EPM Drug Delivery Supplement 2017

DR VO UG LU M DE E LIV 3: ER Y

SERIES

SMART THINKING Drug delivery connectivity beyond the smartphone from Phillips-Medisize

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EDITOR’S DESK

Drug delivery is evolving to enhance medicine efficacy and patient compliance in our increasingly digital world.

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ithin the area of pharmaceutical drug breakthroughs, we have witnessed a lot of news, such as big blockbuster drugs hitting (and running away with) the market, controversies over side effects and targeting new diseases, to name but a few.

However, more and more, we are seeing a rise in the level of interest and the development of drug delivery techniques. Not only do therapies need to be effective and clinically safe, but now we are also expecting a degree of specificity in how those drugs are delivered.

toxicity to healthy cells. Additionally, a Swedish study is underway to examine a drug delivery system that directly accesses the brain for the treatment of Parkinson’s patients.

There has been a wave of recent news items describing delivery methods to transverse the blood–brain barrier. Researchers at Johns Hopkins have unveiled a modification to a drug structure to allow it to cross the protective barrier to the brain and thus target cancers more easily avoiding the usual issues of mass

Adding to these considerations, is the complication of modern technological devices and the role they play in patient compliance and monitoring of outcomes. What role can/ should these devices play? How can they be incorporated into the developmental procedure?

Then there are the new ways in which drugs are encapsulated to ensure they are released over a longer period of time or are released at a targeted location. Self-administration techniques are also of importance as this frees up patients to be more independent from a clinic or GP’s office.

The long and short of it is, making medicines more effective is of high priority. As drug formulations continue to evolve so must the delivery methods. Ensuring that patient compliance and adherence to their therapeutic schedules are maintained will improve real-world outcomes and with the digital revolution well under way (over half of the world’s population now using smartphones) this seems a logical route to explore.

Contents head office

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A brief round-up of recent developments in drug delivery

Examining the challenges and opportunities in the growing injectables market

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REVOLUTIONARY PARENTERALS

editor felicity thomas felicity.thomas@rapidnews.com

Felicity Thomas gets to the core of the EU-funded project, Cupido

Evonik looks at the positives and pitfalls of advanced parenteral formulations

deputy group editor dave gray david.g@rapidnews.com

A DOSE OF NEWS

AT THE HEART OF IT

PUSHING THROUGH

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Daniel Simmons reveals the role of human factors in medical adherence

We discuss softgel capabilities with Catalent in this Q&A

THE SENSE IN SENSE

A SOFT SPOT

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group editor lu rahman, lu.rahman@rapidnews.com reporter reece armstrong reece.armstrong@rapidnews.com publisher duncan wood

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ON THE COVER — SMART THINKING

robert anderton tel: +44 (0)1244 680222, rob@rapidnews.com

Phillips-Medisize highlights how modern technology can be incorporated into drug delivery connectivity

damien challenger tel: +44 (0)1244 680222 damien.challenger@rapidnews.com

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NEWS

A dose of news In this round-up, we discuss recent news, breakthroughs and updates in the drug delivery sector, including vaping medicinal cannabis and a molecular slingshot.

Vaping medical cannabis

On the brain

Molecular slingshot

Kanabo Research is using a modified vaporiser to deliver new formulations of medical cannabis extracts to treat specific central nervous system disorders.

Renishaw’s chronic drug delivery system has been selected for use in a clinical Phase I-II study in Parkinson’s patients. The drug delivery system will be used in partnership with Herantis Pharma’s cerebral dopamine neurotrophic factor (CDNF) drug candidate.

Scientists from the University of Rome To Vergata and the University of Montreal have reported the synthesis and design of a nanoscale DNA-based drug delivery system.

The vaping system, VapePod vaporiser, is currently undergoing certification as a medical device by the Ministry of Health in Israel and is anticipated to be available in the last quarter of the year.

“We are dedicated to exploring and developing new plant based therapies and improved methods of administration for unmet needs for the benefit of patient populations,” said David Tsur, part of Kanabo Research’s leadership team. “I am confident in Kanabo Research’s team to develop unique solutions using medical cannabis.”

Neurodegenerative diseases, such as Parkinson’s, are difficult to target therapeutically as a result of the protective blood–brain barrier.

In light of this, Renishaw has worked with neurosurgeons to develop a system that can bypass this protective layer.

In the clinical investigation, to be performed in Sweden, 18 patients will have a small port implanted into the skull, close to the ear, which will allow clinicians to deliver CDNF to target areas.

