1050 GR Ondrugdelivery Issue 49

Home , Dermal patch

TRANSDERMAL DELIVERY: INTERVIEW: DESIGNING AN A NEW SOURCE FOR PATRICK ALEXANDRE, CEO, ULTRASOUND-ENABLED P04 BIOPHARMA INNOVATION P18 CROSSJECT P22 INSULIN PATCH

TRANSDERMAL DELIVERY, MICRONEEDLES & NEEDLE-FREE INJECTION 49 O

TM ISSUE N • 2014 2014 TH MAY 16 MAY Contents

ONdrugDelivery Issue No 49, May 16th, 2014 Transdermal Delivery, Microneedles CONTENTS & Needle-Free Injection This edition is one in the ONdrugDelivery series of publications from Frederick Furness Publishing. Each Introduction: Skin in the Game: issue focuses on a specific topic within the field of Transdermal Delivery as a New Source for drug delivery, and is supported by industry leaders BioPharma Innovation in that field. 04 - 06 Dr Kevin Pang, Research Director EDITORIAL CALENDAR 2014/15 Lux Research May: Pulmonary & Nasal Drug Delivery Overview: Transdermal Delivery Device Design May/June: Injectable Drug Delivery: Devices Focus Bruce K Redding, Jr, President & CEO June: Injectable Drug Delivery: 08 - 09 Transdermal Specialties, Inc Pharmaceutics Focus July: Novel Oral Delivery Systems Your Solution for Successful Sep: Drug Formulation & Delivery Solutions Intradermal Delivery & Services Dr Paul Vescovo, Project Manager, Oct: Prefilled Syringes 10 - 14 and Dr Laurent-Dominique Piveteau, Nov: Pulmonary & Nasal Drug Delivery Chief Operating Officer Dec: Delivering Biotherapeutics Debiotech SA Jan: Ophthalmic Drug Delivery Feb: Prefilled Syringes Dermal Delivery of Biologics Dr Richard Toon, SUBSCRIPTIONS: 16 - 17 Technical and Business Development Manager To arrange your FREE subscription (pdf or print) Nemaura Pharma Limited to ONdrugDelivery Magazine: E: [email protected] 18 - 19 Interview: Patrick Alexandre, Crossject SA SPONSORSHIP/ADVERTISING: Contact: Guy Furness, Proprietor & Publisher T: +44 (0) 1273 78 24 24 21 Company Profile: Crossject SA E: [email protected] Designing an Ultrasound-Enabled Patch MAILING ADDRESS: for Insulin Frederick Furness Publishing Ltd 22 - 26 Bruce K Redding, Jr, President & CEO The Candlemakers, West Street, Lewes, Transdermal Specialties, Inc East Sussex, BN7 2NZ, United Kingdom Novel Transdermal Delivery Systems ONdrugDelivery Magazine is published by for Treatment of Diabetes Frederick Furness Publishing Ltd. Registered Office: The Candlemakers, West Street, Lewes, 28 - 30 Dr Alan Smith, Vice-President, East Sussex, BN7 2NZ, United Kingdom. Clinical, Regulatory & Operations Registered in England: No 8348388. 4P Therapeutics VAT Registration No: GB 153 0432 49. ISSN 2049-145X print ISSN 2049-1468 pdf Copyright © 2014 Frederick Furness Publishing Ltd All rights reserved

The views and opinions expressed in this issue are those of the authors. Due care has been used in producing this publication, but the publisher makes no claim that it is free of error. Nor does the publisher accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

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ZZZSKDUPDF\XPDU\ODQGHGX Introduction

INTRODUCTION SKIN IN THE GAME: TRANSDERMAL DELIVERY AS A NEW SOURCE FOR BIOPHARMA INNOVATION

By Kevin Pang, PhD, MBA

Transdermal delivery technologies, despite a new fifth generation of devices and a new great promise, have thus far failed to live source of delivery innovation for biopharma up to their potential as powerful delivery companies and patients (Figure 1). devices for the sustained and controllable Current or fourth-generation platform delivery of active pharmaceutical ingredi- technologies use active or electronic deliv- ents (APIs). Although an almost-30-year-old ery, e.g. Nupathe’s (now Teva) iontopho- platform technology, today only about 16 retic sumatriptan patch. The combination of drugs are actively on market for delivery via active delivery with advanced formulation for enhanced skin penetration constitutes our definition of a fifth-generation platform. “If we assume that only The unique strength of 20% are US FDA- and/or EU EMA- transdermal patch delivery is approved over the next the ability to deliver constant regulated levels of API for the 2-3 years, then we can expect treatment of chronic condi- to see at least 16 new transdermal tions. Treatment of neurologi- patch products come to market” cal diseases and conditions like Parkinson’s disease, depression and pain are extremely well suited to this unique strength, transdermal patches. Hurdles to adoption avoiding the typical peak and trough phe- range from cultural and consumer prefer- nomena experienced with oral solids (Figure ences, to drug abuse problems, to limited 2) as well as first-pass clearance for greater API application due to solubility and pen- sustained bioavailability. An example of this etration issues. is Nupathe’s 2013 US FDA-approved ion- However, we believe that this is about tophoretic sumatriptan delivery patch for to change in a big way. The convergence of migraine, prompting Teva Pharmaceuticals advanced formulation technologies, com- to quickly purchase the company for its bat- bined with printed electronics, will transform tery powered transdermal patch franchise the adhesive transdermal patch platform into and technology platform. Dr Kevin Pang Research Director Poultices Reservoir driven Matrix Active delivery Active Lux Research and plasters patches embedded APIs + Formulation

Contact:

Carole Jacques Gen 1 Gen 2 Gen 3 Gen 4 Gen 5 Director of Marketing & Client Services T: +1 617 502 5314 E: [email protected]

Lux Research, Inc Ciondine, Estradiol,1986Fentanyl, 1986Nicotine, 1990 1991 234 Congress St., 5th Floor Rotigotine, 2007 Scopolamine, 1979 Rivastigmine, 2007Sumatriptan, 2013 Boston, MA 02110 Nitroglycerine, 1981 Methylphenidate, 2006 United States

Figure 1: A brief and compressed history of transdermal delivery. www.luxresearchinc.com

Yesterday Today Tomorrow

Peak-Through Dosing Zero order Programmable, Electronics enables much more con- constant delivery adaptive delivery stant and dose effective delivery today. Increasing sophistication and application Figure 2: Transitioning into increasingly sophisticated delivery paradigms. of software, algorithms, sensor incorpora- tion, web and analytics, along with increas- than half for nervous disorders, pain man- We predict that combining active electronic ingly effective at-will skin penetration and agement, and behaviour modification such delivery with advanced formulation will pro- delivery, will drive personalised and adap- as drug and smoking cessation (see Figure 3). vide unprecedented innovation by expanding tive drug delivery. One of the major barriers to skin-based the size range of deliverable APIs, and efficacy The promise of thin, flexible, printed delivery is the low permeability of skin of delivery of APIs, greater bioavailability, and circuits and batteries layered on top of that makes it difficult to deliver molecules controlled release that is not just chemical and the transdermal platform is the increasing potential capability to titrate and customise drug delivery, in effect, personalising drug delivery tied to an individual’s metabolism “We predict that combining active electronic and disease state. Further convergence and delivery with advanced formulation will provide application of advanced microfluidics, sen- unprecedented innovation by expanding the size range sors, and web-based analytics will enable the eventual build of powerful biofeedback of deliverable APIs, and effi cacy of delivery of APIs, loops for even more exquisite near real-time greater bioavailability, and controlled release that is modulation. At the same time, innovators not just chemical and thermodynamically derived, but in the sector will push the miniaturisation frontier, resulting in increasing ergonomics electronically enhanced and programmed per individual” and comfort, and lower the development and production cost curves. As a result, we believe transdermal drug greater than 500 Da in size. Figure 4 details thermodynamically derived, but electronically delivery is in the midst of experiencing a a few examples of companies that are work- enhanced and programmed per individual. renaissance in development and application ing on advanced formulation to enhance Fifth-generation transdermal delivery should as part of the armamentarium of intelligently delivery, not just of small molecules, but not only open up more effective and effica- and co-ordinately dealing with multiple med- even biologics of 106 Da or greater in size, cious ways to deliver drugs to patients, but ication management. Advances in micro- and as either biological drugs or vaccines. Many also provide new forms of intellectual property nano-needle technology (e.g. Micropoint); are working on enhanced large molecule extension for biopharma companies. the use of ultrasound (e.g., Transdermal delivery, including biomolecules such as To provide an example of how big Specialties), iontophoresis (e.g. Nupathe), hyaluronic acid, vaccines, enzymes, and and dynamic we expect the transdermal electroporation (e.g., Ichor Medical Systems), potentially therapeutic antibodies. patch drug delivery market to grow, we and even heat generation (e.g., MedPharm), more effectively to drive drug delivery; the 30 Cardiovascular use of printed electronics and algorithms to create feedback loop driven mini-pumps; 25 Hormone therapy and advances in physiological knowledge with integration into circadian rhythms, will 20 Metabolic enable transdermal patches to be much more powerful and functional to the patient. 15 Microbial infection The number of transdermal patch-deliv- 10 Nervous disorders and ered drugs in clinical trials provides a rich Number of trials pain management landscape by which technology providers 5 can partner with drug companies to enhance Smoking and drug functionally and create multiple product line 0 addiction cessation extensions in the future. An estimated 81 clinical trials are ongoing currently, more Figure 3: A robust clinical trial pipeline.

