Increased drug product complexity, the rise of biopharmaceuticals, novel therapeutic technologies, bioavailability challenges and the demand for the demonstration of strong drug performance are all factors driving unprecedented drug-delivery technology innovation. In addition, cost pressures in the healthcare system and patients’ busy schedules are requiring increasing levels of self-administration.
These demands call for advanced drug-delivery technologies that improve drug efficacy and safety by controlling the time, rate and place of drug release in the body. In addition, pharmaceutical companies are seeking to improve patient compliance, extend patent protection and achieve competitive differentiation.
Reinforcing the importance of advancing drug-delivery technologies, in the United States alone, more than 50 percent of prescribed medications are taken incorrectly or not at all. It is sobering that the incorrect use of medications has been linked to up to 125,000 deaths annually, and the IMS Institute for Healthcare Informatics reported that more than $200 billion might be saved each year by increasing patient adherence.
This report explores some of the fascinating advancements in drug-delivery technologies, including oral dosage form innovation, biopharmaceutical drug delivery, smart drugs and targeted drug release.
ORAL DOSAGE FORM INNOVATION
Oral drug delivery remains patients’ preferred method of drug delivery. Compared to injectables, oral dosage forms are much easier and more comfortable for patients to self-administer. This ease and comfort increases patients’ adherence levels. Additionally, solid dosage forms are often less expensive to manufacture.
However, many pharmacology advancements in recent decades have been large-molecule drugs or other complex therapeutics that are extremely difficult to manufacture in solid dosage forms. Even many small-molecule drugs are difficult to deliver effectively. As a result, approximately 70 percent of molecules exhibit poor solubility, which could limit bioavailability.
One new oral dose approach is dropwise additive manufacturing of pharmaceutical products (DAMPP) as an alternative to conventional pharmaceutical manufacturing methods for oral solid dosage products. This technology uses drop-on-demand printing technology for the automated and controlled deposition of solution-, melt- or suspension-based formulations onto edible substrates. The advantages of drop-on-demand technology include the highly reproducible production of small droplets, adjustable drop sizing, high placement accuracy and flexible adaptability for different formulations. These features enable the production of individualized dosing - even for low-dose and high-potency drugs - and suggest a promising manufacturing technology as personalized medicines continue to advance.
Another exciting and promising oral delivery technology is being achieved by molecular farming. Molecular farming is the use of plants for the production of scalable and safe, high-value recombinant proteins for use in pharmaceuticals. Several approaches are being explored utilizing proteins produced by molecular farming. However, one of the most promising approaches is the use of edible plant organs that express biopharmaceuticals for direct oral delivery. This technology holds the promise of eliminating many costly aspects of biopharmaceutical production, including expensive processing, purification, cold chain storage and transportation costs.
TRENDS IN BIOPHARMA DRUG DELIVERY
While nearly all biopharmaceuticals to date have been injectables, much progress is being made in the development of drug delivery that is less invasive and easier to self-administer. New biopharmaceutical drug-delivery formats in active development include oral, inhaled and micro-needle administered dosage forms.
As with chemically synthesized small-molecule drugs, the oral delivery of biopharmaceuticals is generally viewed as the most desired route of administration. There are, however, many obstacles to delivering biologics by non-injection methods, often because of temperature and other sensitivities of proteins. Delivery methods including lipid-based formulations within softgels and next-generation orally disintegrating tablet (ODT) formulations, as well as inhaled, transdermal and ocular delivery, are showing promise.
Advanced particle engineering is facilitating the oral delivery of biologics to the lungs. For example, in 2014, the FDA approved Afrezza, an inhaled form of insulin that catapulted inhalation devices to the front and center of drug-delivery innovation.
While the non-injectable delivery of biologics is actively being pursued, many biologics, for the near future, simply must be injected. The need to reduce healthcare costs and patients’ busy schedules dictate that self-administration will rise as the use of biologics increases. Packaging and delivery solutions, including prefilled syringe systems, wearable pumps, auto-injectors and wearable patch injectors, are helping to solve some of the administration constraints that have inhibited the use of biologics in the past.
Oral delivery of biopharmaceuticals remains a very sought-after goal. Novo Nordisk, in pursuit of advancing the effort, formed a research collaboration with Professor Robert Langer’s laboratory at MIT to develop drug-delivery devices for the oral delivery of peptides. The goal of this work is to overcome challenges in developing and manufacturing peptide delivery vehicles that meet both efficacy and reliability objectives. Among the many challenges that need to be overcome are premature degradation in the body, poor peptide transport over epithelial barriers and variability of absorption. In addition to these drug performance considerations, technologies that facilitate manufacturing cost-effectively and at the needed scale are leading challenges.
Electroporation-mediated DNA drug delivery is yet another area of innovative biopharmaceutical delivery currently in clinical trials. Electroporation is a delivery method that uses brief electrical pulses to transiently alter cell membranes, facilitating the entry of DNA into cells that would otherwise be difficult to permeate.