“This is an important step forward in the use of the Renishaw drug delivery system, and in gathering clinical data for the delivery of therapeutics across the blood–brain barrier,” stated Paul Skinner, general manager for the company’s neurological products division. “We are very pleased to be able to contribute our engineering technology and experience to this important trial.”

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The paper, published in Nature Communications, reports that the molecular ‘slingshot’ could deliver drugs at precise locations inside the human body once triggered by specific disease markers.

Made of a synthetic DNA strand that is only a few nanometres long, the delivery system essentially works as a rubber band would in a slingshot. Specificity is achieved by two anchoring moieties on the two ends of the DNA strand, which adhere to a target antibody expressed in response to different pathogens, such as bacteria and viruses. When the anchoring moieties recognise and bind to the arms of the target antibody, the DNA strand stretches and releases the drug.

“One impressive feature about this molecular slingshot is that it can only be triggered by the specific antibody recognising the anchoring tags of the DNA rubber band,” emphasised Francesco Ricci, PhD, associate professor of chemistry at the University of Rome Tor Vergata. “By simply changing these tags, one can thus programme the slingshot to release a drug in response to a variety of specific antibodies. Since different antibodies are markers of different diseases, this could become a very specific weapon in the clinician’s hands.”

COLLABORATIONS

Heart of the matter An EU-funded project, Cupido, is researching the application of nanotechnologies in drug delivery in the cardiovascular field. Felicity Thomas explains more…

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ardiovascular diseases (CVDs), such as cerebrovascular disease, coronary heart disease and peripheral arterial disease, are the number one cause of death worldwide, according to WHO.1 Within Europe, CVDs are the causative factor for more than half of all deaths and is more of a disease burden on the region than that caused by AIDS, tuberculosis and malaria combined.2 Moreover, there is the financial burden to consider. In research published by the Centre for Economic and Business Research (Cebr), the financial impact of CVD on six major European countries was predicted to rise to €122.6 billion by the year 2020.3

Novel approaches required Currently, for patients with established disease there are several therapeutic options available. These include aspirins, beta-blockers, angiotensin-converting enzyme inhibitors and statins.

However, implementation of these therapeutic options is an issue and as they show several weak points concerning efficacy and longer term benefits, novel approaches are fast becoming necessary.

As the available drug delivery methods are oral and intravenous, the drug is able to circulate the blood stream systematically, which leads to several side effects and a reduction in treatment efficacy. During late-stage disease administration of therapies may become more invasive, for example through catheters or implantable pumps.

These drug delivery methods may be uncomfortable and inconvenient for the patient as well as being costly to the healthcare system.

On this note, an EU-funded project that was started in February 2017, Cupido, proposed the use of nanotechnologies within the cardiovascular field.4 The aim of the project is to develop inhalable nanoparticles that can deliver a therapeutic directly to the heart through the simple act of breathing it in.

Nanoparticles are tiny particles, between 1 and 100 nanometres in size, which may offer a revolutionary route of administration for cardiovascular therapeutics. Additionally, this method would be the first non-invasive and heart-specific therapeutic approach.

1. Nanoparticle preparation Bioactive molecules are encapsulated by negatively charged calcium phosphate nanoparticles, which then act as a drug delivery system through the formation of life-compatible nano-pores allowing cellular internalisation.

2. Nano-embedded microparticle production and inhalation

A consortium of expertise Cupido represents a consortium of six academic research groups, five SMEs, two industries and one pharmaceutical company. By drawing on the combined expertise of the various participants of the project, nanoparticles that are biocompatible and biodegradable are under development that can self-assemble and encapsulate drugs (novel or available) in a suitable format for the treatment of CVD. These nanoparticles will be administered through inhalation and once they have entered the patients’ lungs will translocate to reach the heart in a quick and efficient way. Once the heart has been reached the drug will be released. The inhalation delivery devices are being developed by pharmaceutical company Nemera.5 To specifically target the heart, the nanoparticles will be chemically and magnetically guided. This specificity will reduce the chances of adverse side effects and will lower the amounts of therapeutic compound required.

This four-year project is being funded with six million Euros under the EU Horizon 2020 Framework Programme.