Company Technology

Halozyme Hyaluronidase skin penetration enhancer for biologics

Apricus Biosciences Small molecule amphiphilic amino acid-fatty acid moiety skin penetration enhancer

Nanocyte Sea anemone injectors to form channels in skin

JRX Biotechnology Oils/alcohol/PEG formulation for large molecule delivery

Salvona Technologies Micro- and nano-encapsulation platform

Transdermal Technologies Polar solvent matchup to API for ionic liquid formation

Convoy Therapeutics 11-mer peptide skin penetrant directly conjugated to API or embedded in liposome

NewGen BioPharma Multiphase oil:water emulsion (licensed from Novavax)

Nuvo Research Membrane penetration enhancers + heat generation

Figure 4: Example companies developing skin penetration enhancement technologies. constructed potential demand curves EU EMA-approved over the next 2-3 years, companies will give rise to fifth-generation for Nupathe’s (now Teva) sumatriptan then we can expect to see at least 16 new devices. We see several non-traditional play- iontophoretic delivery patch for chronic transdermal patch products come to mar- ers poised to participate in the transdermal migraine (see Figure 5). Conservative esti- ket. While each market is different, in patch drug delivery evolution. Examples mates of prevalence growth and market general our model assumes 9-10 years from include: Blue Spark Technologies, which is penetration still indicate the potential for a launch to peak year sales, that many of already targeting thin-film printed batter- blockbuster drug for Teva by 2021, despite the targeted disease indications will yield ies for patches; PragmatIC Printing, which the API, sumatriptan (Imitrex™) being opportunities in the US$500 million to prints logic circuits for potential sensor generic, and available for injection via $1 billion peak year sales levels, we there- hookups; and ThinFilm’s recent acquisition, prefilled syringe. Patch convenience, which fore expect to see up to an additional Kovio Technologies, which combines its obviates the need for patient self-injection; $10 billion in annual sales via transdermal printed memory and sensor platform with and the ability to program desired kinetics, patch delivery by 2025. near field communications for wider range we believe are powerful drivers in favour of Even a few successes with the current communication (e.g. remote analytics and this revitalising delivery platform. pipeline would be highly stimulatory for services). Conversely, firms like MC10, Given the 81 ongoing clinical trials, it further innovation in this field. The pre- which prints flexible adhesive integrated seems likely that some will be approved. If we dicted three ball collision between pharma, circuits for remote biosensing, might them- assume that only 20% are US FDA- and/or electronics, and formulation and delivery selves evolve to become drug delivery platform companies. $700 The potential for personalised delivery $600 of vaccines, nutrients, and both small- and large-molecule drugs via intelligent transder- $500 mal patches is here. Furthermore, the true Chronic $400 Migraine (USA) potential of personalised delivery lies in the $300 integration of physiologic feedback loops, Chronic i.e. sensors and analytics to create low cost, $200 Migraine (EU) accurate, highly convenient patches, perhaps

Expected Sales $(’000) Expected $100 linked to services, making the transdermal $0 patch a truly powerful platform. 2012 2014 2016 2018 2020 2022 2024 Kevin Pang, PhD, MBA, was the lead ana- Year lyst on the Lux Research report, “Skin in the Figure 5: Estimated demand curve for Zecuity based on chronic migraine prevalence Game: The Coming Rise of Transdermals”, and incidence rates in the US and EU. (Application is assumed for chronic migraine which was published in January 2014, and only and forecasted out 10 years from 2013. Total sales expected to hit $1B by 2021. is available to clients of Lux Research. Find Nupathe estimates that key patents covering their platform extend through 2027, out more at: https://portal.luxresearchinc. covering our forecasted range.) com/research/report_excerpt/15923.

ONdrugDelivery 2014/15 EDITORIAL CALENDAR

Publication Month Issue Topic Materials Deadline

June Injectable Drug Delivery: Pharmaceutics Focus May 12th

July Novel Oral Delivery Systems June 9th

September Preﬁ lled Syringes August 4th

October Drug Formulation & Delivery, Services & Solutions September 15th

November Pulmonary & Nasal Drug Delivery (OINDP) October 13th

December Delivering Biotherapeutics November 10th

January 2015 Ophthalmic Drug Delivery December 15th

February 2015 Preﬁ lled Syringes January 12th

March 2015 Transdermal Patches, Microneedles & Needle-Free Injection February 6th

April 2015 Pulmonary & Nasal Drug Delivery March 2nd

May 2015 Injectable Drug Delivery: Devices Focus April 13th Overview

OVERVIEW: TRANSDERMAL DELIVERY DEVICE DESIGN

By Bruce K Redding Jnr

The product development process for a Matrix Type Patch transdermal drug delivery (TDD) system is Similar to the reservoir type patch design multidisciplinary in nature. Much of the sci- but has two distinguishing characteristics: entific literature in the field of transdermal • The drug reservoir is provided within a delivery pertains to skin permeation and semisolid formulation methods of skin penetration enhancement • There is no membrane layer because these are the fundamental issues that must be addressed for any transdermal drug Commercial examples include: candidate. However, in addition to the basic • Habitol® (nicotine) questions of skin permeability and dose • Nitrodisc® (nitroglycerine) delivered, the development process must • ProStep® (nicotine) also address other basic questions, such as the following: Drug-In-Adhesive Type Patch • What is the appropriate patch design? The drug in adhesive (DIA) patch is a type • What are the appropriate materials to use of matrix match, characterised by the inclu- in the patch construction? sion of the drug directly within the skin-con- • Will the target drug be compromised by tacting adhesive (Wick, 1988). In this design either the design or the materials used in the adhesive fulfills the adhesion-to-skin func- the patch construction? tion and serves as the formulation foundation, • Choice of the skin pathway, either sweat containing the drug and all the excipients pore, hair follicle, micro-fissure penetra- (Wilking, 1994). This category also has two tion or poration of the skin. sub-sections: monolithic and multilaminate.

CONVENTIONAL PATCH DESIGNS Commercial examples include: • Monolithic DIA: Climara® (estradiol) The two main traditional/conventional • Multilaminate DIA: Nicoderm® (nicotine) types of patch design – reservoir patches and matrix patches – are shown in figures 1 and The DIA patch design has several advan- 2, respectively. tages in reducing the size of the overall patch and provides a more concentric seal Reservoir Type Patch upon the skin. DIA patches tend to be more Characterised by the inclusion of a liquid comfortable to wear and very thin. A typical reservoir compartment containing a drug DIA patch is 165-200 μm thick. solution or suspension, which is separated Major disadvantages include a longer from a release liner by a semipermeable drug delivery profile. The release of the membrane and an adhesive. drug from a DIA patch follows first-order kinetics, that is, it is proportional to the con- Commercial examples include: centration of drug within the adhesive. As • Duragesic® (fentanyl, Janssen) the drug is delivered from the DIA patch the • Estraderm® (estradiol, Novartis drug concentration will eventually begin to (discontinued)) fall. The delivery rate therefore falls off over Bruce K Redding, Jr ® • Transderm-Nitro time and this fact needs to be considered in President & CEO (nitroglycerin, Novartis) the clinical evaluation phase of development. T: +1 484 716 2165 F: +1 610 356 1866 E: [email protected]

“Each of these approaches to delivering Transdermal Specialties, Inc drugs through the skin brings with it unique 1 Kathryn Lane Broomall advantages but at the same time challenges, be they PA 19008 technical, clinical, regulatory or commercial” United States www.transdermalspecialties.com

Figure 1: Reservoir transdermal patch construction. Figure 2: Drug-in-adhesive matrix patch construction.

A significant problem with most of the main forms of transdermal patch is the intermingling of the drug with adhesive compositions. These result in new profiles and in many instances the drug is degraded through the interaction with the adhesive composition. The chemistry of the adhesive can alter the stability, performance and function of certain drugs. In the case of insulin, for example, the intermingling of the adhesive with the drug can denature the insulin and any deposited insulin would now be a mixture of insulin + adhesive, which may not be a safe blend for dosing purposes. Additionally there are limits to the molecule size of drugs, which can be delivered via a passive system. Typically drug can- didates are below 500 Da for DIA patches Figure 3: The basic structure of human skin. and below 1,000 Da for matrix and reservoir patches, even through the use of skin between 500 and 1,000 Da require skin allow certain large molecule drugs to be enhancers. enhancers such as alcohol or surfactants absorbed into the stratum corneum. to increase skin absorption. 6) Accelerating the drug to high speeds so it GETTING THROUGH THE SKIN 3) Dilation of the skin pore. The normal pore has enough kinetic energy to pass straight diameter is 50 μm (on the body). Dilating through the stratum corneum and other The skin is a natural barrier, as shown in the pore to expand its diameter can allow skin layers, coming to rest at the required Figure 3. To deliver a compound transder- larger molecule drugs to be absorbed. depth, as with liquid and powder needle- mally your options are: 4) Dilation of the pore surrounding the free injection systems. 1) Microporate the skin such as through hair follicle. The normal hair follicle a catheter or needle. Essentially punc- pore diameter is 50 μm (on the body). Each of these approaches to delivering ture the skin. Mirconeedle systems and Dilating the pore, to expand its diameter, drugs through the skin brings with it unique reduced length injectables are designed can allow larger molecules to wick down advantages but at the same time challenges, to reduce the pain associated with skin the hair to the root and from there into be they technical, clinical, regulatory or puncturing. the epidermis. commercial. On the following pages in 2) Passive absorption through the stratum 5) Fracturing of the skin micro-fissures. this issue of ONdrugDelivery Magazine, corneum. Drugs less than 500 Da in By using an energy medium the skin the abovementioned techniques will be size can more easily be absorbed. Drugs micro-fissures can be dilated and this will described in more detail.

IN WHICH EDITION COULD YOUR COMPANY APPEAR? www.ondrugdelivery.com

YOUR SOLUTION FOR SUCCESSFUL INTRADERMAL DELIVERY

In this article, Paul Vescovo, PhD, Project Manager, and Laurent-Dominique Piveteau, PhD, MBA INSEAD, Chief Operating Officer, both of Debiotech, discuss the design of the DebiojectTM microneedle device and inserter, and its applications, particularly in intradermal delivery of vaccines. Clinical development is underway and encouraging preliminary results are reported.

For many years, the transdermal route has In addition to the advantages relating to been considered an interesting alternative the injection mode, the skin presents par- to the oral or standard parenteral routes ticularly interesting characteristics. Several for the injection of drugs. Compared with studies have shown that the pharmacokinet- the former, it prevents the active ingredient ics of certain compounds can be dramati- undergoing degradation in the gastrointes- cally modified when infused within the skin. tinal tract as well as the first-pass hepatic The peak time of insulin, the molecule form- metabolism. Compared with the latter, it ing the basis of diabetes treatment, can be prevents patient pain induced by the shot as halved compared with subcutaneous injections. For vaccines, when compared with intramuscular injections, doses required to reach “The peak time of insulin can sufficient immune response can be halved compared with be reduced by a factor of up to subcutaneous injections. For ten (as this is the case for rabies) or, at constant dose, immune vaccines, when compared with response can be enhanced sig- intramuscular injections, doses nificantly (such as for flu in Dr Paul Vescovo elderly patients). required to reach suffi cient immune Project Manager All these factors have response can be reduced by encouraged the develop- a factor of up to ten or, at constant ment of a variety of tools to dose, immune response can facilitate the crossing of the upper layer of the skin by a be enhanced signiﬁ cantly.” wider range of molecules. Two major approaches have been followed. The first one, using well as safety risks associated with contami- chemical methods, has focused on the nated needles. Despite this, there are very modification of the molecules or on their few drugs that are delivered today using combination with other molecules to facili- Dr Laurent-Dominique Piveteau this method. tate their passage through the stratum Chief Operating Officer The top layer of skin, the so-called corneum. The second one has been focus- T: +41 21 623 60 44 stratum corneum, which has a thickness of ing on physical methods to create passages F: +41 21 623 60 01 E: [email protected] 10-15 μm, acts as a tight barrier that pre- through which molecules can penetrate vents most chemical compounds penetrat- into the skin. Electrical currents (electro- ing into the body. Only small molecules, phoresis) or ultrasound (sonophoresis) for Debiotech SA Avenue de Sévelin 28 with adapted lypophilicity and sufficiently example are used to make the stratum 1004 Lausanne solubility may potentially be delivered in corneum porous for a certain period of Switzerland this way. Unfortunately, the vast majority of time. By placing a simple drug container APIs do not match these criteria. on the treated surface, the drug could then www.debiotech.com

Figure 1: DebioJectTM is very easy to use. slowly diffuse into the tissue. Microneedle technologies are part of these physical approaches. By their form, microneedles dig passages through the protective layer of the skin that will be used by the drug to diffuse into the tissue. They are four different ways usually described to perform intradermal injections Figure 2: Single microneedle mounted Figure 3: Multiple microneedles using microneedles: on a connector. mounted on a connector.

