Patient adherence is an important consideration when designing drug-delivery systems, devices, and related components and is leading advances in drug delivery.

This patient-centric innovation is driving new ways to integrate pharmaceuticals, drug-delivery devices, wearables, and mobile technology as well as to develop greater patient-friendly drug-delivery devices that facilitate self-administration of drugs, including highly concentrated biologics. DCAT Value Chain Insights (VCI) examines the leading trends and product developments in this new era of drug delivery.

The marriage of mobile technology and drug delivery
The integration of mobile technology with drug-delivery devices, sensors, or pharmaceuticals is a growing, but still nascent area. A recent study from the IMS Institute for Healthcare Informatics estimates there are now more than 165,000 mobile health applications available to consumers as developers incorporate data collection features linked to sensors and wearables. The study found that one in ten apps has the capability to connect to a device or sensor for providing biofeedback and physiological function data from the patient. Nearly a quarter of consumer apps are focused on disease and treatment management while two-thirds target fitness and wellness, according to the IMS report.

Although disease management comprises a smaller portion of mobile healthcare applications, the potential is strong. A recent analysis by BCC Research, a Norwalk, Connecticut-based market research firm, estimates that the global market for select health self-monitoring technologies reached $1.1 billion in 2013 and nearly $3.2 billion in 2014 and projects that the market will grow at a compound annual growth rate of 42.9% to reach $18.8 billion in 2019. These health self-monitoring technologies include wristbands, smartwatches and other peripherals, mobile self-monitoring software applications, smartphones, and other mobile “hub” devices that collect data from peripherals as well as their own onboard sensors. The report notes that the current, early generation of self-monitoring tools enables users to monitor and record details of their daily activity, from counting steps or miles walked, and floors climbed, to monitoring calorie consumption, as well daily patterns and hours of sleep. The firm says that future developments will expand the range of physiological variables that can be self-monitored and enhance the usefulness of the data thus collected.

Although a still emerging area, mobile healthcare tools are driving innovation in drug delivery. “Trends toward wearable technology, including the Fitbit and Apple Watch, provide information that enable patients or wearers to make decisions to help make improvements to their overall health,” says John Paproski, president, Pharmaceutical Delivery Systems, West Pharmaceutical Services, Inc. “Similar to these trends, is the opportunity to use such data when completing a therapeutic regimen, particularly when an integrated delivery system can be used. Every dosing event has the opportunity to provide potential information that can be used to track adherence as well as the functionality of the delivery system itself. These data points can tell patients, caregivers, or clinicians when the dose was delivered, and if it was delivered property and in full. That information can help improve patient compliance and adherence.”

Advancements in drug-delivery systems
The potential of mobile healthcare is engendering innovation among pharmaceutical companies, manufacturers of drug devices and components, and specialized healthcare providers. A case in point is West Pharmaceutical Services, which is partnering with HealthPrize, a provider of digital technologies for patient engagement and medication adherence. In September 2015, the companies announced the completion of the first two phases of their four-phase strategic collaboration. The companies are working to integrate HealthPrize's Software-as-a-Service (SaaS) medication adherence and patient-engagement platform with West's injectable drug delivery systems to provide an end-to-end connected health solution for pharmaceutical companies and patients. The combined offering will provide voluntary, electronically connected drug delivery systems that track when patients take their medication. The HealthPrize system engages and educates patients to increase adherence and medical literacy, rewarding interaction and compliance with prescribed treatment plans, and contributing to better health outcomes.

Phase 1 of the platform allows for patient self-reporting once the medication has been injected. Phase 2 simplifies the self-reporting process through bar coding or QR coding of self-injection systems, which, when scanned, reports use of the injection system to the HealthPrize patient-engagement system via a secure cloud environment. Bar coding allows for the recording of other medication details, including manufacturing information, pedigree, expiration date, dosage, and other information.

The final phases of development that are currently in progress are fully integrated injection systems with onboard monitoring and built-in wireless communication capability (integrated connected health) and the connection of legacy, mechanical injectors to the HealthPrize platform via an adaptive attachment (legacy connected health). In all four phases, data captured over time will also provide pharmaceutical companies insight into trends and analytics regarding the actual use of their products.

Other companies also are advancing the integration of drug delivery and mobile healthcare solutions. In June 2015, Teva Pharmaceutical Industries and Microchips Biotech, a Lexington, Massachusetts-based provider of microchip-based implants for drug delivery, partnered to apply Microchips Biotech's implantable drug-delivery device to Teva's portfolio of products with the goal of enhancing clinical outcomes for patients on chronic drug therapies. Microchips Biotech's electronic device is made up of microchip arrays that can store therapeutic doses of drug for periods ranging from months to years and releases each dose at scheduled times.