References: 1. http://www.who.int/mediacentre/factsheets/fs317/en/ 2. http://www.euro.who.int/en/health-topics/noncommunicable-diseases/cardiovascular-diseases/data-andstatistics 3. https://www.cebr.com/reports/the-rising-cost-of-cvd/ 4. http://www.cupidoproject.eu 5. http://www.epmmagazine.com/news/nemera-participates-in-project-cupido/

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The breathing heart

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Nanosized calcium phosphates (CaPs), that are between the range of 1–3 µm in size, can be deposited at the alveolar level. Transforming these particles into a dry powder allows inhalation and hence transmission into the patients’ lungs. Once there the microparticles will dissolve in the lung fluid.

3. Nanoparticle release and translocation to the heart Just as oxygenated blood is transferred from the pulmonary circulation to the heart via the pulmonary vein, the inhaled CaPs will transverse the alveolar-capillary barrier to reach the myocardium.

4. Monitoring and guidance to the heart Using radiolabelling, the fate of the nanoparticles and their biodistribution will be monitored in vivo, which will allow the selection of the most promising delivery systems.

Aptamers will be employed by Cupido to ensure selective drug delivery to the myocardium thereby avoiding adverse side effects.

DESIGN

The sense in sense Helping people to help themselves, Daniel Simmons, principal human factors consultant, reveals the role of human factors in medical adherence and how patients use their senses to make sense of things.

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nsuring patients take their medications at the right time, in the right quantities is a key challenge for device designers and manufacturers. Adherence levels remain stubbornly static at, on average, around 75%, and in some circumstances can fall as low as 25%.

While the reasons for low adherence are complex, one route to improvement is a better understanding of users, their needs and their behaviours. It was this reason that FDA regulations were created.

The 510(k) Human Factors Guidance requires that manufacturers make a systematic assessment of users, the conditions under which it will be used, how it will be used and whether it can be used safely. This provides a baseline, but improving adherence means ensuring that human factors are not just considered during development, but are central to the design and development process.

The aim is to make a device so intuitive that it becomes an integral part of users’ lives and their experience is more positive.

Aiming for intuitive A device is intuitive when users understand it without reasoning, experimentation, assistance, or special training. This is a challenge when everyone has a different background, experience or expectations — what is intuitive to one person may not be to another.

This is where human factors’ practitioners bring a different dimension to the design process by suggesting a design approach that is based on human behaviour — how people live their lives and how a device can fit more easily into that.

Considering instructions for use, how visual information is arranged and grouped will influence how the user interprets and understands the product and how easy or difficult it is to use. The same is true of touch, which has significant influence on our response to things, and designers can use tactile sensation to improve usability.

Designers must understand how users sense the world, how their brains interpret those sensations and how they think and act on what they perceive. Using this understanding, designers can provide cues that enable devices to be operated intuitively, confidently and safely.

Functionality is key — a device must work as intended, without question.

The key to creating an intuitive medical product lies in aligning the design with the user’s mental model of similar objects and visual cues present on the device.

Mistakes will happen!

People will always make mistakes: it’s impossible to design a perfectly fail-safe system. Anticipating potential mistakes allows designers to design those mistakes out. Performing a failure modes and effects analysis (FMEA) can identify cognitive errors users could make.

These are part of the FDA’s design control regulations, but often they identify potential mechanical failures only. A human factors approach identifies cognitive errors from the users’ perspective to minimise potential error.

Positive reinforcement

With a new product, there is always a learning curve — the shorter the better. This can be achieved by reducing the amount of new information to be digested to reduce cognitive overload.

People are motivated by progress, mastery and control. Small signs of progress can have a big effect. Providing feedback is especially important because it lets the user know they are progressing.

In processing information, our brains are subject to three types of demands, or loads; cognitive (including memory), visual and motor.

Each demand requires a different amount of mental effort.

The closer we are to a goal, the more we focus on what’s remaining and this makes us more motivated. This creates a positive feedback loop.

Users will be more engaged and this will promote a positive experience.

Trying to remember something or do a mental calculation requires the most mental effort. Users, therefore, tend to want to keep things as they are. As we use up mental effort, our attention span lapses. However, we also lose attention if too little mental effort is required.

We have a fundamental drive to seek out information, and this concept of cognitive load suggests that a medical product design that is too plain won’t hold our attention. A design that is too complex will overload us, and too much choice inhibits decision-making. A balance must be found.

Sensory importance When we interact with any object, our first impression is visual — we see the object before the brain starts interpreting the visual stimuli. The importance of the visual system to medical products is in understanding that we make connections even when information is missing.