POKE AND PATCH Although the innovative hollow The so-called “Poke and Patch” method microneedles are the heart of the system, is similar to what we described earlier with the inserter plays an essential role. the electro- and sonophoresis approaches. Microneedles are used to create pathways MICRONEEDLES in the skin mechanically, which are then covered by a patch containing the drug to Due to the thin nature of the dermis be delivered. As long as these pathways stay THE DEBIOJECTTM SYSTEM layer, the needles must be very short – less open, the drug diffuses into the skin. than 1 mm – in order to ensure delivery The DebioJectTM System is intended for of the medical substance into the tar- COAT AND POKE injecting any liquid substance or drug fluid geted region (Figure 5). They are made of into the dermis. This CE marked device is high-purity monocrystalline silicon cov- In the “Coat and Poke” approach, nee- very easy to handle and doesn’t require any ered with a native thin layer of silicon dles are coated with a formulation com- special skills (Figure 1). The depth of injec- dioxide. Silicon offers very interesting prising the active agent combined with a polymer that will dissolve after insertion of the needles into the skin. Minutes after placement, the needles are removed, the “Silicon off ers very interesting mechanical properties. coating has disappeared and the active agent It is a non-ductile material with an incredibly high has been delivered. tensile strength and hardness. With such mechanical POKE AND RELEASE properties, and as it was demonstrated experimentally, there is nearly no risk of microneedle breakage in the skin.” In the “Poke and Release” approach, needles are made of a soluble material containing the medicament. Once in the tissue, the needles will dissolve and release the tion and the amount of substance delivered mechanical properties. It is a non-ductile active principle. are both reached precisely and in a controlled material with an incredibly high tensile way. DebioJectTM can inject a bolus of up to strength and hardness. With such mechani- POKE AND FLOW 500 μL within less than five seconds. cal properties, and as it was demon- The system comprises two main ele- strated experimentally, there is nearly no Finally, in the so-called “Poke and ments: risk of microneedle breakage in the skin. Flow” approach, hollow microneedles play • a single or an array of hollow microneedles Furthermore, silicon and silicon oxide the same role as conventional needles by (Figures 2 and 3) in fluidic connections have excellent biocompatibility. creating a mechanical channel through the with a reservoir containing the medical Microneedles are monolithic and made skin which will be used by a liquid formu- substance to be delivered into the dermis without any assembly. They consist of a lation to penetrate the tissue. DebioJect™ • an inserter (Figure 4) to place the micronee- flat substrate sustaining the microneedle microneedles, recently named as MDEA dles into the dermis at the targeted depth part. A fluidic micro-channel goes through Awards 2014 finalists, are part of this lat- and maintain them in place during the the whole needle, from under the substrate ter category. whole injection. to the delivery hole which is placed, not

any required depth between 150 μm and 900 μm. A microneedle can have one or several delivery holes placed circumferen- tially (Figure 7). The outer shape of the microneedle is designed with a very sharp tip to puncture the skin easily. The micro- channel drives the injected fluid from the injection line through the delivery hole into the patient’s skin. DebioJectTM microneedles are produced using well established industrial Micro Figure 5: Comparison between a microneedle and a 25G needle. Electro Mechanical System (MEMS) technologies (Figure 8). MEMS are manufac- The manufacturing process developed with tured using modified semiconductor device Leti/CEA is completely compatible with the fabrication technologies, commonly used major industrial MEMS foundries. to manufacture IC circuits. It allows the The needles are processed on 200 mm manufacturing of very small devices with (8 inch) diameter silicon wafers. About 1,500 a sub-micron precision, far better than microneedle chips can be produced on a single standard micromechanical technologies. wafer. The entire process is conducted in an DebioJectTM microneedles are currently ISO Class 3 cleanroom environment. MEMS manufactured by Leti (Grenoble, France), technologies enable the manufacturing of high Figure 4: Two kinds of inserters. which is part of CEA, one of the world’s volumes of devices at a very low cost. largest organisations for applied research on the tip of the microneedle, but on its in micro-electronics and nanotechnology. INSERTER side (Figure 6). It offers extensive facilities for micro and The length of the microneedle and the nanotechnology research, including fabrica- The inserter must provide the micronee- position of the delivery hole can be changed tion lines, 11,000m2 of cleanroom space, dle with the right dynamic parameters by design in order to deliver the fluid at and first-class laboratories and equipment. (force, velocity, energy) to ensure its full

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Figure 8: Microneedles on a wafer.

tioned at the tip of the microneedle. The tip of the needle is compressing the tissue and as a consequence it increases the fluidic resistance in this area. It’s therefore very benefi- cial to place the delivery hole on the side of the microneedle as the fluid will be delivered into a region which is less compressed and presents a lower fluidic resistance. Another advantage is that it tends to push the injected liquid in the dermis, and not in the subcutaneous tissues (Figure 10). The fluidic jet is oriented horizontally at the exit of the needle Figure 6: SEM image of a 700μm long Figure 7: SEM image of a 700μm long microneedle with single hole. microneedle with mutiple holes. (contrary to “classical” needles) and the delivered drug will have a natural tendency penetration into the skin without any could lead to a medical treatment failure. to pursue its course in the same direction. rebound. Once the needles are in place, The design of the microneedles and the Another major advantage of a delivery hole it has to maintain its position throughout inserter must be adapted to satisfy each which is not placed at the microneedle tip the whole injection procedure. The issue application and targeted population. is of the absence of coring and as a con- is very challenging, as the inserter must sequence of clogging of the micro-channel ensure precise positioning on a soft sub- DEBIOJECTTM KEY ADVANTAGES / which may lead to high fluidic resistance or strate, even though both the patient and the ID INJECTION CHALLENGES even complete occlusion when using conven- practitioner will undoubtedly make normal tional straight-hole needles. uncontrolled tiny movements. Regarding As described above, the stratum cor- the length of the microneedle, even very neum forms a strong barrier to protect the PRECLINICAL & CLINICAL STUDIES small motions below 1 mm are critical. This underlying tissues yet in order to reach the issue has been extensively studied in vivo in dermis the microneedle has to go through DebioJectTM microneedles have under- humans with a micro camera mounted on this layer. It must therefore have a sharp gone several preclinical and clinical studies. an inserter (Figure 9). tip to easily pierce the tissue and be made Preclinical studies conducted on various of a strong and hard material, especially animal models such as mice, rats or pigs, are since the microneedle will contact the skin covering areas ranging from basic research at a relatively high speed, to penetrate it. to preliminary tests for clinical trials of new “The ﬂ uidic jet is The microneedle contact area with the skin drugs. In the more fundamental trials, the oriented horizontally must be minimal to facilitate the penetration objective is to understand the distribution and limit tissue damage. For the patient this of an injected fluid into the dermis pre- at the exit of the needle means no pain, a fast healing and no leakage cisely. Here the control in depth that can be and the delivered drug will at the base of the microneedle. achieved thanks to the design of the needle have a natural tendency to Even though the microneedle diameter is of particular interest. must be as small as possible, the inner pursue its course in microchannel has to be large enough to the same direction” limit the fluidic resistance and allow a good passage for the drug. Thanks to that, even highly viscous solutions have been successfully injected with the device. A properly designed inserter should guar- The structural components of the dermis antee injections without any leakage which are collagen, elastic fibers and extra-fibrillar is one of the major issues of intradermal matrix. It forms a dense and incompressible injection with microneedles. It’s particularly structure. For this reason the hydrostatic critical as even a tiny leak may be significant pressure will tend to increase during injec- Figure 9: Microscopic view of an relative to the small injected volume, and tion, especially if the delivery hole is posi- injection on human skin in vivo.

the method used. These results tend to show non-inferiority of the DebioJectTM approach.

CONCLUSION

When speaking about intradermal injection, the first application that comes to mind is undoubtedly the vaccination. Since the visionary work of Charles Mantoux and Louis Tuft at the beginning of last Figure 10: Transverse histological section of mouse skin after injection with DebioJect™. Century, many studies have focused on Clinically, both the DebioJectTM is described by each volunteer on a scale this path often with encouraging results. microneedles and the effectiveness of the of zero to 10 (zero for no pain and 10 for More recently these have included the intradermal route are being tested. For the maximal pain). This distinction allows for treatment of skin cancer, desensitisation, former, the perception by the patient and the segregating the impact of the microneedle of but also various applications in the field of possible side effects of the DebioJectTM are the effect of the infused drug product itself. cosmetics that have been developed. With evaluated, while for the latter the response The order in which injections are done is the emerging availability of technologies to different molecules injected intradermally changed at each visit in order to limit the enabling successful intradermal injections (sometimes at lower doses) is compared comparison effect. Side and adverse events without special education or in-depth train- with that obtained when using conventional such as redness, pruritus and irritation are ing, there are undoubtedly many other subcutaneous or intramuscular injections. also recorded. Finally, during each session application areas that will generate interest A study currently underway and con- as well as three weeks after completion of for this delivery route. ducted in collaboration with the Vaccine the last injection, a blood sample is taken DebioJectTM microneedles have been and Immunotherapy Centre of the Centre and analyzed by RFFIT to determine anti- conceived to replace conventional needles, Hospitalier Universitaire Vaudois (CHUV) rabies IgG levels. but their very particular design allows con- in Lausanne, Switzerland, compares the A first series of intermediate results has sidering for the future having them filled injection of rabies vaccine (Vaccin rabique already revealed some highly interesting with solid formulations that will dissolve Pasteur®, Sanofi Pasteur, Lyon, France) information. Upon insertion of the needle, over time inducing a controlled release over intramuscularly, with the Mantoux method the perceived pain is slightly higher for the long duration. and using DebioJectTM microneedles. The intramuscular injection than the Mantoux sixty-six volunteers involved in this study method. The use of a DebioJectTM micronee- ABOUT DEBIOTECH are divided into three groups. Each group dle is significantly less painful. Upon injection receives injections with all three methods, of the active agent, the perceived pain of the Debiotech SA is a Swiss Company with but only one of the injection devices is intramuscular shot and of the DebioJectTM more than 20 years’ experience in devel- filled with antigen, the other two contain- is similar, but statistically lower than that oping innovative medical devices, based ing placebo. perceived when using the Mantoux method on micro- and nanotechnology, micro- In this double blinded study, each patient (Figure 11). The absence of leaks (or partial electronics, and innovative materials. The after an inclusion visit receives three series leaks) during the injection is also a notice- company concentrates on implantable and of injections: one at T0 (where the antibody able point. These results are very favour- non-implantable systems, in particular for level baseline is also measured), a second able to the approach using DebioJectTM. As drug delivery and diagnostics, with a dem- one at T0 + 7 days and a third one at T0 + 28 the study has not yet been unblinded, it is onstrated competence lying in the identifica- days. For each injection, the pain perceived impossible to attribute the different IgG lev- tion of breakthrough technologies and their during the insertion of the needle as well els measured to the different immunisation integration into novel medical devices. as the pain perceived during the injection routes. It is however interesting to note that Devices developed by Debiotech are of the active ingredient are measured. This all patients are fully immunised, regardless of ultimately licensed to major international pharmaceutical and medical device companies, and Debiotech has a track-record 10 of over 40 license agreements worldwide. 9 Examples of products, in addition to the 8 **** p=0.0033 7 **** DebioJect™ microneedles for intrader- 6 mal injections, include: the I-Vantage™ 5 IV pump for hospital and home-care; the 4 CT Expres™ Contrast Media injector for

