What is the Future of Noninvasive Routes for protein- and peptide-based drugs?

Keywords:

• biotechnology
• iontophoresis
• microneedle
• noninvasive
• peptides
• proteins

Peptide and protein therapeutics have come a long way from the approval of recombinant human insulin by the US FDA in 1982, to drugs such as Humira^®, Enbrel^®, Remicade^® and Neulasta^®, which are the top-selling drugs in the world right now. Advances in biotechnology has resulted in a range of therapies called biologics, which consist of vaccines, cell or gene therapies, therapeutic protein hormones, cytokines, tissue growth factors and monoclonal antibodies. Based on worldwide sales in 2012, eight out of twenty bestsellers drugs were protein-based drugs [1–3]. In future, most of the new chemical entities would be protein-based or at least the gap between new drug approvals of protein-based medications and small-molecule drugs will become close.

Protein and peptides drugs have become irreplaceable due to their various therapeutic uses but their widespread application is restricted due to chemical and physical instabilities, enzymatic degradation and rapid elimination from circulation. From a drug delivery perspective, their highly charged, large size and hydrophilic nature makes them poor candidates for traversing biological barriers. Administration of peptide and proteins via injection has helped in solving some of these obstacles. However, due to the short half-life of most peptides and proteins, repeated dosing results in an oscillating concentration of the drug in the blood, in addition to the high costs and painfulness associated with the repeated therapy [4,5].

Due to the inefficiencies associated with parenteral delivery systems, a number of other routes such as oral, transdermal, pulmonary, nasal and buccal delivery routes have been explored as promising needle-free alternatives to injections. The biggest challenge for noninvasive delivery of proteins is the low bioavailability as compared with parenteral route. Still, lot of interesting work is going on to make these delivery systems more amenable for protein delivery. These routes come with the advantages of avoiding first-pass effect, patient friendliness, reduced frequency and painless administration. The recent developments in the area of noninvasive delivery of protein-based drugs will be summarized in this paper.

Oral route is the most preferred route for drug delivery. A lot of additives such as enzyme inhibitors, permeation enhancers and polymeric carriers are required for oral delivery of proteins. Peptides being smaller are better suited to oral routes than proteins. Various researchers are working with modulators to change the tight junctions of cell layers to increase the paracellular transport of these hydrophilic peptides and proteins. The risk here is the question of reversibility of opening of tight junctions, as once opened these tight junctions become permeable to other toxins and undesirable molecules too. In addition to permeability enhancers, mucoadhesion, nanoscale carriers and liposomes are also being evaluated as approaches to increase the delivery of these macromolecules. A successful oral protein formulation in the future can also utilize the smart polymeric nanoparticles which can protect and target the proteins to the specific site and release when required [6,7].

The development of a successful oral delivery could lead to better patient acceptability, and use of the revolutionizing proteins and peptide drugs will help in better disease management. Currently, two candidates, IFN-α and human growth hormone are in advanced stages of clinical evaluation employing oral route of drug delivery [8].

There is a lot of research already done in the transdermal field in the delivery of peptides, even though delivery through the skin of these large bulky molecules would be considered as one of the least sort after routes. One of the biggest reasons for transdermal route being a promising route for delivery of protein-based drugs is the ready access of the skin to compromise or breach the stratum corneum barrier. Due to this reason, various techniques such as iontophoresis, electroporation, microneedles and sonophoresis have been explored to facilitate permeation of macromolecules through the skin. Other passive techniques have been studied for protein delivery, such as a study by Magnusson et al. employing use of ethanol as an enhancer to increase the flux of a peptide [9]. The peptide in question, however, was a smaller thyrotropin releasing analog hormone with a molecular weight <400 Da, which would be considered a dwarf as compared with insulin (MW ~5800 Da), which is the most studied drug for transdermal delivery. Other techniques such as derivatization of peptides into lipophilic diastereomers have also been explored, but derivatization would not ideally be recommended for large peptides that rely on spatial conformation for their activity [10]. Hence, the more active techniques mentioned above such as microneedles and iontophoresis seem to be more attractive for getting macromolecules through the skin. The applications of micorneedles in vaccination have been taken to greater leaps by collaboration between Georgia Institute of Technology and Emory Institute for the PATH foundation for affording needleless vaccination to the masses [11]. One of their biggest challenges would be to keep both the complementary properties–painlessness and penetrability at an even keel. In spite of the attempts in academic research on these techniques and proteins, their success in the clinical setting has been limited. Cost and regulatory hurdles make widespread use of these techniques debatable. The microneedle technology seems to have come furthest in being successful in delivering protein-based drug. In a Phase II trial by Radius Health, Inc., abaloparatide-TD, a microneedle delivery system for the parathyroid hormone-related protein was shown to have positive effects on the bone mineral density levels of patients. The preliminary studies have shown this application to be at par with their abaloparatide-SC, a subcutaneously delivered version that is in Phase III of clinical trials [12]. A Phase II clinical trial by Corium International, Inc. has also shown positive results in osteoporosis using a similar microneedle technology (MicroCorR PTH) delivering teriparatide (human parathyroid hormone) [13].

