Delivery

Th e e volution of Tra nsdermal and tre at in g mi gra ine

Oral drug delivery is the most common and convenient route of drug administration due to a high rate of patient compliance, cost-effectiveness, portability, ease of production and pre-determined dosage.

owever, there are limitations with oral Mercurial Ointment, used as a treatment for By Dr Mahmoud drug delivery, such as incomplete deliv - syphilis when Salvarsan and other arsenicals were Ameri and H ery due to the unpredictability of gas - in use, before the discovery of penicillin. Even the Hayley Lewis trointestinal . Parenteral route of composition of this ointment was remarkable; it administration, such as , is another com - contained 50% of elemental mercury! mon drug delivery method. Advantages of par - enteral drug delivery include rapid onset of action First-generation TDD and circumvention of gastrointestinal degradation TDD offers advantages over conventional par - of the drug, but this method is invasive and some - enteral or oral routes. They ensure controlled times painful. It also has a lower rate of patient absorption and more uniform plasma drug concen - compliance and requires a trained administrator. trations. Bioavailability is improved by avoiding Drug Delivery (TDD) is a promis - first-pass hepatic metabolism and enzymatic or ing method for drug application that has major pH-associated deactivation. advantages over some of the most common routes The first generation of TDD is responsible for of drug administration. TDD involves the non- most of the transdermal patches that have thus far invasive delivery of through the skin been in clinical use. More than 30 years ago the surface and when applied can deliver the drug at a revolutionised cessation by predetermined rate across the skin to achieve either continuously suppressing the smoker’s craving for a local or systemic effect. a cigarette. Catapres ® is the first patch that delivers seven- History of transdermal day dosing of clonidine to hypertensive patients delivery development who otherwise would have to adhere to taking one Transdermal delivery of medications is not a new twice a day. This is the first example of a concept. The use of transdermal delivery of home - non-injectable sustained-release that made medicinal preparations dates to the early achieves seven-day delivery for a small molecule. It 20th century. Mustard plasters were used for demonstrates the therapeutic benefit of a dosage severe chest congestion. The Belladonna Plaster, form that can sustain a flat blood level profile and containing 0.25% of Belladonna alkaloid, had a has the convenience of a once-a-week dosing for place in the US pharmacopeia as a transdermal chronic treatment. analgesic. Perhaps the most remarkable forerunner DURAGESIC ® transformed post-surgical of modern transdermal was Stronger breakthrough care by providing a non-oral,

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Triptans for migraine relief. Triptans are a class of medications that are selective serotonin receptor agonists, meaning they work by stimulating serotonin (5-HT), a neurotransmitter (NT) found in the brain. Triptans are often used in treating migraine because they reduce inflammation, constrict blood vessels and block pain pathways in the brain

non-injectable sustained-release opioid pain-man - to attain dermal analgesia on intact skin. agement that lasts three days per applica - Imparting dermal analgesia prior to venipunctures tion. The Exelon ® patch, a rivastigmine patch takes 10 minutes, much faster than a topical introduced in 2007, embodies an innovative treat - anaesthetic such as EMLA (eutectic mixture of ment route for dementia patients and their care and prilocaine) topical , which givers. It affords a visible reminder to both may take up to one hour. In spite of its medical patients and their caregivers that they have taken benefit, eg faster onset of action, the treatment the medicine. The Exelon patch has a superior cost compared with a conventional topical cream safety profile. eg less nausea and vomiting and a limited its commercial success. Vyteris decided to convenient once-a-day dosing interval, compared remove Lidosite from the market in 2008 after with the and oral solution. Its precipitous only two years on the market. SYNERA ®, a topi - success exemplifies how development of a trans - cal anaesthetic patch with a controlled heating dermal patch can be a sound approach for product pod, delivers lidocaine and tetracaine to numb lifecycle management. intact skin in 20 minutes, prior to minor needle procedures for pediatric patients. Although both Second-generation TDD of these products illustrate how technological The second generation of TDD recognises that advances in TDDs could foster therapeutic advan - skin permeability enhancement is required to tages, they also make the case that TDDs need to expand the scope of transdermal . All of the proactively address the total value proposition to products that have been commercialised have been the patients and payers while providing a strong, devoted to iontophoresis, which is a method of compelling medical benefit. transferring substances across the skin by applying IONSYS™, an iontophoretic an electrical potential difference. The LidoSite™ for on-demand, self-activating delivery of fen - Topical System, an iontophoretic patch with a tanyl, permits patients to have control of their portable electronic controller and energy source, own pain management. In 2006, both the US FDA delivers lidocaine and epinephrine simultaneously and the European Medicines Agency approved