Pain Score Pain 3 2 CT-Diagnostic Imaging (recently acquired 1 by Bracco Imaging); the JewelPUMP for 0 diabetes care; the DialEase™ home-care Insertion Pain Injection Pain miniaturised dialysis equipment; and others Debioject TM Mantoux Intramuscular under development.

Figure 11: Pain perception comparison.

Nemaura

DERMAL DELIVERY OF BIOLOGICS

Here, Faz Chowdhury, PhD, Chief Executive Officer, and Richard Toon, PhD, Technical & Business Development Manager, both of Nemaura Pharma, describe one of the company’s key technologies for the delivery of biologics, the MicropatchTM.

Nemaura Pharma provides solutions for in widespread development and have been drug delivery through the skin using its successfully clinically tested for a number proprietary platform technologies. The of different molecules. However, there are a MicropatchTM skin insertion platform offers number of significant challenges that must be a versatile topical or transdermal delivery addressed before they can be commercialised: platform for a large range of molecules, • Dose loading is very low, and doses deliv- including biologics. ered are usually in the microgram to low An increasing number of drug companies milligram range. are turning to transdermal drug delivery • Larger doses require larger patch sizes but platforms both for existing molecules as well larger patches are associated with uncon- as for the delivery of new chemical entities trolled non-reproducible skin application and biologics, as an effective means of pain- thus poor reproducibility of dosing. lessly delivering the drug. Nemaura Pharma • Formulations must be able to adhere has a portfolio of proprietary technologies on to the needle surface, or in the case including conventional matrix patches, and where the needles are produced from intuitive microneedle-based technologies for the drug itself the drug must have the the rapid and efficient delivery of a range requisite physico-chemical properties to of molecules. These technologies have been maintain tip sharpness for adequate skin developed to be cost-effective alternatives penetration. Many drugs will not have to conventional modes of drug delivery, yet the requisite properties therefore and thus provide accurate, robust and reproducible- be rendered unsuitable for microneedle dosing with minimal patient intervention. delivery, or require protracted pharmaceutical development programmes. THE POTENTIAL & CHALLENGES OF • It is very difficult to verify that a dose MICRONEEDLES has actually been delivered other than where the needles are required to dissolve Microneedles are needles whose length is into the skin and where upon removal in the hundreds-of-microns range, which can of the patch from the skin there is visual be produced from a wide variety of materi- evidence of the needles having dissolved als including polymers, metals, and the drug and no longer being present on the patch. formulation itself. Microneedle systems are In the case of drug adhesive patches an

Dr Richard Toon Technical and Business Development Manager E: [email protected]

Nemaura Pharma Limited Holywell Park Ashby Road Loughborough Leicestershire, LE11 3AQ United Kingdom Figure 1: Images of hollow drug loaded pellets used in the Micropatch™ Drug Delivery system. www.nemaura.co.uk

A) Needle D) • Depth of delivery can be modulated as required from hundreds of μm to a few Drug carrier / insertion rod mm, depending on the dose and desired penetration depth. • The device is a single mass producible B) C) disposable unit, though a non-disposable Drug pellet applicator and a disposable drug portion can also be accommodated.

This device provides a means for the delivery of both small molecules as well as biologics, with the possibility of modulating drug release based on formulation excipients and processing method. Importantly Skin this provides a means for self-administration of drugs through the skin that may otherwise have to be administered by a Figure 2: Sequence of microneedle delivery via the Micropatch™. healthcare professional. A) Microneedle or needle containing a hollow drug loaded pellet Figure 1 shows images of hollow drug B) The needle is inserted into the skin, engineered to insert to the desired depth. C) Drug carrier slides down the side of the needle inserting the drug into the skin and then pellets used in the Micropatch delivery E) The needle is retracted from the skin with the drug ‘package’ remaining inside the skin. system, Figure 2 shows a schematic of the mechanism by which the Micropatch oper- analogous scenario is delamination of the However, in this case the procedure is precise ates and Figure 3 shows images of the skin patch from the edges of the skin leading whereby the drug is inserted directly into following insertion of the micro-pellets, to inaccurate dosing, however in this case the holes created using the needle(s) after which indicate that the skin complete- the needles would need to remain inserted removal of the needles from the skin, or the ly seals up after administration, and any into the skin over the entire surface area drug is placed into the skin along the side of superficial signs of skin trauma disappear for the duration of dosing. the needle using a ‘carrier’ whilst the needle within an hour of insertion. • The depth of penetration of the micro- is still inside the skin, followed by removal of The Micropatch can be used for the deliv- needles will vary from person to person the needle and carrier from the skin. ery of a single drug or multiple drugs simul- based on skin thickness and toughness and These features impart the following taneously using multiple needles on a single reproducibility of application. advantages to the Micropatch: device. Needle length can be varied from • The residence time of the needles inside • Drug loading may be μg to mg without hundreds of microns leading to minimum the skin cannot be adequately controlled any restrictions to drug insertion being sensation, or several millimeters in length for or determined and movements of the body imposed by the drug physico-chemical deeper depot delivery of drug ‘packages’. The will lead to motions that have potential to properties, thus reducing the complexity drug packages may be formulated accord- dislodge the needles out of the skin given of the pharmaceutical development stage. ing to a range of geometries in the diameter their very shallow depth of penetration. • A finite dose is delivered according to range of tens to hundreds of microns, making Long residence time can also be a source needs, ranging from μg to 10’s of mg or it easy to administer precise doses, effort- of skin irritation that may lead to rubbing more (using multiple doses on a single lessly with minimal pain sensation. of the patch thus dislodging the needles device). Nemaura Pharma already has global from the skin. • The delivery time, and thus residence time license agreements with pharmaceuti- Collectively, the above pose some sig- of the needles inside the skin, is in the cal companies for some of its technology nificant obstacles that must be overcome order of a few seconds, i.e. near instant platforms. Nemaura is actively seeking to before the mass utilisation of microneedle delivery. broaden the list of partnerships and collabo- technologies for drug delivery applications • Dose delivery can be verified as the dosage rations for the delivery of small molecules becomes a reality. is clearly visible within the carrier section and biologics which may otherwise suffer of the device. from drug delivery challenges. BENEFITS OF NEMAURA’S MICROPATCH A) B) C) MICRONEEDLE SYSTEM

Nemaura’s Micropatch was designed and engineered with a view to addressing these challenges. The device can be compared with the “poke-and-patch” method that is defined in microneedle terminology as a process whereby the skin is first prepared by applying the needles followed by the application Figure 3: Insertion of 500 μm BSA particle in porcine skin. A shows the initial insertion of a drug loaded patch or gel for example. of BSA. B after 30 minutes, C after 70 minutes, taken using a USB microscope.

INTERVIEW: PATRICK ALEXANDRE, CROSSJECT

Crossject is developing a pipeline of high-value supergenerics and new therapeutic Our IPO raised €17 million and was entities using its needle-free injection system, Zeneo®. The first Zeneo product is 4.4 times oversubscribed, which was very expected to reach the market in 2015. satisfying. Crossject’s needle-free, prefilled, single-use & fixed-dose Zeneo injection systems are unique in that they can be tailored to deliver drugs intradermally, subcutaneously Q: What will you do with the proceeds? and intramuscularly. This means that Zeneo can allow a wide range of drugs and A: The proceeds from the IPO will be used vaccines for a broad range on indications to be developed and approved in a very mainly to build the commercial produc- short period of time. tion line for Zeneo. We anticipate that our In addition to building its own portfolio, Crossject anticipates partnering Zeneo partners will introduce the first products with other pharma/biotech companies looking to improve the lifecycle management using the Zeneo system in Europe in 2015. of their key drugs or biologics. We are fortunate to be working with first- Shortly after Crossject’s successful IPO on the French NYSE Euronext Paris class partners, including Hirtenberger and Exchange (Paris Bourse), company Co-Founder and Chief Executive Officer Patrick Recipharm, to produce the final product Alexandre spoke about Crossject, its technology and strategy for the future as a that will be commercialised. In addition, we publically traded company. intend to use some of the funds from the IPO to complete the regulatory work in Europe Q: Why did you decide to do an IPO? has the potential to be used to deliver around our two lead supergenerics products. A: We decided to do an IPO because we had a broad range of small-molecule drugs, progressed Zeneo to the point where we and biologics. Another key factor is that Q: How long has Zeneo taken to develop? were close to commercialising this unique A: It has taken about 12 years and an invest- needle-free injection system and we needed ment of close to €60 million to develop additional funding to support and complete Zeneo to this stage. During this process I this process. We felt that executing an IPO “Our IPO raised have been very fortunate to work with some would not only help in terms of funding but €17 million and was great partners who have applied their world- also in raising the profile of the Crossject 4.4 times oversubscribed, leading expertise to help us create the Zeneo business globally. system we have today. Amongst our part- which was very satisfying” ners have been Groupe SNPE (France) and Q: Why was the IPO so successful? Hirtenberger (Austria), both of which are A: I think we had a compelling propo- specialists in propulsion technologies as well sition for public investors. Zeneo (see the development risk associated with the as Schott (high pressure glass, Germany), Figure 1) is great needle-free injection system is close to zero. Taken together Rexam (specialists in nozzle technology, system which has been developed in con- these arguments were persuasive enough UK) and Recipharm (aseptic pharmaceutical junction with world-class partners both in to generate significant interest from both filling, Sweden). France and internationally, it is expected institutional investors and retail investors to generate its first revenues in 2015 and in France. Q: What are the key advantages of Zeneo? A: Zeneo is an excellent needle-free injection system that provides benefits for patients, our pharmaceutical partners and for payers. In the case of patients it provides better safety and efficacy and over- comes the problem of needle phobia. For our partners it provides clear differentiation and is an excellent tool for efficient lifecycle management. It is also able to deliver drugs intramuscularly, subcutaneously and intradermally, which is unique. In the case of payers they benefit from better patient compliance and the ability to control costs due to more patients being able to self-administer the drugs that they need.

