There are four distinct types been employed, such as hiding the needle, In its early stages, Microdermics focused of microneedle design – solid, coated, improving usability, minimising the time on the development of a simple medical dissolvable and hollow – of which hollow required of users and installing needlestick device that could be scaled, eventually microneedles have highest applicability prevention features. patenting a manufacturing process that for a wide range of drugs, since liquid Hollow microneedles can solve many of allows for a novel, scalable microneedle drug formulations can pass through them.5 these challenges through minimally invasive systems. Microdermics has developed a Solid microneedles are typically used to dermal injections. The microneedles back-end technology to compliment the pierce the skin, allowing for improved themselves are small projections that do hollow metallic microneedles during ID penetration of topical drug formulations. not look like traditional needles. These delivery based on the company’s extensive Meanwhile, coated and dissolvable projections only need to pierce the dermis expertise on skin mechanics. As such, the microneedles cater to an implantable design, and are often painless, making them an ideal company’s ID systems accommodate the where the drug coating gradually and alternative to all methods of injection using expansion of the skin during fluid injection, passively dissolves into the skin. Hollow needles, catheters, infusion sets and other ensuring the entire dose is successfully microneedles are the most comparable to types of invasive injector. delivered to the dermis with minimal waste, traditional hypodermic needles as they With the many advantages of ID equivalent to or less than a subcutaneous can directly replace traditional needles in injections using hollow microneedles, the hypodermic needle injection. delivering a liquid formulation into the skin. question remains – why have they not Microdermics has developed a number Microdermics’ intradermal platform been adopted clinically? Although there is of microneedle systems capable of consists of a novel hollow metallic microneedle a plethora of preclinical data suggesting reproducible injections. All Microdermics’ technology that has addressed many of the the advantages of hollow microneedles, systems are simple to use, with no challenges previously limiting intradermal the remaining barriers are largely engineering requirement for complicated or intensive product design. The developed microneedle challenges rather than pharmaceutical training, unlike the Mantoux technique projections can easily and precisely access ones. An approved medical device must be or any needle-based system. They are the dermis and inject drugs reproducibly, simple, manufacturable and reproducible. capable of delivering volumes ranging from eliminating the large variability seen with While many designs exist, few meet all 20 μL to greater than 5 mL, and viscosities other intradermal injection approaches. the requirements necessary for adoption. ranging from 1-100 cP. A standard 0.1 mL Herein lies an opportunity to improve A major hurdle is being able to fabricate dose of a low viscosity fluid (approx 1 cP), the safety, effectiveness, patient care and large quantities of microneedles via as is typical for vaccines and insulin, can compliance around injectable formulations. a scaleable process able to provide for be delivered into the dermis in one second, While SC injections have facilitated the widespread adoption. while a 1 mL dose (approx 1 cP) can be use of many new therapeutics, especially delivered in 4-10 seconds. Volumes greater in home-use settings, they entail a number Microdermics’ Adoptable than 1 mL can be delivered with virtually of drawbacks: Microneedle Platform no pain to the patient at rates as low as The ability to produce drugs and medical 1-5 μL per second. • Bruising at the site of injection is a devices at relevant quantities for patient use One of the early products is an easy- common problem, especially for is a fundamental, and sometimes overlooked, to-use adapter system that can be attached treatments that require repeat injections, requirement in the pharmaceutical industry. to any commonly-used syringe system and such as in vitro fertility treatment.6 Patients and healthcare providers expect discarded after a single use (Figure 1A). • Needle-phobia can hinder compliance, that their treatment will not be hindered by The second product uses a pen design especially when the product is intended a scarcity of life-saving medicines. with prefilled cartridges containing the for home use. drug of interest for repeat use (Figure 1B). • Extensive training is needed before Both approaches have unique niches in patients are comfortable in administering the translation of therapeutics from other their own drugs at home with needle- “All Microdermics’ systems forms of injectables to ID injections for based injection systems. are simple to use, with different patient populations. In fact, these • Needlestick injuries are a commonly no requirement for systems have been used in preclinical and reported incident in the hospital setting, clinical studies and met with success. with associated healthcare costs.7 complicated or intensive Other systems developed by Microdermics training, unlike the focus on wearable devices capable of drug As a result, extensive efforts have been Mantoux technique or any delivery over extended periods, targeting made by drug delivery device designers patients where a lowered burden of to make devices more approachable and needle-based system.” self-administration is particularly important acceptable to patients. Various tactics have for users.