Understanding people enables medical product designers to develop products that are intuitive to use and that appeal to the target user population. Knowing how we sense and make sense of things — how we see, understand and decide — is the essence of good design.

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Understa nding pe ople mea designers ns medic can deve al produ lop prod to use. ct ucts that are intuit ive

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COVER STORY

SMART THINKING Drug Delivery Connectivity Beyond the Smartphone Phillips-Medisize highlights the challenges and opportunities in drug delivery connectivity that arise when incorporating modern technologies with patient requirements.

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s drug delivery devices such as inhalers have become smaller and more portable over past decades, they have simultaneously become more complex and smarter in their functions most recently, featuring the ability to provide and communicate information through appropriate modern connectivity methods.

Morten Nielsen, president of the company’s Medicom Innovation Partner subsidiary, said: “If DFM and DFA are abruptly introduced at the end of the design phase, manufacturing strategy is not aligned with the device strategy, likely introducing late-stage changes that threaten stakeholder requirements or programme feasibility.”

According to Bill Welch, chief technical officer, Phillips-Medisize Corporation, drug delivery device producers need to respond to this trend by a ‘systems engineering’ approach. This aims at reducing financial and other risks in efficient device development meeting more advanced technical requirements, as well as ensuring required devices reach the market within agreed schedules. These risks go right through the value chain, from the biopharmaceutical customer, to the developer and producer of drug delivery devices through to users, patients and health system payers.

Smart connectivity solutions

The systems engineering approach, as applied by Phillips-Medisize, requires the company to pay attention to each individual component contained within drug delivery systems, as well as to the components, sub-systems and overall system. Welch says this approach is more robust than a conventional linear product development route in that it requires some engineers dedicated to systems and others to sub-systems development, as ‘this is what makes the whole system work together’.

System engineering needs to be performed on components, subsystems and overall systems at an early ‘proof-of-concept’ stage. This involves on one hand, higher up-front early development stage costs than with linear product development, on the other hand it saves other expenses later on (eg., if a need arises to trace back the cause for a device not properly functioning at a later stage in development or marketing).

Up-front development costs mentioned by Welch can be minimised by integrating design for manufacture (DFM) and design for assembly (DFA), as ‘80% of product cost and quality is often determined during the first 20% of the product development timeline’.

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While drug delivery device development has tended to be more involved with mechanical functions, incorporating today’s compact electronic technologies into devices requires additional attention. Not only is it important to note how electronic data can be collected by the device, but also how the collected data can best be used to benefit patients, carers, nurses, doctors, payers, insurance companies and so on.

So, there is development emphasis on how sensors can be embedded in drug delivery devices, to communicate by wireless or Bluetooth technology to a smartphone or tablet app, rather than having to plug the device into some other equipment or storage device.

Once data has been captured it can be presented to all those with a justification in receiving and analysing data to optimise treatment solutions. This can include treatment correction communicated back to the patient via a smart device app, potentially reducing exacerbations or the need for hospital treatment. It is the patient who does the monitoring and applies treatment correction.

This an important factor with pulmonary diseases such as asthma, where patients can self-administer today with established dry powder inhalers (DPIs) and metered dose inhalers (MHIs), as well as more recent soft mist inhalers (SMIs).

It also means more attention has to be paid to patients’ data security and privacy rights as there will be an increasing amount of it to be handled and protected. For example, a vast increase in the production of large-molecule biologics drugs is expected to increase the market value for self-administration of such drugs, which will overtake the value of

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the self-administered insulin market — the largest and fastest growing self-administration area so far.

However, before drug delivery device producers start looking at connectivity requirements to provide effective outcome-based healthcare in this new market, they need to have solved how drug delivery devices can be designed to provide primarily self-administered injection of the viscous solutions involved. This is quite a different challenge compared with that of powder inhalation devices.

Patients need to have devices they can easily use for self-administration, as otherwise the ‘Big data’ connectivity reports a poor outcome for the patient due to lower dosing adherence. Additionally, less understanding of the disease is acquired by health system stakeholders.

The problem of poor adherence has been brought to light by the University of Texas Medical Branch (UTMB) in results of a study revealed in December 2014. UTMB found that only 16% of patients surveyed used an epinephrine auto-injector properly. It pointed out: “More than half missed three or more steps, the most common error being not holding the unit in place for at least 10 seconds after triggering epinephrine release.” Other common errors included failure to place the device’s needle on the thigh and not depressing the device forcefully enough to activate injection.

