Several key developments are set to shape and transform the advanced drug delivery arena in the coming years. Understanding and acting on them now is crucial for drug formulators to continue to thrive in a competitive global market.

The rise of patient compliance
Much of the innovation in the pharmaceutical sector is driven by the goal of improving patient compliance. Poor patient compliance is a serious issue, having negative implications not just for the patient’s health, but for the greater pharmaceutical industry. Non-adherence to medication is estimated to cost U.S. drug manufacturers over $250 billion annually, and global drug companies over $637 billion annually.¹

The rate of non-compliance has not changed appreciably in the last 25 years,¹ and there is concern that it will increase in the coming decades. This is due to the growing prevalence of chronic conditions in the global population, such as cancer, eye diseases, heart disease, and diabetes. Some 60% of U.S. adults already have one chronic disease and 40% have two or more²—these figures are set to grow as the population ages.³

Cancer and eye diseases represent a large and growing portion of the clinical pipeline. The number of treatments for these conditions have doubled since 2015.⁴ Drug formulators focusing on these therapeutic areas will need to pay careful attention to the patient experience for their treatments to optimize adherence. Reducing dosage frequency and enhancing ease-of-administration are crucial to delivering the best possible experience for the patient, encouraging them to comply with their treatment regimen.

Biosimilars on the rise
The growth of biosimilars is forcing pharmaceutical companies to either innovate or reduce prices to compete. This is driving innovation in the biologics space.

In 2020, there were 28 biosimilars approved by the U.S. Food & Drug Administration (FDA). Much of this growth came in 2019, when there was a 65% increase in the number of approved biosimilars, and a 157% increase in the number of such products available in the U.S.⁵

As evidenced by the adoption of biosimilars in Europe over the last 13 years, manufacturers, payers and providers in the U.S. expect biosimilar competition will lead to consistent price reduction.⁶ As the number of treatment choices increases for a particular disease or condition, manufacturers will be incentivized to lower the prices of their products or find ways to differentiate products to remain competitive.⁷

Further driving innovation in the segment, global regulatory bodies are encouraging the development of biosimilars to increase competition in the market. The 2019 FDA Biosimilars Action Plan in the U.S. provided mechanisms that favored generic biologics with the goal of reducing time, cost, and uncertainty in drug development. The intent of this was to promote a more virtuous cycle of market-based innovation and competition.⁸

The future of drug delivery techniques to improve patient compliance
Pharmaceutical companies, contract development and manufacturing organizations (CDMOs), and medical device innovators are working together to address patient compliance challenges through long-acting dosage forms and enhanced dosing techniques for biologics.

The evolution of long-acting products
Long-acting drug products have been on the market for decades, and over the years they have diversified into long-acting injectables (LAIs), intravaginal rings (IVRs), as well as implantable dosage forms. However, there is recently renewed interest in long-acting products to address patient compliance in new routes of administration and overcome dosing challenges for biologics.

The goal of these products is to reduce dosing frequency, replacing inconvenient daily or weekly pills or injections, where doses could easily be missed by patients. To achieve this reduced dosing frequency, many such long-acting dosage forms rely on controlled drug release from polymeric systems, such as ethylene-vinyl acetate (EVA), silicone, thermoplastic polyurethane (TPU) or poly(lactic-co-glycolic acid) (PLGA).

Innovation in this space has traditionally been centered on increasing the duration of action. With extended dosing timeframes, it is possible to reduce dosing frequency to weeks, months, or even years at a time. This remains an important area of innovation in 2021 and beyond for both small molecules and peptides. The influx of long-acting ophthalmic programs from pre-clinical through commercial stage—such as Genentech’s Port Delivery System for wet AMD treatment—is a sign of the continued interest in long-acting development.

Another example is Janssen’s Invega LAI product line, which consists of injectable nanosuspensions developed to treat schizophrenia. Reformulation every six years has significantly improved not just drug performance, but the duration of therapeutic action too. When the first product in this line, Invega Sustenna, was launched in 2009, it was approved for a one-month injection. The latest product, Invega Hafyera, was approved in 2021 for a six-month injection, reducing the number of annual doses from twelve to just two.

Innovation to deliver LAI and implantable biologics solutions
Now that the long-acting space has matured, innovators have set their sights on incorporating new active pharmaceutical ingredients (APIs) into LAIs and implantables, such as biologics. Biologic molecules have traditionally posed a challenge for long-acting drug development, due to compatibility issues with the polymers used in long-acting formulations, processing techniques, and the solvents used in product development.

For example, the acidic microenvironment and rigid microstructure of common bioresorbable polymers may hinder biologic diffusion or degrade sensitive biologic molecules, as do solvents used to produce microspheres for injection. Extrusion techniques used to manufacture implants, meanwhile, expose the API to elevated temperatures and shear forces that may also break down drugs such as proteins.