Teva made a $35 million upfront payment to Microchips Biotech in the form of an equity investment and technology access fee. The partnership has an initial focus on one selected disease area, but will provide Teva with the option to later expand the program into several additional therapeutic areas and sensing applications that are proprietary to Teva. As programs advance, Microchips Biotech will receive development and commercial milestone payments and royalties on future product sales. Microchips Biotech will also receive funding to develop products for any future additional indications Teva may develop, and Teva will be responsible for Phase II and Phase III clinical development and regulatory filings.”

In September 2015, Otsuka Pharmaceutical Co., Ltd. and Proteus Digital Health, a Redwoods Shores, California-based digital healthcare company, reported that the US Food and Drug Administration accepted the new drug application filing for the combination product of Abilify (aripiprazole), a drug to treat schizophrenia, bipolar disorder, and depression, embedded with a Proteus ingestible sensor in a single tablet. According to Proteus Digital Health, this is the first time an FDA-approved medication (Abilify) has been combined and submitted for approval with a sensor within the medication tablet (the Proteus ingestible sensor) to measure actual medication-taking patterns and physiologic response. The Abilify tablet contains an ingestible sensor that communicates with a wearable sensor patch and a medical software application for measuring adherence in the treatment of adults with schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I disorder, and as adjunctive therapy for the treatment of major depressive disorder in adults. The drug-device product can provide the patient with a treatment option to help manage symptoms while allowing the caregiver and healthcare professional to measure medication adherence and other patient metrics. The system was filed as a new drug application, where the FDA Center for Devices and Radiological Health (CDRH)-cleared ingestible sensor from Proteus will be embedded at the point of manufacture with the FDA Center for Drug Evaluation and Research (CDER)-approved Abilify as a combination drug-device, communicating with the Proteus patch and associated medical software.

Innovation in biologic-based drug delivery
The imperative and value for improved drug-delivery platforms in biologics is further evident through pharmaceutical company investment in this area. In May 2015, Eli Lilly and Company announced plans to establish a new drug delivery and device innovation center in Cambridge, Massachusetts. The center will serve as a portal for external partnerships and collaboration activities with the company’s existing research facilities in San Diego, New York City, and Indianapolis, Indiana. Construction of the Lilly Cambridge Innovation Center has begun, with an expected occupancy by the end of 2015. Over the next two years, the company will hire about 30 scientists and engineers to fulfill the center’s work. When fully operational, the center will increase the company’s delivery and device research and development space by nearly 50% while increasing its staff by 25%. Lilly’s drug portfolio and pipeline have changed significantly over the past decade. More than half of the company’s pipeline now comprises biologics that require some type of injection. The company expects its revenues from device-enabled products to double by 2020.

The interest to improve patient compliance, combined with the rise in biologic-based drugs, is further advancing innovation in drug-delivery systems and related components to improve dosing, self-administration, and overall drug delivery. “The rise in biologics brings a corresponding increase in self-administration,” explains Karen Flynn, president, Pharmaceutical Packaging Systems, West Pharmaceutical Services, Inc. “Innovative injectable packaging and delivery solutions, including prefillable syringe systems, auto-injectors, and wearable patch injectors, may help to solve some of the technical restraints that have inhibited the use of biologics in the past. Those constraints include drug sensitivity to packaging, a high concentration of the drug product, viscosity, and delivery route. While drug delivery systems are important enabling technologies, they require a new manufacturing approach focused on flexibility of design, rapid time to market, and total cost of ownership. Additionally, manufacturers must consider regulatory compliance and risk mitigation. For example, delivery via device requires greater dimensional control of components such as plungers, and heightened quality focus means greater emphasis on controlling particulate levels and visual defects. Such systems also may fill the need for brand enhancement and differentiation,” she adds. This innovation goes hand-in-hand with the need to advance delivery system design for self-administration. “As the trend toward self-administration continues, there is a need to ensure that an integrated delivery system is developed so that patients not only can use it, but want to use it. Also, by applying Quality by Design principles in delivery system development, manufacturers can help to minimize risk further down the line toward commercialization.”

As an example of an integrated delivery system addressing these issues, Flynn points to the company's SmartDose electronic wearable injector. SmartDose is a single-use, electronic wearable injector that adheres to a patient’s body, usually on the abdomen, and is pre-programmed to deliver high volumes of viscous or sensitive drug products. The needle is automatically shielded before and after use to help prevent the risk of accidental needlestick injury. The primary container is molded from Daikyo Crystal Zenith cyclic olefin polymer, which can eliminate potential problems with glass delamination and allows the integrated delivery system to be molded in multiple designs that may allow for higher levels of dosing. In 2015, West expanded its manufacturing capacity for the SmartDose electronic wearable injector at its facility in Scottsdale, Arizona.