It was further established by UTMB that ‘only 7% of users demonstrated perfect technique and 63% missed three or more steps’. The most common ‘misstep’ here was not completely exhaling before inhaler use, while failure to shake the inhaler before the second medication ‘puff’ was also a common error.

These are the types of problems that can be addressed by incorporating real time error detection, notification and correction in smart drug delivery devices, with audio, visual and tactile feedback. It has also been suggested that problems of device clogging and patients forgetting device advisory information, received from healthcare professionals (HCPs), and/or instructions accompanying the device should be addressed in this way. Furthermore, it is suggested that patient error may also be prevented through the use of electromechanical inhalation devices with breath sensing and other advanced technology.

Smart devices and connectivity were addressed in a joint workshop in April 2017 by Welch and his colleague Kevin Deane, executive VP, Front End Innovation at Medicom Innovation Partner at the RDD Europe Respiratory Drug Delivery conference in Antibes, France.

The workshop participants gravitated around patient-centric benefits as the primary source of value drivers and opportunities for connected health. Themes around improved treatment, better patient education, patient empowerment and social support were discussed by a majority of the groups.

They advocated that a ‘connected health approach’ should cover the entire ‘patient care journey’, saying that the new ‘patient-centric’ approach means the delivery method becomes the key connection point between the drug, its producer and the patient for many therapies entering the market today.

Welch and Deane said that secure cloud storage is a key central element in a fully connected respiratory health service set up, in which two-way interaction takes place via the cloud between the delivery device and the patient, as well as between the patient’s app and a ‘dashboard’ for nurses and other HCPs. While data in the cloud can be a source of information for trend analysis by health system payers and pharmaceutical companies, pharmacies can input data into the cloud. Data arising from the new Industry 4.0 ‘Internet of the Things (IoT)’, as the fourth (digital) industrial revolution, can also find its way into the same cloud storage facility. The amount and type of data available means there can be effective contracting and risk-sharing between payers and the pharmaceutical industry on a ‘no cure, no pay’ basis, there is development Welch and Deane suggested.

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emphasis on how sensors can be embedded in drug delivery devices

Within individualised treatment scenarios in a fully connected health system, they said automated patient adherence monitoring and symptom/event logging benefit above all respiratory drug delivery. Patients can benefit here from individual disease-related information and alerts, such as data on local pollen and pollution levels, and HCPs can remotely monitor their patients.

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Pharmaceutical companies also have benefits such as automated supply chain logistics for medicine re-ordering. However, Welch and Deane questioned whether longer term costs of running and maintaining a well-functioning connected health setup are known. Whether there is clarity on the return of investment (ROI) achievable from up-front investments, or on reimbursement to HCPs for provision of added value services.

The authors emphasised that a successful delivery device design must be, useful in meeting a specific need, user-friendly, desirable through its appeal to the user and capable of efficient and reliable manufacture in commercial volumes. The device strategy to address an outcome-based solution should be combined with a manufacturing strategy to get to market at target quality, cost, time and risk, Welch and Deane maintained.

In the interactive workshop presentation, titled ‘Realizing benefits of connected health in respiratory drug delivery’, the authors referred to healthcare costs taking increasingly high shares of gross domestic product, while ‘dosage forms evolve and connected devices proliferate’. They maintained that increasingly complex, targeted and personalized drugs mean devices are becoming ever more critical to patient acceptance and drug performance.

Connectivity was seen as an enabler for reducing waste, saving costs, personalising treatments, improving clinical trials and even evolving device designs. Furthermore, the challenges to implementing connected health seemed to align around technical issues, poor business cases, concerns around data ownership/ security/privacy, regulatory risks and general reservations about ‘change’ .

That there are already more connected devices than people, with the average person soon to have as many as six devices online, should be seen in the context of the uptake rate of digital infrastructure occurring five times faster than the adoption rate of electricity and telephones, the authors stressed.

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Patient-focused drug delivery devices Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing

www.nemera.net information@nemera.net • Phone: +33 (0)4 74 94 06 54

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INNOVATION

Pushing through SHL Group looks at the important challenges and opportunities facing device manufacturers and pharma companies in the growing injectables market.

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ecent years have witnessed significant global market growth for injectable drug delivery devices. This trend is expected to continue well into the future. Self-injection devices are expected to grow at a CAGR of 16.1%, continuously increasing the market share.1 What explains this growth?

• Growing life expectancy and chronic disease prevalence mean that many treatments are moving from hospital to home.