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IONSYS for the treatment of acute post-operative ity of migraine attacks, migraine treatments need pain. However, following identification of corro - to bring relief to patients quickly and safely. Recent sion in a system component of one lot of IONSYS, advances in the development of TDD for treatment which could trigger self-activation of the system – of migraine show promise. a potentially lethal overdosing risk – the European Medicines Agency recommended of Unmet need the marketing authorisation for IONSYS in Migraine is the most common disease in the world November 2008. Janssen-Cilag, the developer and affecting approximately 39 million people in the marketer of IONSYS, subsequently withdrew US and one billion worldwide. More than 90% of IONSYS from all European markets. IONSYS was migraine sufferers are unable to work or function very much at the leading edge of innovation for a normally during a migraine due to severe head pain TDD system. Its on-demand, patient-involved and associated neurological symptoms including pain-management concept had the opportunity to nausea, vomiting and extreme sensitivity to light showcase what personalised pain treatment could and sound. be. Regrettably, prohibitive technical intricacy and The transdermal route offers a large and varied overwhelming product quality challenges short- surface as well as ease of application. There are circuited, literally and figuratively, this once- limitations for this type of delivery since molecules promising prospect. with molecular weight greater than 1kDa are However, during the past decade TDDs have unable to cross the stratum corneum. essentially remained static and there has been little Triptans are first-line therapies for moderate to change in the composition of the patch systems. severe migraine and come in several formula - Modifications have been mostly limited to refine - tions, including oral pill, and injec - ments of the materials used. One reason might be tion. Each of these routes of administration have that only certain specialised companies can manu - their own set of limitations. Oral pills, the most facture transdermal patches. Another reason is that common way to treat migraine, are slowly only a limited number of drugs fit the molecular absorbed by the body leading to delayed weight, lipophilicity and potency requirements for migraine symptom relief. Nasal sprays can offer transdermal absorption. faster relief but the nasal route has a limited sur - face area and the fast mucociliary clearance and Third-generation TDD drainage into the oesophagus can result in highly The third generation of TDDs is poised to make variable absorption. significant impact on drug delivery because it tar - Although the drug is sprayed nasally, a signifi - gets its effects to the stratum corneum. This target - cant amount of drug is swallowed and then ing enables stronger disruption of the stratum absorbed by the body, which can result in gastro - corneum barrier, and thereby more effective trans - paresis, a common condition among those suffer - dermal delivery. The third generation of TDDs use ing from migraine. The pulmonary route offers a microneedles as a means of circumventing the stra - large and highly-vascularised mucosal surface for tum corneum. Limitations with respect to the drug absorption, but the accessibility with current - molecular weight of the drug is not of concern with ly-available is limited and can additionally this form of microneedle-mediated TDD. For ther - be compounded by variability from patient self- apeutic protein and peptide delivery, while intra - administration. Injection is the most effective deliv - dermal delivery may provide a more advantageous ery route. However, drawbacks of this method pharmacokinetic profile compared with subcuta - include pain, stigma associated with administering neous or intramuscular injections, other tangible injections in public and needle phobia. patient benefits, such as easy self-administration, Research demonstrates that treating migraine is a less perceived pain, enhanced safety and ambient race against time. The faster a patient receives a temperature stability are correspondingly essential drug, the more likely that patient is able to fully to make this a compelling product concept. benefit from it. Although migraine is not life-threat - ening, it is severely debilitating and reduces the Developing TDD to treat migraine quality of life of those who suffer from this disease. Migraine is a disabling neurological disease that involves recurrent attacks of moderate to severe Innovation head pain. It is one of the most disabling diseases Though there are a number of treatment options in the world and is the leading cause of disability available for patients suffering from migraine, among all neurological disorders. Due to the sever - there is still a high unmet need for additional