Q: What is your strategy to build your busi- Figure 1: Crossject’s prefilled, single-use, Zeneo® needle-free injector. ness based on Zeneo?

Figure 2: Zeneo can be tailored to deliver drugs intradermally, subcutaneously and intramuscularly.

A: We have a very clear strategy to gener- In parallel with our own pipeline, we intend ate sales and value from Zeneo. The first to sign selective partnering deals that would element of our strategy is to develop our give pharma or biotech companies access to own pipeline of supergeneric products that Zeneo for their products. We strongly believe we can develop and commercialise through that access to Zeneo would be extremely help- partners in various parts of the globe. At ful for them in providing clear differentiation present we have three supergenerics in our and in developing very strong arguments for pipeline; Zeneo methotrexate for the treat- reimbursement/market access with regard to ment of rheumatoid arthritis, Zeneo adren- the economic benefits of using this patient- aline for anaphylactic shock and Zeneo friendly, needle-free injection system. sumatriptan for the treatment of migraine. The first of these two products have Q: What is the potential for Zeneo to deliver partners and are expected to be launched in biosimilars and biologics? Europe in 2015. We are continuing to look A: We see this as an important market for for partners for this pipeline to provide us Zeneo given the multiple benefits that it can Patrick Alexandre with access to a broader range of markets deliver. In recent years more and more biolog- Chief Executive Officer and to ensure that they are a commercial ics have been provided as prefilled syringes T: +33 3 80 54 98 50 E: [email protected] success on a global basis. and we see the adoption of Zeneo for many We believe that we can further develop of these products as a natural next step. this pipeline of supergenerics through eval- There are several barriers that prevent Crossject SA 60L avenue du 14 Juillet uating other injectable drugs that would injectable products from allowing perfect 21300 Chenôve benefit from delivery via a needle-free injec- self-administration and good compliance, France tion system. of which three of the main ones are: needle- phobia, the risk of needle-stick injury, and www.crossject.com the more complex process of administration Patrick Alexandre is Crossject’s CEO using a needle requires. “In recent years more and a co-founder of the company. We are particularly keen to start work- Patrick has been the driving force in and more biologics have ing with biotech companies with their bio- the development of Crossject’s tech- been provided as preﬁ lled logic drugs during the actual development nology since its inception 1997 when process so that when these products come it was a research effort at Fournier Laboratoires. He has more than 15 syringes and we see the to market they provide a clear and signifi- years’ experience in the pharmaceu- adoption of Zeneo for cant advance in terms of therapy, patient tical industry. Patrick also has ten many of these products as convenience and economics. years industrial R&D experience in As you sense we have great confidence the steel industry. Patrick graduated a natural next step” in our Zeneo system and what it can deliver as an engineer from Supélec, France. for patients, partners and payers.

IMG Conference Centre, Prague, Czech Republic

Course No. 6557

Skin Forum 14th Annual Meeting Percutaneous penetration - measurement, modulation and modelling

Keynote Speakers:

• Gopinathan K. Menon, Ashland Specialty Ingredients, United States • Michael Horstmann, Acino-Pharma AG, Switzerland • Majella Lane, UCL School of Pharmacy, United Kingdom • Georgios Stamatas, Johnson & Johnson, France • Jacob Thyssen, University of Copenhagen, Denmark

A conference organised by The International Association for Pharmaceutical Technology in partnership with Skin Forum

MAKING SCIENCE WORK Company Profile

TECHNOLOGY PROFILE: ZENEO®

ZENEO®: THE NEXT REVOLUTION IN INJECTABLE MEDICINE

ZENEO® is a unique, automatic needle- free jet injector for SC, IM and ID routes, developed by Crossject. With ZENEO®, injection is fast, easy and secured: • 10% of the population has a needle phobia • The prefilled system ensures the accuracy of administration, even in emergency The ZENEO® prefilled, automatic, disposable, needle-free jet injector (left) situations and a cut-away image with the outer case removed, showing the device’s • The injection can neither fail, nor harm, internal mechanism (right). the patient : improved comfort, autonomy and compliance in treatments for a better READY FOR MANUFACTURING healthcare outcome “Pharma companies • Ergonomic, automatic and very simple Crossject’s partners are Hirtenberger and to use, ZENEO® is perfectly designed for will maximise the Recipharm. The industrial production lines self-injection (Figure 1). lifecycle of their products ... will be built for the end of 2015, in order • ZENEO® reduces hospital admissions & two to three years to be ready for marketing and sales. Thus spending on healthcare due to a self & Crossject should market ZENEO® from secured automatic injection. between feasibility, the moment it obtains marketing authorisa- bioequivalence study & tions for its first products, epinephrine and “With ZENEO®, our ambition is to revo- marketing authorisation” methotrexate, which are expected in 2015. lutionise treatments requiring injections in emergency situations, such as with chronic conditions. Thanks to its flexibility, our ZENEO® device can address more than 200 three years between feasibility, bioequiva- injectable drugs currently on the market. lence study & obtaining marketing author- ZENEO® will allow patients to take their isation,” said Crossject’s Chief Business treatments more easily and health care Officer, Tim Muller. organisations to reduce their costs. Last but The ZENEO® prefilled, automatic, dis- not least, pharma companies will maximise posable, needle-free jet injector (Figure 2): the lifecycle of their products thanks to a • Allows three routes of administration: SC, quick route to commercialisation: two to IM, ID • Delivers an automatic injection in one tenth of a second • Has more than 400 patents granted Dr Tim Muller Chief Business Officer & Executive • Has benefitted from €60 million and 12 Board Member years dedicated to R&D T : +33 6 45 52 35 40 • There have been more than 10.000 tests E : [email protected] completed E : [email protected] (Main Email) • Seven preclinical & seven clinical studies have been performed Crossject SA • Will have three products on the market 60L avenue du 14 Juillet from 2015 21300 Chenôve France • Its developer, Crossject, is headquartered in Figure 1: ZENEO® is perfectly designed France, a spin-off from Fournier in 2001, www.crossject.com for self-injection. recently listed on Euronext Exchange.

DESIGNING AN ULTRASOUND- ENABLED PATCH FOR INSULIN

In this piece, Bruce K Redding Jr, President & CEO, Transdermal Specialties, Inc, tells the story of the design and development of the U-Strip™ Insulin Transdermal Delivery System, which involved the development of an electronic delivery controller attached to an insulin transdermal delivery device. Various electronic delivery signals were considered but it was determined that ultrasound had the most promise.

ELECTRONICALLY ASSISTED approach included insufficient intra-appli- TRANSDERMAL DEVICES cation dose control as the absorption of the porated skin section can have an irregular There are several approaches used to penetration diameter through the skin; and assist transdermal delivery electronically, that the skin tends to seal such capillary including iontophoresis, laser and sonopho- punctures on its own. resis ultrasound. These systems are designed So we faced the following challenges for either to increase the flow of drugs across transdermal insulin delivery: the stratum corneum or to microporate the • Insulin is too large a molecule to pass pas- skin, to allow the delivery of macromol- sively through the skin. ecules across the stratum corneum into the • Skin enhancing chemicals could interact dermis or underlying tissue. with insulin and denature the drug. Such electronically assisted transdermal • Ionotphoresis could denature the drug. delivery devices (TDDs) often use an outside • Laser or IR transmissions sent through the electronic system, which is not connected to skin would photo-damage the insulin. a drug-containing patch, or the patch has • Sonophoresis, sinusoidal ultrasound, electrodes within it to assist in ionic trans- through cavitation can cause severe damage fer. Direct connection to a disposable trans- to the skin and discoloration and lead to a dermal patch is often impractical because breakdown of the drug. the electrodes, or ultrasonic transducer system, are not disposable. We decided to go for ultrasound. Of all Any electronic signal sent through the the electronic systems, ultrasound offers the TDD to liberate insulin from the patch must most promising capability for transdermal be reviewed for damage to the drug itself. insulin delivery. It has an ability “push” Iontophoresis was found to induce electrical the drug from the TDD through the skin charges to the insulin which was found to because of vibrational energy. We were be deleterious to its protein structure. Laser aware that sinusoidal ultrasound-induced and infra-red transmissions through the cavitation could damage both the drug TDD photo-damaged the insulin. and the skin. Therefore, in order to use Bruce K Redding, Jr Sonophoresis, the application of sinusoi- ultrasound, the problem of cavitation had President & CEO dal ultrasound through the skin, can induce to be defeated. T: +1 484 716 2165 cavitation, which can usefully microporate At this point in our design attempt to F: +1 610 356 1866 and develop micro pathways through the bring an insulin TDD into fruition, the first E: [email protected] skin, but the explosive energy of cavitation obstacle was to find a method to deliver a can heat and damage the insulin, and cause 6,000 Da compound through the skin. That Transdermal Specialties, Inc severe damage and discoloration to the was accomplished by the use of the sawtooth 1 Kathryn Lane Broomall skin. Therefore a two-step approach was ultrasonic transmission, and through the PA 19008 tried – initial microporation of the skin, skin pathway choice of targeting the skin United States after which a patch containing insulin was pores for dilation. Our next problem was placed over the skin site. Problems with this cavitation via traditional ultrasound. This www.transdermalspecialties.com

was solved by interrupting one waveform Skin Dilation Skin Transport with a switch to another wave form. In this case sawtooth to square wave (see Figure 1).