• Biological drugs are on the rise. They were providing 22% of big pharma sales in 2013 and are expected to account for 32% by 2023.2 • A rise of biosimilars leads pharmaceutical companies to use delivery devices for drug life-cycle management and product differentiation.

These trends mean that drug delivery devices are becoming an integral part of the healthcare industry. Therefore, both device manufacturers and pharma companies have to stay well informed of the most important challenges and opportunities for innovation.

Higher viscosities Since the creation of the first recombinant DNA molecule in 1973, the advances in biotechnology and genetic engineering have been driving the growth in biological drugs. Now they are used across a wide range of indications, including diabetes, autoimmune diseases and cancer.

One challenge posed by the new generations of s livery device biologics is that able drug de ct je in . r re fo The trend l into the futu el w many of them are ue in nt to co is expected large molecules and have to be administered in high concentrations. The resulting formulations reach high viscosities, sometimes together with high volumes, thus creating a challenge for traditional delivery systems. Is there a way to provide these drugs for self-administration?

Considering that adherence is one of the major issues in chronic condition management, the challenge of high viscosity must be approached with patient comfort and device usability in mind. These were the main considerations during development of SHL’s Rotaject technology. Using clock spring technology for injections, this system allows for delivery of formulations with viscosities up to several hundred centipoise. At the same time, it can be encased into a two-step disposable auto injector using a 1.0 mL or larger 2.25 mL syringe.

Patient-centricity With major pharma companies introducing chief patient officers3 and FDA considering the new ‘Office of Patient Affairs’,4 the patient is becoming not just the recipient of the innovation, but also one of the main gate-keepers. Powered by human factor engineering and usability studies, device companies consider satisfying end-user needs to be one of the most important requirements for their products.

Behind this is the simple fact that a patient will not benefit from the treatment that he can’t administer. From fear of needles to dexterity issues to the variety of feedback mechanisms — every feature of an injection device has to be thought through and based on the needs of the particular a patient will not benefit patient population.

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from the treatment that

One of the most important steps here he can’t administer. are user studies conducted to see how a device works in the real world. The data from such studies should be collected, centralised and analysed to guide the design, revealing what real patients want from their interaction with a drug delivery device. For this reason, SHL has invested in a new design centre that will include a dedicated interview studio featuring equipment for recording and documenting patient experience and feedback.

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Digital health Digitalisation of healthcare is happening and connected solutions will continue to play an increasing role for patients, healthcare providers, payers and pharmaceutical companies. In drug delivery, connectivity is realized by enabling the drug delivery device to communicate with a mobile or the cloud. The collected data can be used by patients, carers, physicians, payers, pharma and other stakeholders. From simple reminders to in-depth understanding of the therapy, this information can help improve adherence and health outcomes, streamline communication and save costs. Importantly, it provides new and exciting insights into the current and future needs, inspiring and guiding further innovation.

Whether realized through an existing device add-on or developing a completely new connected auto injector, a smart connected product is a timely and necessary innovation. Combining internal knowledge and experience with active partnerships, SHL Group has already started a number of initiatives in the digital space to stay ahead of the curve and bring innovation to the market.

References: 1. Injectable Drug Delivery Market: By Devices, Therapeutics & Formulations 2015–2020, Research and Markets, 2015.

2. Going Large, The Economist, 2015, http://www.economist.com/news/business/21637387wave-new-medicines-known-biologics-will-be-good-drugmakers-may-not-be-so-good 3. Sanofi aims for outcomes with brand-new Chief Patient Officer, March 2014 http://www.fiercepharma.com/sales-and-marketing/sanofi-aims-for-outcomes-brand-newchief-patient-officer 5. FDA Considers Creating New ‘Office of Patient Affairs’, March 2017 http://www.raps.org/Regulatory-Focus/News/2017/03/13/27103/FDA-Considers-CreatingNew-Office-of-Patient-Affairs/

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INNOVATION

(R)evolutionary parenterals Evonik outlines new opportunities for drug delivery via advanced parenteral formulations, the positives and the pitfalls.

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he parenteral drug delivery landscape is undergoing a revolution, due to a combination of new drug findings and transforming formulation technologies. Not surprisingly, each of these topics has an influence upon the other.

The interest in the development of drugs such as peptides, for example, has spurred the search for novel formulations. Peptides, as is the case with many potent new drugs, cannot be administered orally because of poor absorption and stability. Yet daily injections are tedious to perform and thus result in low patient compliance.