PRECLINICAL & CLINICAL STUDIES

ID drug delivery has been shown to improve the efficacy of vaccines and the bioavailability of many biologic and small molecule therapeutics. Microdermics A) B) recently completed preclinical studies assessing how its novel microneedle adapter systems compare with SC ® injection of epinephrine and Fiasp insulin Figure 1: Microdermics intradermal drug delivery platform has been integrated as aspart (Novo Nordisk) in terms of (A) syringe adapter and (B) microneedle pen designs. pharmacokinetic profile and therapeutic efficacy. While others have examined the animals showed no post-injection signs of the increasing availability of antibody and application of insulin via ID injection with bruising or other dermal trauma. While the large protein therapeutics; these compounds success, Microdermics is the first to test molecules described are small-molecular- are expensive, thus greater bioavailability Fiasp® – the world’s fastest acting insulin weight drugs, Microdermics has assessed the could save in healthcare costs. formulation. These studies show clear absorption rate of large-molecular-weight Microdermics has recently completed its improvements in Fiasp® absorption (fast on, antibodies upon dermal and SC injection. first-in-human clinical study assessing the fast off) when it is injected intradermally Preliminary results show improvements safety and efficacy of microneedle injections via microneedles, compared with traditional in drug absorption upon ID injection via using a syringe adapter system. The results SC injection. Although these studies tested microneedles. Identifying an improved, suggest that this adapter system can be the effects only upon a single injection, the safer means of injection is important due to easily integrated with modern healthcare practices. While the aim remains to create a medical device suitable for at-home use, the ABOUT THE AUTHORS success of the study suggests the engineering of the medical device is user-friendly for Dr Moe Wehbe is a Drug Delivery Strategist at Microdermics. He specialises in preclinical healthcare professionals as well. To date, drug development and has been involved in the evaluation of microneedles for vaccine, only saline has been injected into humans anti-cancer and anti-inflammatory indications. He earned his PhD in Pharmaceutical using this device and further work is being Sciences at the University of British Columbia under Dr Marcel Bally and Dr Helen Burt. performed on a variety of pharmaceutical Dr Wehbe’s research interests are in nanotechnology, pharmacokinetics and medical formulations and commonly-used excipients device development. to examine possible adverse effects at the preclinical level. It is expected that ID Dr Iman Mansoor is a Co-Founder and Vice-President of Engineering for Microdermics. injections via hollow microneedles will He has been involved in research and development of microneedles for more than ten allow for an improved patient experience, years. He received his PhD in Electrical Engineering in 2014 from the University of British with less bruising and tenderness compared Columbia. Dr Mansoor’s research interest is the application of Micro-Electromechanical with SC injections. Systems (MEMS) to life sciences. He currently holds several patents on various MEMS- based drug delivery systems. CONCLUSION & FUTURE WORK

Dr Sahan Ranamukha is a Co-Founder and Vice-President of Research and Development This article has outlined current successes for Microdermics. He has been involved in development and testing microneedle-based of the Microdermics platform for ID drug delivery technologies for more than five years. He earned his PhD in Biomedical injections via hollow microneedles. As Engineering at UBC under Dr Stoeber, and was a recipient of the Vanier Canada medicine evolves, the devices used to deliver Graduate Scholarship. Dr Ranamukha’s research interests are in drug delivery, medical that medicine must also evolve. Whilst SC device development, and therapeutic drug monitoring. injection has allowed for the administration of many novel therapeutics, ID injection

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can address many of its disadvantages and on research at the University of British injection device for intradermal unlock benefits that may not have been Columbia, that works with pharmaceutical delivery of a cell-based therapy”. thought to be possible. Microdermics is companies to unlock the biomedical Drug Deliv Transl Res, Oct 2017, planning on assessing the capability of potential of the skin. Through an innovative Vol 7(5), pp 695-708. the hollow microneedles to improve manufacturing process, its intradermal 4. Škalko-Basnet N, “Biologics: the immunisation upon vaccination and delivery platform provides easy and precise access role of delivery systems in improved of anti-cancer compounds. Additionally, to skin for breakthrough applications therapy”. Biologics, 2014, Vol 8, microneedles are being tested in the delivery in drug delivery. Broad formulation pp 107-114. of nanoparticle formulations for local capabilities, together with a customisable 5. Ita K, “Transdermal Delivery of controlled-release delivery of therapeutics. injection system, enables product lifecycle Drugs with Microneedles-Potential These innovative research projects extensions, innovative applications or the and Challenges”. Pharmaceutics, will provide a rationale for considering accommodation of specific patient needs, Jun 2015, Vol 7(3), pp 90-105. microneedles in the development of including safe and simple self-administration. 6. Engmann L et al, “Local side effects investigational new drugs, potentially of subcutaneous and intramuscular aiding in their success through improved REFERENCES urinary gonadotropins for ovarian safety, efficacy and drug bioavailability. stimulation in in vitro fertilization: Microdermics’ goal is to develop a simple 1. Prausnitz MR et al, “Microneedle- a prospective, randomized study”, medical device to move ID injections into based vaccines”. Curr Top Microbiol Fertil Steril, May 1998, Vol 69(5), a clinically relevant route of administration Immunol, 2009, Vol 333, pp 369-393. pp 836-840. for both small molecules and biologics, so 2. Norman JJ et al, “Reliability and 7. Mannocci A et al, “How Much as to truly unlock the potential of the skin accuracy of intradermal injection by do Needlestick Injuries Cost? in drug delivery. Mantoux technique, hypodermic needle A Systematic Review of the Economic adapter, and hollow microneedle in Evaluations of Needlestick and ABOUT THE COMPANY pigs”. Drug Deliv Transl Res, Sharps Injuries Among Healthcare Apr 2014, Vol 4(2), pp 126-130. Personnel”. Infect Control Hosp Microdermics Inc is a Vancouver (Canada)- 3. Leoni G et al, “Preclinical Epidemiol, Jun 2016, Vol 37(6), based medical device company, built development of an automated pp 635-646.

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