Engineering biopharmaceutical formulations to improve diabetes management

Abstract

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.

Fig. 1.. Metabolism and current delivery challenges.

(A) In patients without diabetes, insulin, amylin and glucagon are secreted from the endocrine pancreas and work in tandem to maintain glucose homeostasis. Insulin and amylin work synergistically, where insulin promotes glucose uptake by cells and amylin slows gastric emptying and increases satiety. Glucagon, responsible for promoting glucose mobilization through glycogenolysis, is suppressed at mealtimes through paracrine signaling. (B) In patients with type 1 diabetes, subcutaneous delivery of insulin analogues (e.g., lispro, aspart, glulisine) can restore glucose uptake at mealtimes, but in the absence of replacement of amylin or its analogues (e.g., pramlintide) the effects of slowed gastric emptying and post-prandial glucagon suppression are lost – exacerbating prandial glucose excursions. (C) Therapies to deliver insulin, amylin analogues (pramlintide) and glucagon exist, but ideal use is highly burdensome, and the high costs preclude their use for many patients. Current drug delivery challenges include protein instability, burdensome treatment administration, and pharmacokinetics that do not sufficiently mimic endogenous hormone secretion to allow for optimal glucose control.

Fig. 2.. Formulation excipients, insulin aggregation, and stabilization techniques.

(A) Aggregation of biopharmaceuticals such as insulin typically occurs as a result of protein-protein interactions at a hydrophobic interface (e.g., the air-water or vial-water interfaces) that nucleate aggregation events. (B) Excipients, such as tonicity modifiers, antimicrobial preservatives, and stabilizing agents can affect insulin association state and are carefully chosen to balance stability in the vial and absorption upon subcutaneous administration. (C) Ultrafast acting insulins aim to shift the equilibrium of insulin association states from the insulin hexamer towards the insulin monomer to promote more rapid absorption and commensurate onset of action, as well as to reduce the duration of action. New excipient platforms look at displacing insulin from the air-water and vial-water interfaces using amphiphilic copolymers to prevent protein-protein aggregation. (D) Judicious design of polyacrylamide-based copolymer excipients can generate an ultrafast absorbing lispro (UFAL) formulation comprising mostly monomeric insulin that is significantly more stable even than current commercial fast-acting insulin formulations (e.g., Humalog). (E) Pharmacokinetic exposure curve and time to peak exposure for this UFAL formulation in diabetic pigs indicates a 2.8-fold decrease in the time-to-peak when compared to Humalog. (F) Simultaneous non-covalent PEGylation of insulin and pramlintide using cucurbit[7]uril-poly(ethylene glycol) (CB[7]-PEG) provides a protective “wrapper” on each protein that allows for stable co-formulation of the two historically incompatible therapeutics at pH=7. (G) Supramolecular PEGylation with CB[7]-PEG enables insulin-pramlintide co-formulations to be more stable to stressed aging than even commercial Humalog. (H) Pharmacokinetic curves for a CB[7]-PEG stabilized insulin-pramlintide co-formulation in diabetic pigs demonstrating increased overlap of insulin and pramlintide action compared to the current clinical approach of separate administrations. Adapted from (24, 38).

Fig. 3.. Sustained insulin delivery strategies.

Long-acting insulin analogues aim to mimic physiological basal insulin secretion and control blood glucose concentrations during fasting periods. Long-acting insulin analogues, such as insulin glargine, detemir, and degludec, are absorbed more slowly with an onset effect in 1.5–2 hours that plateaus and remains relatively flat for the entire duration of action. (A) Supramolecular PEGylation of insulin with CB[7]-PEG demonstrates an opportunity for both rapid initial insulin response and tunable duration of action in diabetic mice by changing the length of the PEG chain attached to the CB[7]-PEG excipient. (B) A glucose-responsive insulin with a phenylboronic acid (PBA) pendant group on an aliphatic chain allows for both prolonged circulation in the blood and rapid response to glucose changes in diabetic mice. (C) Basal insulin PEGLispro (BIL) is a long-acting insulin analogue where insulin lispro is covalently modified on the B28 lysine with a 20‐kDa PEG chain, increasing the hydrodynamic radius of the insulin that results in a hepato-preferential insulin biodistribution with flat pharmacokinetic and pharmacodynamic profiles in human patients. Adapted from (25, 62, 69).

Fig. 4.. Design challenges for alternative dosage forms.

Alternatives to insulin injections have the potential to reduce patient burden and increase patient compliance. Oral and transdermal insulin delivery systems are in the early stages of development. but there are currently no clinically approved treatments available. These technologies transport peptides like insulin and glucagon past barriers that typically block the absorption of biologics. To this end, two main strategies are being pursued: increased permeability to facilitate absorption and penetration of a tissue barrier. (A) Anionic nanoparticles (NP) are used as a formulation excipient to decrease tight junctions and increase permeability to allow insulin absorption in the small intestine (data shown in mice). (B) Self-orienting millimeter-scale applicator (SOMA) is a pill that can be swallowed and then activates in the stomach (a spring is released after a sugar disc dissoves) to inject an insulin millipost past the stomach mucosal lining, where the insulin can be absorbed into systemic circulation (data shown in pigs). S.C., subcutaneous. (C) Choline and geranate (CAGE) ionic liquids facilitate transdermal delivery by enhancing insulin permeability through the stratum corneum and into the dermis (data shown in rats). (D) Glucose-responsive microneedles penetrate the stratum corneum and allow for insulin release into the dermis in response to hyperglycemia (data shown in pigs). Blue arrows indicate meals. An oral or transdermal insulin would present a major advance in reducing the number of required injections. Current intermediate kinetics observed in (A, B and D) preclinical animal studies may suggest that oral and transdermal insulin may be best suited for prolonged basal insulin delivery or for use in helping to manage type 2 diabetes. Clinical pharmacokinetic and pharmacodynamic data in humans will be necessary to understand the true translational potential of these formulations for diabetes management. Figures are adapted from (, , –93).