Several potential solutions to these challenges are being considered. Many companies are exploring improvements in polymers as a starting point.

For example, researchers are investigating modified bioresorbable chemistries that are compatible with biologics, often incorporating hydrophilic components. Lipid-based depot systems that protect the API and offer controlled release offer another avenue to biologic compatibility. The general public was exposed to lipid technology through the COVID-19 vaccine development program, but researchers have been exploring lipids as controlled release excipients and solubility enhancers for many years.

Companies are also considering new and improved manufacturing techniques. These include novel approaches to produce microspheres or suspension-based depot injections, which have the potential to improve efficiency and reduce shear force to protect sensitive large-molecule APIs. Changes in solvent systems to avoid degradation are also being explored. 

Other dosing challenges facing biologic developers
The creation of effective long-acting formulations is not the only tactic to optimize patient convenience and compliance. Improving the dosing experience is another promising mechanism of achieving higher patient compliance.

Traditionally, biologics have been administered via weekly injections or monthly infusions. In the case of infusions, dosing can take anywhere from 10 minutes to several hours. This is costly and inefficient for patients, who must visit a hospital or outpatient center regularly for treatment. Due to their complex nature and instability, biologics cannot be delivered via the oral route today. They are also often formulated as highly viscous liquids, which can be challenging to both fill into injector systems (as an alternative to hospital infusions) and to administer from those devices.

However, there are changes on the horizon that are set to transform this segment and significantly improve patient convenience, with positive consequences for patient compliance.

Shifts to treatment in the home
We are seeing growing interest in shifting away from infusions towards injector devices. Several companies are developing wearable injector devices that have the potential to enable at-home administration of biologics. This shift is driving innovation in biologics formulation, particularly for those drug products that traditionally require multi-hour infusions. Researchers are investigating ways to expand dosing options for these drugs to make them compatible with novel injector devices.

For example, Halozyme’s recently developed Enhanze technology enables the reformulation of biologics formulations away from intravenous infusion towards subcutaneous injection. This reduces administration times from several hours down to just several minutes.

Other technologies are also being developed to improve the stability of biologics and to reduce the viscosity of highly concentrated formulations. This will hopefully extend shelf lives and enable more administration options for biologics in the future.

With these advances in injector devices, access to sterile fill/finish services is vital. As such, many medical device companies and their partners are turning to pharmaceutical CDMOs, such as LLS Health, for support in aseptic filling, as well as in device design and formulation development. This need for sterile processing will drive increased collaboration between pharmaceutical and medical device companies in the coming years.

Finally, several drug delivery companies are investigating oral and transdermal delivery of biologics, which have the potential to significantly improve patient convenience. This is a goal that has evaded drug developers for decades. However, researchers are employing novel excipients and dosage forms to try and solve the challenges. Mucoadhesive technologies, for example, are being explored in this area. These have long been used for small molecules but are being increasingly applied to biologics in order to maximize the absorption and bioavailability of the actives.

A market in flux
The drive to overcome patient compliance issues is becoming ever more pressing for drug manufacturers, both for small and large molecule APIs. As chronic conditions continue to rise in prevalence, advanced drug delivery offers a means to offset the costs of poor medication adherence and greatly improve the patient experience.

It is no surprise, then, that there has been so much recent innovation in the fields of long-acting formulation and medical device development aimed at improving patient compliance.

For this innovation to succeed, manufacturers need expert support. By working with CDMOs with expertise in long-acting drug products and the development of injectable or ophthalmic combination products, manufacturers can be confident they have the expertise and resources they need to enhance the convenience and usability of their drug products. As a result, they can differentiate from competition and minimize the risk of patient non-adherence in the future. 

References

1. HealthPrize, 2016
2. National Center for Chronic Disease Prevention and Health Promotion, CDC
3. https://www.americanactionforum.org/research/chronic-disease-in-the-united-states-a-worsening-health-and-economic-crisis/
4. 2020 Drug Delivery and Formulation Report, PharmaCircle
5. Amgen 2020 Biosimilar Trends Report
6. https://www.nejm.org/doi/full/10.1056/NEJMp1714908
7. https://www.healio.com/news/endocrinology/20150317/j500_1303_01_news_print_4
8. https://www.prnewswire.com/news-releases/remarks-from-fda-commissioner-scott-gottlieb-md-as-prepared-for-delivery-at-the-brookings-institution-on-the-release-of-the-fdas-biosimilars-action-plan-300683127.html

---

Nick DiFranco,  MEM, Market Manager – Long-Acting Drug Delivery and Combination Products, Lubrizol Life Science Health