ALTERNATING ULTRASONIC WAVEFORM DYNAMIC

A unique alternating ultrasonic transmission was developed whereby ultrasound wave forms are altered just before cavitation could develop. An unusual function of saw- Sawtooth Waveform Square Waveform tooth waves is the ability, when contacting a surface, to transverse that surface later- Figure 1: Alternating the waveform of the ultrasonic transmission eliminated or ally instead of vertically. So a sawtooth wave reduced the effect of cavitation. transmission can flex the pores of the skin, dilating the skin pathway into a larger diameter. The sawtooth wave has been shown to dilate and enlarge human skin pores from the normal diameter of approximately 50 μm up to 110 μm within 10 seconds (Figure 2). The pores remain dilated as long as the ultrasound is active but return to original size three hours after ultrasound cessation. The square waveform is the “ramming force” which pushes the drug into the enlarged pores. As the waveform switches from one to the other the potential for cavitation is minimised. By increasing the time on the square wave transmission we were able to obtain deeper drug penetration of Figure 2: Pore dilation due to ultrasonic excitation. the insulin within the skin. A 30-second sawtooth-only waveform ary waveform. For insulin delivery to the adhesive or polymer component within transmission at the start of the signal genera- dermis, the sawtooth + square alternating the patch design, a new-patented two-part tion, known as skin priming, has the effect of waveforms work best. transdermal patch, Patch-Cap™ was devel- dilating the pores. Therafter the alternating oped. It is designed specifically for ultra- signal engages, sequencing between sawtooth TRANSDERMAL PATCH DESIGN sonic and other electronic drug delivery and squarewave transmissions, with no deg- applications where a conventional patch radation of the insulin and no skin damage. To solve the problems of electronically is unsuitable due to its reliance of a drug/ assisted transdermal delivery systems, to adhesive mixture. TRANSDUCER DESIGN enable them to become more portable or In the Patch-Cap (see Figure 3) an absor- wearable by the patient, and in considera- bent pad is used to store the drug until ultra- We found that conventional piezoelectric tion of conventional patch designs wherein sound, delivered from a snap-on transducer transducers could not develop the alter- drug contamination or denaturing may coupler, liberates the drug from the cap and nating waveform effect. No matter what be caused through interaction with an onto the patient’s skin surface. electrical signal was given, they generated a sinusoidal wave, which is to be avoided in Ultrasound ultrasonic drug delivery. A new approach with changes in the Sonic membrane Backbone material design and the material selection for Insulin the U-Strip transducers produced the Absorbent Generation-5 transducer, which could con- vert the electrical waveform into a sonic Semi-permeable Peel-away ﬁlm waveform at the same wave shape, period, ﬁlm frequency and intensity. The transducer’s mechanical force out- put will mirror exactly the electronic signal given to it from the ultrasonic driver circuit within the control device. An alternating No adhesive comes into contact with the drug waveform can be generated, consisting of any combination of primary and second- Figure 3: Use of an adhesive pad to store and release insulin. Elimination of adhesive.

through a semi-permeable film which acts to retard the flow rate of the insulin and also acts as an on/off valve. It limits the maximum rate at which insulin can be released from the patch to no more than two units per minute, irrespective of ultrasound intensity, or the length of time the ultrasound is present. This top limit of dose control prevents over-dosing. In addition the semi-permeable film will not permit insulin release from the patch until the ultrasound is active. No ultrasound, no delivery. This on/off valve func- Figure 4: Low-profile Patch Cap Figure 5: A filter at the bottom of the tion is therefore also a safety mechanism to with butterfly shaped backbone patch gives a dot pattern distribution of prevent any extra insulin delivery after the (7.5 cm across). insulin on the skin, improving delivery. controller switches the ultrasound off.

The Transducer Coupler contains up to the Patch-Cap, but the drug-in-adhesive, Delivery Pattern upon the Skin four miniature ultrasonic transducer ele- matrix or reservoir designs are discarded in To improve the speed of drug absorp- ments and is powered by the re-usable favour of an absorbent pad which is held tion upon liberation from the patch, the U-Strip Ultrasonic Drug Delivery System. in place in the cap by the use of an inner delivery pattern of the insulin is directed to The Patch-Cap contains the drug, and is snap ring. enter the skin at the site of the skin pores. disposable. The current design holds up to A filter at the bottom of the Trans-Insulin 150 units of insulin, enough for a two-day Ultrasonic Signal Emmitter-Skin Coupling patch reduces the drug to miniature drop- supply for most diabetics using the U-Strip In conventional ultrasound systems a lets which approximate the spacing for the delivery system. The Patch-Cap is designed hydrogel is used to provide a coupling skin’s pore structure. As a result the insulin to be replaced every 24 hours. agent. The use of a gel-coupling agent could is absorbed more completely into the skin possibly interfere with and even contami- and at a faster pace. See Figure 5, where Absorbent Pads to Contain the Drug nate an active drug substance liberated from the insulin is marked with a blue dye, and is In reservoir, matrix and drug-in-adhesive the patch onto the skin surface. The Patch- more readily absorbed at the pore distribu- versions of transdermal patches only a low Cap avoids the requirement for a coupling tion sites. drug concentration is possible. The delivery gel by using the liberated drug itself as the The insulin droplet pattern approach rate is often dependent upon the surface coupling agent to transmit the sonic signal reduced the quantity of insulin needed to area of the patch. In the Patch-Cap the from the transducer to the patient’s skin. be stored within the TDD and increased thickness of the absorbent pad can be varied the speed of absorption into the skin. In to marry with the absorbency factor, so that Low-Profile Patch clinical testing of the original design of the more of the active drug can be contained Initial Patch-Cap designs was somewhat Patch-Cap it took five hours of constant within the fabric of the absorbent pad. For bulky so continued development lead to a ultrasound to reduce the glucose by just example a 1 cm2 of cellulosic pad can hold much smaller, more compact TDD, called 40 points, compared with just 30 minutes up to 12 times its weight in moisture at the Low-Profile Trans-Insulin Patch, which for 87% of the volunteers tested using the 1 mm thickness. The same pad thickness, was more easily worn by the patient. The device with the dot pattern. but using a nylon pad holds only three times backbone of the patch is butterfly shaped its weight. By varying the material used and with wings containing an adhesive border to DELIVERY RATES, DURATIONS AND altering the thickness the absorbent pad can enable it to stick to the skin (Figure 4). The SCHEDULES be adjusted to meet a desired release rate centre section of the patch holds the insulin, and longevity, far exceeding that of conven- but the patch is designed so that no adhesive The U-Strip® Desktop Unit is designed tional patches. comes into direct contact with the insulin. to provide fast glucose reduction for both excessively high starting glucose and for No Drug-Adhesive Contact Dose Limiting Safety Feature emergency situations. The portable device, The use of adhesives that directly con- The U-Strip insulin TDD has a special which can be worn on a belt (Figure 9) or tact the drug is eliminated in this design. on/off feature. Insulin is liberated from the on the arm, is designed to deliver insulin at Adhesives may be used in the border of patch by ultrasonic transmission and passes a rate of no more than 7 units/hr.

Patch Designation Load Capacity Liberation rate Duration Max Constant Duration Max Using Standard +15/-45 Ultrasound Delivery Schedule

U-100 100 u 15.1 u/hr. 6.62 hrs. 26.43 hours

U-150 150 u 16.6 u/hr 9.03 hrs 36.01 hours

Figure 6: Table comparing delivery longevity from U-Strip devices with two different load capacities (desktop control unit).

Patch Designation Load Capacity Insulin Liberation rate at full U/S downward to ensure glucose does not drop too low during the night. Just before waking U-150 150 u Lispro R A = 1.9 to 7.65 /hr.... the U-Strip increases the insulin delivery to capability for 1-4 hours enable the patient to wake with the glucose U-150 150 u Lispro R B= 1.2 to 5.125/hr. capability level of a healthy non-diabetic. Glucose sta- for 4-6 hours bility exceeded the glucose control variants of metformin, the most widely prescribed oral U-150 150 u Lispro R C= 1.9 to 7.65 /hr.... capability for 6-8 hours medicine for Type-2 diabetics.

Figure 7: Three possible delivery schedules from U-Strip (mini control unit). SAMPLE CLINICAL DATA

The recommended delivery rate for a 90 more than 1.9 units/hr these patches could In one clinical trial, named HPT-6A, in kg (200 lb) male for Lispro insulin is 15.2- last more than three days (see Figure 6). volunteers given a meal immediately before 30 units per eight hours, or 1.9-3.75 units/ One of the most prevalent problems with treatment, the U-Strip system defeated the hr. The delivery rate of the U-Strip Desktop diabetes is high morning glucose. This is glucose spike that would normally occur Unit can be as high as 16.6 units/hour. due to a slacking off of the insulin potency post-meal. The post-meal application of The U-Strip, holding 100 units or up over the night from a standard injection Lispro insulin from U-Strip brought each to 150 units can provide 6.6 or 9.0 hours, therapy, and in the morning the liver can volunteer to the range of healthy / normal in respectively, under constant ultrasound. produce more glucose, in anticipation of as little as 35 minutes. The plasma glucose in An intermittent activation schedule has the day’s events. A unique delivery schedule all volunteers dropped by 8-10 points in just been developed whereupon the device is has therefore been developed using U-Strip the first five minutes of treatment. Additional activated for 15 minutes out of every hour whereupon insulin is pulsed from the patch trials are underway, including a 500 patient and remains deactivated for the balance for the first four hours. As shown in Figure 7, trial, before applying for regulatory approval. of 45 minutes of each hour for standard under the “A” schedule the patch is set to In over 200 Type-2 patients studied there basal operations. Under this schedule, at deliver from 1.9 to a high of 7.65 units/hour have been no adverse events, with complete the maximum liberation rate the patches for the first four hours, assuming an eight- reduction and stabilisation of glucose levels would supply insulin for up to 36 hours. hour sleep. For the two hours between hour at healthy normal range (85-110 mg/dl) Since most Type-2 diabetics would not need four and hour six, the delivery rate ramps from starting levels as high as 300 mg/dl.