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options that are non-invasive, fast acting and bypass the . In recent years, Dr Mahmoud Ameri is the Vice-President of innovators in the field have been working to pro - Research & Development at Zosano Pharma. As vide new options that address these unmet treat - one of the company’s co-founders, he brings 20 ment needs. years of drug delivery, preclinical and early ex-US In 2013, the United States Food and Drug clinical development of combination products to the Administration (FDA) approved Zecuity ®, a sin - company. He is responsible for research and devel - gle-use migraine patch that delivers sumatriptan opment. Prior to Zosano, he was at Alza/J&J where through a mild-powered electrical current. he co-invented and developed the Adhesive Developers of Zecuity recognised that sumatriptan Dermally Applied Microarray system and holds is an effective, already-approved drug for the more than 20 patents and patent applications all treatment of migraine and worked to improve relating to the Zosano drug delivery technology. Dr delivery of the drug to patients suffering from Ameri earned his PhD from the School of Pharmacy migraine to potentially provide faster symptom at the University of Manchester in the UK. relief. To do this they employed the use of an ion - tophoretic transdermal system to deliver suma - Hayley Lewis is the Senior Vice-President of triptan directly to the bloodstream, bypassing the Operations at Zosano Pharma, where she oversees gastrointestinal tract. However, in 2016, less than the functional areas of Nonclinical, R&D, a year after Zecuity launched, the FDA issued a Analytical Development and QC, Operations and safety warning regarding the risk of burns and Engineering, Manufacturing, and Regulatory possible scarring due to the patch. Despite this set - Affairs, and continues to be responsible for over - back, development of TDD for the treatment of seeing all regulatory interactions with the FDA and migraine has not stalled. other government agencies. She joined the compa - Zosano Pharma is currently developing ny as the Vice-President of Regulatory Affairs and Qtrypta™ (formerly M207), its proprietary formu - Quality in October 2015. Prior to joining Zosano, lation of zolmitriptan delivered utilising its she spent more than 11 years in Regulatory Affairs Adhesive Dermally Applied Microneedle™ at Depomed, Inc, a specialty pharmaceutical com - (ADAM) technology. Zolmitriptan is an effective pany, where she was involved in the approval of FDA-approved treatment for migraine but is only three commercial products. Over the course of her available as an oral tablet and nasal spray, and not career, she has enabled eight investigational prod - as an injectable. Innovators at Zosano recognised ucts to be studied in humans, five of which have that there is room for improvement in the delivery advanced to completion of Phase III trials. Her of this migraine drug to potentially provide faster pharmaceutical development experience, spanning relief to patients. more than 20 years, covers solid oral dosage forms The company’s TDD system consists of a titani - and combination products, such as systemic and um microneedle array attached to an adhesive local products, a single-entity combina - patch seated in a retainer ring, which is applied tion injectable and transdermal systems. Ms Lewis with an applicator. When the patch is applied to earned her BS in Pharmaceutical Sciences from the the skin, microneedles coated with zolmitriptan University of Greenwich in the UK, and has physically break the stratum corneum and pene - attained several management diplomas from trate the epidermis/, where the dry drug Kellogg School of Management, as well as coating is dissolved by the surrounding skin inter - Stanford’s Graduate School of Business. stitial fluid, delivering the drug directly into the bloodstream. Clinical results to date demonstrate its potential to provide positive symptom relief to patients with migraine.

Conclusion Transdermal Drug Delivery technology offers com - pelling opportunities to address a number of issues associated with commonly-used drug delivery methods. In time, it is anticipated that technological advancements in TDD will lead to improvement in quality of life for those suffering from migraine and potentially other diseases. DDW

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