TARGETED DRUG RELEASE
Targeted drug release technologies have made strides, particularly in oncology, in recent years. As one example, the field of peptide-based drug conjugates (PDCs) is advancing rapidly. While no PDCs have obtained regulatory approval, the goal of targeting specific cell surface receptors through structural compatibility has encouraged the use of peptides as highly specific carriers and is proving promising in bypassing non-target cells, reducing the side effects common to traditional chemotherapy.
In addition, tethering active product ingredient (API) to nano- or microparticles to deliver drugs to affected cells while avoiding healthy cells shows promise for oncology as well as other therapeutic areas. Nanoparticle technology is being used in both passive and active targeting of diseased tissue. Passive targeting utilizes the enhanced permeability and retention (EPR) effect, a physiological characteristic of tumor vessels that leads to the accumulation of nano- and microparticles within the tumor. In contrast, active targeting relies on the conjugation of nanoparticle surfaces by targeting species such as antibodies, aptamers, peptides or others. This gives nanoparticles loaded with APIs the ability to recognize and bind to the diseased sites.
Drug targeting technologies are also offering improved lung delivery for lung-specific diseases, gut-specific delivery where delivery of a compound to a specific area of the gut is needed for optimal absorption, and many other target delivery advancements.
SMART TECHNOLOGIES FURTHER INNOVATION
The combination of smart drug-delivery devices, pharmaceuticals and mobile technology is in fairly early stages but is rapidly advancing. A study conducted by the IMS Institute for Healthcare Informatics estimates that more than 165,000 mobile health applications are now available to consumers as developers incorporate data collection features linked to sensors and wearables. While many of the apps focus on fitness and overall wellness, approximately two-thirds of the applications were expressly designed to facilitate disease and medical treatment. Additionally, the disease management portion of the application market is expected to continue to grow quickly.
An example is the partnership of West Pharmaceutical Services, an injectable drug-delivery solution provider, with HealthPrize, a provider of digital technologies. 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 a connected health solution for healthcare providers, patients and pharmaceutical companies. The system will track when patients take their medication, striving to increase patient compliance and to proactively identify scenarios that might indicate that a patient is experiencing challenges.
Yet another example of connected drug device technology is the collaboration of Teva Pharmaceutical and Microchips Biotech. Microchips Biotech is a manufacturer of microchip-based implants for drug delivery. The partnership allowed Teva to apply implantable drug-delivery devices to Teva’s portfolio of products to improve clinical outcomes for patients on chronic drug therapies. Microchips Biotech’s devices can store drug doses for periods ranging from months to years. In addition, the devices will have wireless control features and can be programmed to release specific drug dosages on a pre-determined schedule.
The collaboration of Otsuka Pharmaceutical and Proteus Digital Health produced Abilify (aripiprazole), a drug to treat schizophrenia, bipolar disorder and depression. While experiencing setbacks within the FDA, the promise remains quite exciting. An ingestible sensor provided by Proteus is embedded in the drug tablet manufactured by Otsuka. The sensor within the tablet communicates with a wearable sensor patch and a medical software application to monitor patient compliance. The smart drug-device product notifies healthcare professionals about patient adherence and other patient metrics.
REGULATORY FUTURE
The need for drug-delivery innovation will not slow. In fact, as new medical and pharmaceutical science discoveries are made, the need for inventive drug delivery will only escalate. One concern in the industry is the ability of the FDA to effectively review and approve drug applications that use innovative drug-delivery technologies. However, it is hoped that the Combination Products Policy Council (CPPC) and other initiatives by the FDA to pool needed expertise on new drug products utilizing different technologies will be sufficient.
Adapting the regulatory structure through moves like the creation of the CPPC will be one of the most important factors in advancing drug-delivery technology as disciplines such as small-molecule formulations, biologics, medical devices, electronics, computer programming and packaging are married to create these new products.
ABOUT THE AUTHOR
Joseph Marks is the Director of CPhI North America and has been working diligently with his U.S. team and his counterparts in Europe to launch the latest edition to the CPhI family – CPhI North America. CPhI North America will take place May 16 -18, 2017, at the Pennsylvania Convention Center in Philadelphia, PA. For more information, visit www.cphinorthamerica.com.
REFERENCES
“Drug Delivery Quantified Through Nanoparticles Inside a Cell,” Science Daily, Oct. 3, 2016
“Trends in Drug-Delivery Devices,” Nancy Crotti, MDDI, Aug.3, 2015
“Dropwise Additive Manufacturing of Pharmaceutical Products for Solvent-Based Dosage Forms,” Laura Hirshfield, Arun Giridhar, Lynne S. Taylor, Michael T. Harris, Gintaras V. Reklaitis, Journal of Pharmaceutical Sciences, February 2014
“Patient-Centric Innovation: The Next Era in Drug De-livery,” Patricia Van Arnum, DCAT Connect, Jan. 5, 2016
“New Drug-Delivery Methods: From Concept to Patient,” Cynthia A. Challener, BioPharm International, Oct.1, 2016
“Study Identifies $200+ Billion Annual Opportunity from Using Medicines More Responsibly,” IMS Institute for Healthcare Informatics, Press Release, June 19, 2013