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180 Baseline, Blankschtein D, Langer R, “A 160 U-Strip Mechanistic Study of Ultrasonically- 140 Glucose Enhanced Transdermal Drug 120 Proﬁle, Delivery”. J Pharm Sci, 1995, Vol U-Strip 84(6), pp 697-706. 100 8. Johnson ME, Blankschtein D, Langer 80 System Baseline, R, “Evaluation of Solute Permeation 60

Glucose, MG/DL Pump Through the Stratum Corneum: Lateral 40 Diffusion as the Primary Transport Glucose 20 Proﬁle, Mechanism”. J Pharm. Sci, 1997, Vol Pump 86(10), pp 1162-1172. 0 9. Kost J, Mitragotri S, Gabbay RA, 0 100 200 300 400 Pishko M, Langer R, “Transdermal Time, Min Monitoring of Glucose and Other Analytes Using Ultrasound”. Nature Figure 8: Glucose reduction over 5hr – U-Strip compared with an insulin pump. Med, 2000, Vol 6(3), pp 347-350. Compared with an insulin pump (Figure their daily routine (Figure 9). The device 10. Miyazaki S, Mizuoka H, Kohata Y, 8) the U-Strip was just as effective in obtain- regulates the dosing of insulin in both basal Takada M, “External control of drug ing glucose control, except the U-Strip was and bolus delivery needs. release and penetration”. Chem Pharm totally non-invasive and can achieve the The use of a two-Part TDD solved many Bull, 1992, Vol 40(10), pp 2826-2830. same results with far less delivered insulin. critical concerns limiting the use of transder- 11. Kral LP (Editor), “World Book of In these trials the efficiency of ultrasoni- mal patches in drug delivery applications, Diabetes in Practice”, 1988, pp 160- cally administered insulin was found to be especially considering electronically assisted 163. Published by Elsevier. 400% greater than pump delivered insulin delivery systems. 12. Kanikkannan N, Singh J, Ramarao P, in obtaining compatible glucose control. “In vitro transdermal iontophoretic The bioavailability and pK values of ultra- REFERENCES: transport of timolol maleate: effect of sonically delivered insulin are greater than age and species”. J Controlled Release, that provided by insulin pumps. 1. US Patents: 4,751,087; 5,209,879; 1999, Vol 59(1), pp 99-105. 5,271,881; 5,455,342; 5,460,756; 13. Zegzebski JA, “Essentials of SUMMARY 6,908,448; and 7,440,798. Ultrasound Physics”, 1996. Published 2. Barrie-Smith N, Lee S, Kirk Shung by Mosby (St Louis, MO, US). U-Strip is a transdermal delivery sys- K, Roy RB, Maione E, McElligott S, 14. Stansfield D, “Underwater tem capable of delivering large-molecule Redding BK, “Ultrasound-Mediated Electroacoustic Transducers”, 1990, pp drugs through the skin, non-invasively. The Transdermal Transport Of Insulin 79-257. Published by Bath University company is presently developing an insu- In Vitro Through Human Skin Press (Bath, UK). lin patch aimed at Type-1 and insulin- Using Novel Transducer Designs”. J 15. Wilson OB, “An Introduction to Theory dependent Type-2 diabetics (market poten- Ultrasound Med Biol, 2003, Vol 29(2), & Design of Sonar Transducers”, 1998, tial 4 million patients in the US alone). The pp 311-317. pp 89-108. Published by Peninsula (Los patient can wear the insulin patch product, 3. Mitragotri S, Blankschtein M, Langer Altos CA, US). in the form of a two-part transdermal drug R, “Ultrasound-Mediated Transdermal 16. Shung KK, et al, “Principles of delivery device, the Patch-Cap, powered Protein Delivery”. Science, 1995, Vol Medical Imaging”, 1992, pp 102-123. by an ultrasonic delivery controller, during 269, pp 850-853. Published by Academic Press. 4. Mitragotri S, Blankschtein M, Langer 17. Williams J, “A Fourth Generation R, “Transdermal Drug Delivery Using of LCD Backlight Technology”. Low-Frequency Sonophoresis”. Pharm Application Note 65, 1995, pp 1-124. Res, 1996, Vol 13(3), pp 411-420. Linear Technology Corporation 5. Johnson ME, Mitragotri S, Patel (Milpitas, CA, US). A, Blankschtein M, Langer R, “ 18. Agbossou K, Dion JL, Carijnan S, Synergistic Effects of Chemical Abdelkrim M, Cheriti A, “IEEE Enhancers and Therapeutic Transactions on Ultrasonics”. Ultrasound on Transdermal Drug Ferroelectrics & Frequency Control, Delivery”. J Pharm Sci, 1996, Vol 2000, Vol 47, pp 1036-1041. 85(7), pp 670-679. 19. Wilking SL, Husberg ML, Ko CU, 6. Kost J, Langer R, “Ultrasound- Wick SM, “Effect of Excipients Medicated Transdermal Drug on Physical Properties of Selected Delivery”, in “Topical Bioavailability, Acrylate, Polyisobutylene & Silicone Bioequivalence and Penetration”, 1993, Pressure Sensitive Adhesives Commonly Figure 9: The U-Strip System, pp 91-104. Published by Plenum Press, Utilized in Transdermal Drug Delivery comprising arm-mounted mini (New York, NY, US). Systems”. Pharm Res, 1994, Vol 11, controller and patch. 7. Mitragotri S, Edwards DA, Suppl 226.

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NOVEL TRANSDERMAL DELIVERY SYSTEMS FOR TREATMENT OF DIABETES

In the context of a diabetes epidemic, which he characterises in terms of incidence, prevalence and healthcare costs, Alan Smith, PhD, Vice-President, Clinical, Regulatory & Operations, 4P Therapeutics, outlines the stages of Type 2 diabetes treatment, progressing to extenatide and insulin injections, and makes the case, using clinical data, for the transdermal route as a viable alternative to injections.

DIABETES EPIDEMIC properly, and glucose remains circulating in the blood in excess (hyperglycemia) damag- According to the International Diabetes ing body tissues over time. This damage can Federation, as of 2013, 382 million people lead to disabling and life-threatening health worldwide suffered from diabetes of which complications. Type 1 diabetes occurs due 46% are undiagnosed. In the US, there are to insulin deficiency caused by destruction 24 million people with diabetes and 27% are of the pancreatic beta cells and requires undiagnosed. The number living with diabe- daily insulin administration. Type 2 dia- tes worldwide is expected to grow to 592 betes occurs due to insulin resistance and million by the year 2035 (a 55% increase). deficiency. Worldwide, approximately 10% of people with diabetes have Type 1 diabetes and 90% have “A safe and eff ective Type 2 diabetes. As the majority of people non-injectable method to with diabetes are Type 2, it is treat diabetes has been pursued critical to get the disease under since insulin therapy was ﬁ rst control early in its progression and prevent further deteriora- developed more than 90 years ago” tion in health. As patients move through treatments needed to achieve glycemic control, they The burden of diabetes is significant causing typically start with diet and exercise and one more than five million deaths every year (one oral antidiabetic (metformin), proceed to death every six seconds) and treatment of multiple oral therapeutics (including insulin diabetes and its complications costs a signifi- sensitisers and dipeptidyl peptidase-4 (DPP- cant amount of all healthcare expenditures. IV) inhibitors), and then eventually to injec- In 2013, US$548 billion was spent on dia- tions after the orals fail to maintain control. Dr Alan Smith betes worldwide which is 11% of the total Injections include either basal insulin Vice-President, Clinical, worldwide spending on healthcare. This is (insulin glargine, insulin detemir, insulin Regulatory & Operations projected to exceed $627 billion by 2035. degludec), or glucagon-like peptide-1 (GLP- T: +1 770 263 1900 Diabetes is a chronic disease that occurs 1) agonists (exenatide, liraglutide, lixisena- E: [email protected] when the body cannot produce enough insu- tide), or combinations thereof. It is generally lin or cannot use insulin effectively. Insulin accepted that the majority of people with 4P Therapeutics is a hormone produced in the pancreas that Type 2 diabetes will eventually need insulin 1 680 Engineering Dr, Suite 150 Norcross allows glucose from food to enter the body’s and that early initiation of injected therapy GA 30092 cells where it is converted into energy need- will slow down and potentially prevent United States ed by muscles and tissues to function. A per- further deterioration of pancreatic beta cell son with diabetes does not absorb glucose function (see Figure 1). www.4ptherapeutics.com

Earlier Introduction of Basal Insulin or GLP-1 Could Slow Progression of Type 2 Diabetes

deteriorating

Undiagnosed β type 2 -cell function

Diet/Exercise One oral Multiple orals Diagnosed type 2

Insulin/GLP-1 + orals type 2 on injections (mealtime/basal) Intensive insulin type 1 on injections (mealtime/basal)

Figure 1: Conventional Type 2 diabetes treatment sequence and relationship with pancreatic beta cell function: need for early initiation of injected therapy.

UNMET CLINICAL NEED basal injections. The Pfizer/Inhale (now trointestinal tract which typically contrib- Nektar Therapeutics) inhaled insulin prod- utes to the very low bioavailability of oral There is reluctance by patients and uct, Exubera®, was taken off the market formulations of proteins and peptides. In healthcare professionals to initiate insu- in 2007 as a result of low sales and poor addition, transdermal delivery is well suited lin therapy for several reasons including market uptake mainly due to issues of for steady infusion throughout the day as the patients’ fear of disease progression device size, ease of use and high cost. a way to meet the basal insulin needs of and needle anxiety; mutual concerns about Mannkind Corporation is awaiting a deci- patients. Basal insulin typically accounts for hypoglycaemia and weight gain; and health sion on approval in the summer 2014 for 50% of the daily insulin needs of patients professionals’ use of insulin as a threat to its Technosphere® inhaled insulin, Afrezza®, with diabetes. Transdermal patches are con- encourage compliance with earlier thera- which offers a more rapid absorption profile ventionally used to achieve steady serum pies.2 Despite advances in less painful insu- than subcutaneous injection, and Dance levels of drug and avoid the “peak-valley” lin injections and pens, insulin injections Biopharm/Aerogen are making headway effect; however they are limited for use are seen as a last resort by patients and with their aerosol insulin product, OnQ™, with small-molecule lipophilic drugs. This providers. Finally, there is the real concern towards Phase III trials planned for 2015. is mainly due to the barrier function of the of insulin injections causing hypoglycaemia. However, there is a risk that there will stratum corneum, which is rate-limiting for Physicians, particularly general practition- always be the safety concern of delivering transdermal transport. ers (GPs), may lack the support services a growth factor such as insulin to the lungs There is a plethora of methods used to required to train patients on how to deter- which will potentially limit uptake of the deliver insulin through the skin, including mine the correct dosage and to perform product in the marketplace. iontophoresis, permeation enhancers, solid injections properly. Other options in development include and hollow microneedles, microporation by Once patients start on injections, they oral pills or sprays and varying degrees of thermal ablation, radiofrequency ablation, struggle with compliance. Most patients will success have been achieved by several groups erbium:YAG laser used directly on the skin, only inject at home and one-third will skip including Generex (Oralyn™ mouth spray), ultrasound, electroporation, pressure waves, injections once per week. Noncompliance and the recent initiative undertaken to devel- nanoparticulate and microparticulate systems affects glycaemic control and treatment out- op an oral insulin tablet by Novo Nordisk. and use of carrier molecules. However, each comes. Clearly, injections are a barrier to of these methods has limitations in terms of initiating therapy and maintaining compli- TRANSDERMAL INSULIN DELIVERY success, typically limited to academic set- ance, but what alternative delivery options tings in preclinical models. Two approaches are there? A safe and effective non-injectable Insulin is a 5,808 Da peptide that that though – microneedles and microporation – method to treat diabetes has been pursued is produced and stored in the pancreas as a have been utilised to deliver insulin in human since insulin therapy was first developed hexamer (35 kDa) but active as a monomer. subjects at therapeutic levels. more than 90 years ago. In spite of this long It is typically administered as a subcutane- Microneedles can be used to deliver pep- history, however, no satisfactory non-inject- ous injection either as a bolus before meals tides and proteins through the skin but the able insulin delivery system has emerged. or as a once or twice daily long-acting injec- dose per needle may be limited when using Certainly, inhaled insulin has made tion to achieve a basal profile. microneedles with a shallow depth of pen- significant progress towards providing a Transdermal delivery of insulin offers etration and maintaining a reasonable patch non-invasive alternative to mealtime insu- several potential benefits. Delivery through sizes. In addition microneedle systems are lin injections and possibly even once-daily the skin bypasses metabolism in the gas- more suited for bolus pharmacokinetic pro-