Other companies also are advancing drug delivery systems for biologic-based drug delivery. In 2015, Unilife Corporation, a developer, manufacturer and supplier of injectable drug-delivery systems, introduced its Imperium platform of instant patch pumps for insulin. Imperium is a prefilled, disposable, multi-day wearable insulin pump that does not require filling or assembly by the patient. Because it is prefilled and pre-assembled like an insulin pen, three steps are required to commence continuous subcutaneous insulin infusion with on-demand bolus delivery available to the user. Imperium can include wireless connectivity systems, such as Bluetooth LE, to integrate with smartphone apps for patient reminders and status updates. With data connectivity available, healthcare providers also have access to real-time or historic data to tailor the insulin therapy for each patient to achieve and maintain glycemic control.

In 2015, Schott introduced a new polymer prefillable syringe designed to improve the safety and stability of sensitive drugs, Schott TopPac SD which offered features for reducing extractables and leachables (E&L) profile. The syringe features a barrel of cyclic olefin copolymer that releases no ions or heavy metals and reduces the chances of a chemical interaction with sensitive drugs. Additionally, the PFS (prefilled syringe) was developed with pure elastomer components in order to reduce the E&L profile. The company is currently expanding the manufacturing capacity for its Schott TopPac prefillable polymer syringes at is facility in St. Gallen, Switzerland.

Needle-free systems are another area of research in drug delivery. 3M Drug Delivery Systems is advancing microneedle technology through hollow microstructured transdermal systems for intradermal delivery of biologics. 3M conducted a human tolerability study with the goal of selecting the appropriate microneedle array for use in clinical studies, and the system is now available for clinical testing.

Portal Instruments, a clinical-stage drug-delivery device company, with financial backing from Sanofi Sunrise, an early-stage innovation arm of Sanofi, is developing a computerized needle-free drug delivery system for injectable biologics for chronic diseases to allow patients to self-administer biologics without injections. The underlying technology is supported by an intellectual property portfolio conceived and prototyped at the Massachusetts Institute of Technology (MIT) by Ian Hunter, PhD, Hatsopoulos Professor of Mechanical Engineering and Head of the Bio Instrumentation Laboratory at MIT, who founded the company in 2012. The technology seeks to offer an alternative way to administer high-viscosity, high- concentration biologics that are needle-injected subcutaneously.

In 2015, Enable Injections, a Cincinnati, Ohio-based developer and manufacturer of wearable injectable technology for self-administration of large-volume drugs subcutaneously, reported on two technology advances for its system: (1) a wearable Injector with Bluetooth connectivity for compliance monitoring and data capture with a mobile app and (2) further development to allow delivery of up to 50 mL doses of high volume and/or viscous biologics subcutaneously. In 2015, the company completed its first-in-human pilot trial. The study evaluated dose delivery, injection pain, and ease of use in subcutaneous self-delivery. In 2014, CSL Behring and Enable Injections formed a long-term development agreement for a drug-delivery system for subcutaneous dosing.

Other advances
Oral delivery of biologics orally is a highly desired and still elusive goal, but companies are advancing technology in this area. In 2015, Novo Nordisk formed a research collaboration with Professor Robert Langer's laboratory at MIT to develop drug-delivery devices for the oral delivery of peptides. The aim of the research collaboration, which is being conducted at both MIT in Boston, and at Novo Nordisk’s research facilities in MÃ¥løv and Hillerød, Denmark, is to develop drug-delivery devices as an alternative to parenteral or injection-based delivery of peptides. The partners point out that there are many challenges in developing and producing a reliable peptide delivery vehicle. They include avoiding premature degradation in the body, overcoming poor peptide transport over epithelial barriers, limiting variability of absorption (caused, for example, by interaction with food in the stomach), and producing both peptide and the delivery vehicle in sufficient scale and numbers cost-effectively. The initial term of the collaboration is three years with the option to extend for up to three additional years.

In 2015, Rani Therapeutics, a San Jose, California-based company developing an oral biotherapeutics drug-delivery platform, partnered with Novartis to begin feasibility studies to evaluate how select Novartis’ proprietary biologics can be delivered into the bloodstream using Rani’s oral route of administration. After successful completion of the feasibility studies, which will be conducted by Rani Therapeutics over the next 18-24 months, Novartis will have the right to enter into a more extensive collaboration with Rani and/or license Rani’s technology for specific fields of use. Rani was founded in 2012 and spun out of InCube Labs.

Electroporation-mediated DNA drug delivery is another area of research for biologics. Earlier this year, Ichor Medical Systems, a San Diego, California-based company, formed a product development collaboration and worldwide license agreement with Janssen Pharmaceuticals, Inc., part of Johnson & Johnson, for developing and commercializing DNA-based vaccine products for treating chronic hepatitis B using Ichor's TriGrid electroporation technology for clinical administration. Electroporation is a delivery method that uses brief electrical pulses to transiently alter cell membranes, facilitating entry of DNA into cells. Ichor's patented TriGrid Delivery System is currently being tested in clinical trials.