Engineering biopharmaceutical formulations to improve diabetes management

Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic agents and complexity of maintaining multiple infusions. In this review, we highlight the advantages and limitations of recent advances in drug formulation that improve protein stability and pharmacokinetics, prolong drug delivery, or enable alternative dosage forms for the management of diabetes. With controlled delivery, these formulations could improve closed-loop glycemic control.

Engineering biopharmaceutical formulations to improve diabetes management
BY CAITLIN L. MAIKAWA, ANDREA I. D’AQUINO, RAYHAN A. LAL, BRUCE A. BUCKINGHAM, ERIC A. APPEL
SCIENCE TRANSLATIONAL MEDICINE27 JAN 2021
This Review provides an overview of developments in formulation engineering and delivery strategies of insulin for the treatment of diabetes as well as the following outlook:

FUTURE DRUG DELIVERY OPPORTUNITIES IN DIABETES MANAGEMENT
In normal physiology, insulin is released into the portal circulation along with carefully titrated quantities of amylin and glucagon. Current state-of-the-art commercial closed-loop technology uses interstitial glucose sensing and slow subcutaneous insulin delivery tied together with control strategies originally intended for industrial processes. Without technological breakthroughs, it is unlikely that these commercial systems can match the innate biological control systems that have been finely tuned by billions of years of evolution. Multiple converging technologies are required to overcome the limits of the insulin-only approach to glucose control for management of diabetes.

Computational approaches to automated insulin delivery can refine current systems, but they rely on outside information or assumptions about individual behaviors. Formulation and excipient design to develop insulin that reduces blood sugar instantaneously without residual hypoglycemic effect would allow for the simplest of control strategies. Combination therapies with amylin to slow and reduce glycemic excursions or glucagon to allow hypoglycemia rescue are possible but currently cumbersome given the need for separate wearable and coordinated devices. Co-formulations can overcome this weakness. Existing formulations and technologies, when used optimally, allow sufficient glycemic control to avoid more prominent microvascular complications.

Unfortunately, these tools and their optimal use are a luxury afford- ed primarily to the socioeconomically privileged and those engaged in disease management (i.e., clinicians and diabetes technology developers). Using advances in formulation engineering and drug delivery technology to develop accessible and easy-to-use formulations and delivery platforms for diabetes management would improve outcomes and reduce burden for many patients. The development of glucose-responsive delivery strategies with increased safety profiles could be an attractive alternative to closed-loop control. Moreover, mealtime alternative dosage forms, like an oral insulin suited for prandial glucose coverage, could reduce patient burden and improve patient compliance. By fostering accessible technologies that allow for insulin delivery that more closely mimics endogenous delivery, people with diabetes could live safe from complications with much reduced effort.