70 Basal Insulin Patch 1.0 U/h SC Infusion 60

30 pharmacokinetic profile suitable to maintain a steady state level after repeated daily dosing, transdermal insulin therapeutic levels Serum Insulin (U/mL) 20 were achieved within two hours and the pharmacokinetic profile indicated a faster 10 transdermal infusion rate in the first six hours than the second six hours. This may be desir- 0 able from a pharmacodynamic perspective 0246810121416(tailored profile to match morning or evening Time (h) needs as a daytime or nighttime patch). The relative bioavailability of the patch compared Figure 2: Basal insulin microporation patch versus continuous subcutaneous with the CSII was approximately 4% using infusion pump (CSII) set at 1.0 U/hr. At 12 hr, patch removed and insulin pump a non-optimised system. The transdermal turned off/infusion set removed. (Mean +SE, N=7). insulin patch was well tolerated and the skin files. However, relatively long microneedles subcutaneous insulin infusion (CSII insulin response was limited to mild transient ery- have been used to achieve a therapeutically pump).8 The study was conducted to dem- thema at the application site. relevant intradermal injection of insulin onstrate unambiguous therapeutic insulin The study demonstrated that the basal as an alternative to SC injection.3 The levels in comparison with CSII as all sub- insulin microporation patch achieved a ther- microporation approach (thermal ablation) jects were required to be C-peptide negative apeutic basal infusion rate comparable with is well suited for relatively large doses and (no endogenous insulin secretion). Subjects that achieved by a continuous subcutane- for a sustained basal delivery pharmacoki- stopped use of long-acting insulin injection ous insulin infusion pump in patients with netic profile, although it depends on the (48 hours prior) or discontinued insulin Type 1 diabetes. specific technology being utilised. pump use prior to dosing (eight hours prior). Microporation technologies have been Subjects were randomly assigned to one of TRANSDERMAL EXENATIDE developed that overcome the stratum cor- two treatment arms: insulin patch applied DELIVERY neum barrier by creating micropores by for 12 hours followed by CSII treatment at thermal ablation that extend into the via- 1.0 U/hr for 12 hours or CSII treatment at Exenatide (exendin-4) is a GLP-1 recep- ble epidermis. Micropores are created by 1.0 U/hr followed by an insulin patch. In tor agonist with a molecular weight of the rapid localised application of thermal clinical use, insulin infusion basal rates are 4,186.6 Da (39 amino acid peptide amide). energy to the skin surface that results in the typically 0.5 U/hr to 2.0 U/hr. It is a synthetic version of a salivary pro- vaporisation of the stratum corneum cells The basal insulin microporation tein found in the Gila monster lizard. It in a microscopic area. One microporation patch had an active area of 12 cm2 with exhibits similar glucoregulatory effects to approach that has had some success utilises 80 micropores/cm2 and contained a dry- the naturally occurring incretin hormone an array of resistive filaments applied to polymer film formulation of 15 mg recom- glucagon-like peptide-1 (GLP-1) but has a the skin surface which are briefly heated by binant human insulin. The CSII treatment longer half-life. applying a short pulse of electric current to consisted of a Medtronic Paradigm 722 GLP-1 is a naturally-occurring pep- create micropores approximately 100 μm insulin pump with Humulin® R 100 U/mL tide that is released within minutes of wide and 50 μm deep, which extend through (Eli Lilly). Glucose levels were clamped at eating a meal. It is known to suppress the stratum corneum into the viable epider- 100 mg/dL which was initially reached by glucagon secretion from pancreatic alpha mis. This technique has been investigated in IV infusion of insulin lispro and maintained cells and stimulate insulin secretion by clinical studies for the rapid extraction of after insulin treatment by IV glucose infu- pancreatic beta cells. The half-life of GLP-1 skin interstitial fluid for glucose monitoring4 sion (D-20). Serum samples were analysed is approximately two minutes due to and for the delivery of insulin5-8 for the for insulin using an insulin-specific ELISA dipeptidyl peptidase-4 (DPP-IV) inactiva- development of a basal insulin micropora- (no cross-reactivity to lispro). tion. Exenatide is 53% identical to native tion patch intended for daily administration The basal insulin patch mean serum insu- human GLP-1. It binds to known human in patients with Type 1 or Type 2 diabetes. lin concentration curve reached a Cmax of GLP-1 receptors on pancreatic beta cells An open-label randomised crossover 42 μU/mL at five hours. The insulin pump in vitro and is resistant to dipeptidyl pepti- pharmacokinetic / pharmacodynamic (glu- (1.0 U/hr CSII) reached a steady state level dase-4 (DPP-IV) inactivation. As a result, cose clamp) and safety study in C-peptide of 27 μU/mL at seven hours until the pump the half-life of exenatide is 2.4 hours which negative patients with Type 1 diabetes evalu- was discontinued at 12 hours (see Figure 2). is 10 times longer than GLP-1. ated transdermal insulin versus continuous Although the patch did not achieve a Exenatide was developed by Amylin and

500 SCSC (10 (10 mcg mcg bid) bid) MPMTDPDP PPatch PatP (1(a1t.c9h (1.9 m(1(1g. 9mg qmd god)) od)od ) 400

300

Insulin Administered Using Microneedles 200 in Type 1 Diabetes Subjects”. Diabetes Technology & Therapeutics, 2011, Vol 13(4), pp 451-456. 100 4. Smith A, Yang D, Delcher H et al,

Plasma ExenatideConc. (pg/mL) “Fluorescein kinetics in interstitial fluid Patch harvested from diabetic skin during flu- 0 Off orescein angiography: Implications for 0 6 12 18 24 30 glucose monitoring”. Diabetes Technol Therapeut, 1999, Vol 1, pp 21-27. SC SC Time (h) 5. Smith A, Eppstein JA, Delcher HK et al, “Transdermal insulin infusion through Figure 3: Plasma exenatide concentration comparing SC injection to transdermal thermally created micropores in humans.” microporation patch (TDP) (patch mean+SD, SC mean-SD; N=8). Diabetes, 2001, Vol 50(2), p A132. 6. Smith A, Woods T, Williams DJ et al, Lilly and is currently marketed by Bristol- maintained above 50 pg/mL for 21 hours “Transdermal basal insulin delivery Myers Squibb and AstraZeneca (co-marketing (median) with a range of 14-25 hours. The through micropores”. Diabetes, 2002, arrangement). It is administered as a twice- minimum effective plasma exenatide con- Vol 51(2), p A47. daily subcutaneous injection given one hour centration required for a glucose lowering 7. Smith A, Zerkel K, Roerig P, Mills S, before the breakfast and dinner meals (Byetta® effect is 50 pg/mL.10 The relative bioavail- Humphries C, Durland R, Spratlin 5 μg or 10 μg) or as a once-weekly subcuta- ability of the exenatide patch compared V, “Transdermal Delivery of Insulin neous injection (Bydureon® 2 mg exenatide with the 10 mcg SC injection treatment was in Patients with Type 1 Diabetes”. extended-release microsphere suspension). approximately 3% using a patch formula- American Diabetes Assoc, 2008, 8th A Phase I clinical study was conducted tion that was not optimised for bioavail- Scientific Sessions, Abstract 309-OR, using a transdermal exenatide micropora- ability. There were no skin reactions and the Diabetes 57 Supplement 1:A88. tion patch.9 The study design was a dou- exenatide patch was well tolerated in terms 8. Smith A, Roerig P, Zerkel K, Mills S, ble-blind, placebo controlled, three-period, of skin response. As the exenatide micropo- Spratlin V, “Transdermal Basal Insulin three-treatment study evaluating the phar- ration patch is a drug delivery system, with Delivery in Patients with Type 1 macokinetics/ pharmacodynamics (PK-PD) several key variables that can be optimised, Diabetes: Pharmacokinetic Comparison and safety of the exenatide transdermal the film formulation can be adjusted to to Continuous Subcutaneous Insulin patch (TDP) in nine Type 2 diabetics. On decrease the delay and increase bioavail- Infusion” Tenth Annual Diabetes separate days, subjects received a single dose ability while maintaining sustained plasma Technology Meeting, 2010, (Bethesda, of exenatide TDP (1.9 mg exenatide, 3 cm2, exenatide concentrations for 24 hours. MD, US), Abs A157. 120 microchannels/cm2) or exenatide SC (10 The studies reported here showed that 9. Smith A, Kothare P, Tagliaferri F, μg bid Byetta®). The investigator and subject insulin and exenatide can be administered Roerig P, Ng W, Mace K, Linnebjerg were blinded to exenatide/placebo patch by the transdermal route resulting in sus- H, “Transdermal Exenatide Delivery content for assessment of skin responses. tained therapeutic blood concentrations in Patients with Type 2 Diabetes: Standardised breakfast, lunch and dinner suitable for treatment of diabetes. Pharmacokinetic and Pharmacodynamic meals were provided. The skin response to Evaluation,” Eleventh Annual Diabetes the patch was evaluated by visual scoring REFERENCES Technology Meeting, 2011, (San (modified Draize scale) and transepidermal Francisco, CA, US). water loss (TEWL) measurements. Exenatide 1. Cefalu WT, “Concept, Strategies, and 10. Fineman M, et al, “Pharmacokinetics concentrations were determined by ELISA. Feasibility of Noninvasive Insulin and Pharmacodynamics of Exenatide After a single exenatide patch appli- Delivery”. Diabetes Care, (2004), Vol Extended-Release after Single cation, plasma exenatide concentrations 27, pp 239–246. and Multiple Dosing”. Clinical increased gradually for 10 hours reaching 2. Korytkowski M, “When Oral Agents Pharmacokinetics, 2011, Vol 50(1), a Cmax of 301 pg/mL. On average, plas- Fail: Practical barriers to Starting pp 65-74. ma concentrations were sustained after 10 Insulin”. Int J Obesity, 2002, Vol 26, hours at approximately 250 pg/mL until the Suppl 3, S18-S24. • “IDF Diabetes Atlas, 6th Edition”. patch was removed at 24 hours (see Figure 3. Gupta JG, Felner EI, Prausnitz MR, International Diabetes Federation 3). Plasma exenatide concentrations were “Rapid Pharmacokinetics of Intradermal (Belgium, Brussels), 2013.