A good example of the beneficial effect of parenteral drug delivery can be seen with the commercial drug product Doxil, which was one of the first nano drugs to be approved by the FDA. Doxil was created by assimilating the anti-cancer agent doxorubicin, which can have substantial cardio toxicity, into a liposome drug delivery system that sidesteps the heart. Thus, it is an illustration of drug delivery technology used to improve existing drugs.

That drawback has led to increasing exploration into more complex parenteral formulations that take advantage of extended-release capabilities. These offer prolonged efficacy of one week to several months after a single injection and include bioabsorbable delivery forms such as injectable microparticles and implants. Products based on biotechnology, however, require great diligence during formulation to retain stability and circumvent biological barriers that would prevent the dosage form from reaching the intended site.

Modern parenteral drug delivery systems — new therapeutic options With today’s drug delivery technologies, it is no longer the molecular structure of the drug alone that determines where it is released in the body, but also the properties of the carrier. Additionally, these properties can be tailored to specific requirements of the treatment goal. That means the carrier can deliver more of the drug to a pre-determined site, shield it from premature degradation, or isolate delicate organs from the drug and thus diminish toxicity.

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Liposom al formu lations p with uniq rovide e ue adva ffective d ntages s rug uch as re duced to delivery xicity.

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These new methods of delivery also offer potential for designing drugs specifically for use with particular delivery systems, while, as noted earlier, the reverse is also true.

Drug delivery technologies make it possible to develop new types of therapeutics. A case in point is messenger RNA (mRNA), which promises exciting advances in new treatments. As mRNA degrades in vivo and is unable to penetrate cells on its own, it can only function through the use of a suitable drug delivery system.

With sophisticated formulations, it is necessary to consider the entire end-to-end development and manufacturing process, especially in terms of scalability. This means that from the beginning, thought must be given to issues such as material needs for a Phase I study and how those needs might change during clinical testing and commercialization.

Characterization of the formulation is crucial to avoid a complete process re-design at a later date.

Delivering mRNA using lipid nanoparticle technology has enormous potential because the expression of almost any protein can be induced.

This enables its use in treating genetic diseases such as cystic fibrosis where key proteins need replacement due to deficiency or damage.

The mRNA delivery technology could also be applied for the creation of vaccines with antigens capable of direct expression by the body (in situ synthesis). The result would be an improved immune response, as it would appear to the body to be a common viral infection.

Innovative approaches to nanoparticle production have been facilitated by liposomal drug delivery. Today it is possible to deliver substantial quantities of a drug while at the same time augmenting bioavailablity.

Solid lipid nanoparticles, for example, have made pulmonary delivery of large amounts of drug possible — with minimal amounts of excipient delivered to exact targets within the lungs.

s article icrop m ll sma bles less y ena n for pain g lo o n io t h u c e istrib ZE t ormE icle size d t ik’s F Evon rrow par na with ns. io inject

Potential and benefits of targeted drug delivery There is enthusiasm about the potential to target drugs, which includes putting a drug where you need it and delivering it, in place, over a long time-period. For example, work is being done to develop formulations to reduce inflammation within the knee. This would prevent the drug from circulating within Products based on the body and causing unnecessary side effects, biotechnology, however, while allowing efficacious levels of the drug to be contained within the knee area.

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require great diligence during formulation to retain stability and circumvent biological barriers that would prevent the dosage form from reaching the intended site.

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At the same time, many new products have been recently launched, including those for treatments in the sinus, eye and periodontal regions. What the future holds cannot be accurately predicted, but it is not impossible to imagine local delivery to the spine, bones, within the brain or even as a factor associated with tissue regeneration and stem cells — or to rebuild knee cartilage.

Complex parenteral formulations have and will continue to improve patient outcomes, but their development calls for expertise and dedicated experience. Evonik Health Care offers a range of services including consulting, formulation development and commercial manufacturing of complex parenteral formulations. Through innovation, building infrastructure, developing new process technologies — such as FormEZE microencapsulation — and creating intellectual property, Evonik continues to contribute to the commercialisation of these formulations and thus to improved therapies.

Challenges of complex parenteral formulations There are many challenges to developing complex parenteral formulations, which makes it more time-consuming and involved in comparison to conventional formulations. With injectable microparticles, the manufacturing process must be robust and tightly controlled. This is because, together with the drug, a particular polymer morphology will be created within the particles that will be susceptible to the slightest instability. In addition, as more and more highly potent APIs are developed, GMP requirements as well as worker safety become crucial issues that demand increased attention.