Iontophoresis in comparison is comparatively less invasive; however, the cost of the technology and the electrochemical stability of proteins in the delivery environment will have to be modulated to ensure wider applications. Nonetheless, studies such as that conducted by Pillai et al. on iontophoresis of insulin, was a very informative lead into the iontophoretic parameters such as current strengths, duration and on/off ratios, that would ensure maximal penetration and minimal degradation of a protein drug [14].

However, a delivery route that has gained further grounds in its applicability than the transdermal route for protein delivery is the pulmonary route. The lungs offer a large surface area (140 cm²) for absorption along with a relatively thin epithelium. Pulmonary delivery of insulin has been already commercialized with Exubera^® which was the brain child of collaboration between Pfizer and Nektar pharmaceuticals. However, the innovators failed to reap gains from this technology due to its premature exit from the market. Reasons for the failure of the product were attributed to its bulky delivery system and cost-ineffectiveness. Nonetheless, this did not stop Sanofi from launching another inhalable product Afrezza^® in 2014, which similar to its predecessor did not show much success in the market. This was attributed to the requirement of pretesting the patients on a spirometer (an uncommon physicians equipment), which reduced the exposure of the product in the market significantly [15].

Nasal route is technically less challenging than pulmonary delivery and comes with added advantages of quick drug absorption, seamless administration and bypassing first-pass metabolism. Various macromolecules such as thyrotropin-releasing hormone, luteinizing-hormone-releasing hormone (LHRH), vasopressin, calcitonin, oxytoxcin have shown to be delivered across nasal route. Among these, LHRH nasal formulation Kryptocur^® and Calcitonin-Salmon nasal spray Miacalcin^® have been approved by FDA and have already reached the market [16,17]. Other routes such as vaginal, buccal and ocular are in their nascent stages. The research studies have been limited to academic research and have not gained much ground in the clinical field.

Conclusion

Extensive research is ongoing in both academia and industry to explore other noninvasive routes but alternative routes of drug delivery arena have failed to keep up the pace with the discovery of protein-based drugs.

For example, a number of studies have been published delivering insulin via different noninvasive routes and most of them have not been successful clinically. Insulin as a model therapeutic protein needs to be delivered in accurate levels, fast enough and in reproducible manner to control the glucose level of the patient in the blood. The subcutaneous route has proven itself to be a safe and efficient delivery technique for insulin owing to the vast database of trials and successful therapy. Therefore, the key for success of insulin delivery, and for that matter any other protein delivery via any alternative route is to quickly move from preclinical to clinical stages to generate confidence in both clinicians and patients by generating long-term safety and efficacy data. Moreover, the major strategy for making a successful noninvasive delivery system should not only be able to deliver the peptides/proteins via that route but the clinical need, bioavailability, variability, reproducibility, scalability and regulatory approval of the product should also be considered.

There is a need for mutual understanding and concurrence between regulatory agencies and industry to come up with a development pathway and guidance for some of these novel delivery systems such as transdermal microneedles. There is a lack of clear understanding as many of these novel systems are unique drug delivery or drug–device combinations. Also, there is a lack of long-term safety and compliance data for these systems which makes the regulatory approval challenging and complex.

Although there are many problems and challenges in all the noninvasive routes that have to be overcome, but all these routes present immense potential in near future. We are hopeful that in future we will see these routes supplement the parenteral route to deliver protein and peptides.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.