In addition, there is no direct cause-and-effect between plasma concentration and drug activity with injectable nanoparticle formulations. The drug within the delivery system only becomes active after it has been released. So, during development, outcome predictions can only be based on screening models and not on plasma drug levels as with conventional drugs. Also, with these complex formulations, excipients deliver important functionalities that need to be precisely controlled to achieve consistent therapeutic results.

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Q&A

A soft spot As Catalent further expands its softgel drug delivery capabilities with its acquisition of Accucaps, we speak with June Lin, global marketing director consumer health softgel, about the benefits these expanded capabilities will offer.

Q. What was the driving force behind Catalent’s recent acquisition of Accucaps?

Q. This acquisition has come shortly after that of Pharmatek. Could you provide some background on this deal?

A. Catalent’s goal is to help its customers develop and supply products to meet the needs of their end consumers and patients. We partner with our customers to develop best-in-class formulations and products, using innovative drug delivery technologies to enable better treatments in consumer-friendly dosage forms.

The Pharmatek acquisition adds extensive early-phase drug development capabilities from discovery to clinic, brings spray drying into our portfolio of drug formulation and delivery technologies, and expands our capabilities for handling highly potent compounds. The addition of spray drying provides our customers with a comprehensive suite of bioavailability enhancement solutions, while complementing and expanding our award-winning OptiForm Solution Suite platform, a science-driven parallel screening approach to identify the optimal formulation pathway for poorly soluble compounds.

As an organisation, we are constantly looking at ways to expand and deepen our range of technologies, and add capabilities to address our customers’ needs. We undertake our own independent scientific development programmes and, also, look for acquisition opportunities that fit with this strategy.

As part of this approach to technology expansion, we acquired Micron Technologies for particle-size engineering, Pharmatek Laboratories for early drug development and spray drying and, recently, Accucaps Industries Limited to further strengthen our global softgel capabilities and capacity.

The Accucaps acquisition adds two new sites in Ontario, Canada specialising in consumer health softgel products, including overthe-counter (OTC) monograph products, offering ready-to-market dossiers that are available for customers to help speed up the commercialisation process. In addition, the sites have an integrated suite of packaging services, including blistering and bottling functions, allowing us to deliver turnkey solutions to customers.

We now have additional softgel capacity in North America to expand our consumer health presence, adding to that of our flagship site in St Petersburg, Florida, which focuses largely on prescription pharmaceutical products. The two Canadian sites expand our global softgel presence, creating a network of 12 softgel facilities across five continents to meet the needs of both large, global multinational and regional customers.

Q. How will this acquisition expand Catalent’s softgel capabilities?

A. Added capacity and capabilities were key elements in this acquisition.

In particular, Accucaps possesses depth of knowledge in the development and commercialisation of OTC products, including a portfolio of developed dossiers across a wide range of OTC segments that enable accelerated product launches.

Catalent’s customers will benefit from our increased ability to offer turnkey softgel solutions. Significant investments, which have already been undertaken by Accucaps, fit well with Catalent’s own strategic goals, to offer customers access to more products, capacity and integrated solutions for differentiated products and more and better treatments.

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The cGMP San Diego site also expands our West Coast presence and provides additional access to Asia-Pacific markets.

Catalent is continually looking to expand its portfolio of technologies and capabilities, and, as has been seen previously, should the right opportunity present itself, we would look at further acquisitions to differentiate our offerings and add value to our customer base.

Q. What innovations can we anticipate moving forward?

A. Catalent continues to innovate and introduce new softgel technologies for better drug delivery and improved consumer/patient compliance.

As the originator of RP Scherer softgel technology over 80 years ago, Catalent has a long history and heritage of innovation both for pharmaceutical and consumer health Significant investments, which have already been undertaken applications.

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by Accucaps, fit well with Catalent’s own strategic goals, to offer customers access to more products, capacity and integrated solutions for differentiated products and more and better treatments.

It is important that i n n o va t o r s and developers continue to make strides in product performance, and keep consumers in mind when they do so. The innovative development of the technology, such as rapid onset, increased palatability and the ability to tailor appearance and flavour characteristics have all been made in recent years to adapt to changing market needs and consumer demands.

With our experience in prescription and OTC medicines, we can offer new technologies to deliver relevant benefits to meet the evolving needs of today’s patients and consumers.

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