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A Step Closer to Orally-Delivered Insulin for Diabetes

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Diabetes is a metabolic disease that results in an increase in blood sugar also known as hyperglycemia. The prevalence of this disease continues to increase, with the World Health Organization (WHO) stating a rise from 108 million affected in 1980 to 422 million in 2014, highlighting the importance and significance of treatment. Combined with changes in lifestyle, insulin therapy continues to play a vital role in controlling and regulating blood glucose levels, with injection being the primary means of delivering the hormone. However, this administration route is much more invasive compared with oral drug delivery, meaning those diabetes patients with a fear of needles and/or self-injection, may be unwilling to begin insulin therapy.

Technology Networks
recently had the pleasure of speaking with two authors of a Chemical Science paper, Farah Benyettou and Ali Trabolsi to learn more about the advantages of delivering insulin orally. Benyettou and Trabolsi elaborate on the intricacies of the imine-linked-covalent organic framework (nCOF) nanoparticles they are developing and discuss how this approach can help to overcome key barriers associated with the oral administration of the drug.

Q: What are some of the challenges associated with delivering insulin subcutaneously via injection?

Coupled with lifestyle changes, insulin therapy remains a key element in controlling and regulating blood glucose levels of diabetic patients. The primary mechanism to do so is insulin injection. However, studies have shown delays in onset of insulin therapy in a large proportion of people with uncontrolled diabetes, and in those who do eventually undertake treatment; there is a delay of more than two years from first administration.

Reasons why people are unwilling to start insulin therapy can include a fear of needles and self-injection, as well as pain and anxiety. Insulin pens alleviate some of these conditions, as well as overcome dosage issues that exist with vials and syringes; however, this method is not error-free.

Q: What are the key advantages to oral delivery of drugs, more specifically, can you elaborate on the oral bioavailability of insulin?

Orally-delivered insulin is capable of reaching the systemic circulation after passing through the liver, similar to physiological insulin secretion, while subcutaneously injected insulin may result in peripheral hyperinsulinemia and associated complications.

A shift towards oral delivery of insulin has the potential to improve the uptake of insulin therapy and revolutionize diabetes care, since it is a non-invasive therapeutic approach that does not cause the side effects caused by frequent subcutaneous injection.

However, oral drug delivery faces numerous challenges including dissolution, bioavailability, solubility and its stability in the gastrointestinal (GI) tract. The oral bioavailability of insulin is severely hampered by its inherent instability in the GI tract and its low permeability across biological membranes in the intestine (less than 1%). Despite clinical trials of several oral insulin formulations, sufficient commercial development has not been yet achieved.

By using prepared layers of nanosheets with insulin loaded in between each layer, it is possible to protect it. Using this technique, researchers have now developed gastro-resistant imine-linked-covalent organic framework nanoparticles (nCOFs) that exhibit insulin protection in the stomach as well in diabetic test subjects, whose sugar levels completely returned to normal within two hours after swallowing the nanoparticles.

Q: Why has sufficient commercial development of an oral insulin formulation not yet been achieved?

To be considered as an effective insulin oral delivery method, the delivery system must comprise a biocompatible, high-loading platform affording insulin protection against external acidic environments and enzymatic degradation, in addition to targeted drug delivery coupled with a stimuli-responsive drug release such as hyperglycemia.

Nanocarriers such as polymeric, inorganic and solid-lipid nanoparticles have emerged as effective insulin transporters, circumventing many of the problems associated with insulin oral delivery. Those previously mentioned systems show promise for desirable biopharmaceutical and pharmacokinetic properties. However, recent clinical trials have resulted in failure of the nanoparticles due to toxicology, low levels of oral bioavailability and elevated intra-individual difference in insulin absorption – strong evidence that challenges still persist.

Two systems have, so far, been FDA approved for the oral delivery of insulin. The first one, developed by Oramed (ORMD-0801) incorporates both a species-specific protease inhibitor that protects active ingredients and a potent absorption enhancer that fosters their absorption across the intestinal epithelium. However, the system is non-specific and its prolonged use may damage the stomach membrane barrier and may lead to toxicity. The second, HDV-I by Diasome is based on liposomes with hepatic targeting, which suffers from instability in the GI tract, high cost and drug release during storage.

Q: How was the gastro-resistant nCOF prepared and tested in the
latest study?

We developed nCOFs for glucose-responsive oral insulin delivery to overcome insulin oral delivery barriers. The insulin-loaded nCOFs exhibited insulin protection in digestive fluids as well as a glucose-responsive release, and this hyperglycemic release was confirmed in vivo using diabetic rats.

nCOFs feature a long-range ordered structure in which the organic building blocks are spatially controlled in two or three dimensions, leading to regular pores with diameters facilitating the loading and controlled release of large drugs and proteins/enzymes. In addition, their high flexibility in molecular architecture and functional design make them versatile and therefore give them unique responsivity to their environment.

Our technology has the potential to enable the oral delivery of insulin in a safer, more effective and patient-friendly manner; easing the treatment burden that is limited to intravenous or subcutaneous delivery.

In comparison to the two FDA-approved technologies, our system is biocompatible, highly stable in the stomach, cost effective, specific and glucose-responsive. It therefore represents a step forward in the future of insulin oral delivery and a novel pathway toward the treatment of Type I diabetes through nCOF-based insulin oral delivery.

Q: How does the nCOF nanoparticle method deliver the correct amount of insulin based on a subject's blood sugar levels?

In a hyperglycemic episode, the blood sugar level is high. The excess of sugar penetrates the nanoparticles and weakens the interactions between the insulin molecules and the nanoparticle framework, releasing them in the blood. The higher the concentration of blood glucose, the greater the quantity of insulin released. If the glucose level is normal, there is not enough sugar molecules to displace the insulin, which consequently remains within the nanoparticle, safe and protected.

Q: This study is preclinical. What will your next steps be in working towards human clinical trials of the technology?

The next step is to design and prepare a library of biocompatible nCOFs displaying high-loading insulin capacity and simultaneously affording insulin protection against the harsh conditions of the stomach, and a hyperglycemia-induced drug release mechanism.

Instead of using the trial-and-error method based on screening chemical space, which can be tedious, we will use computer-aided design. Candidates that are validated computationally for high performance will be synthesized and fully characterized in the laboratory. The COFs that show superior properties during loading and release, and simultaneously exhibiting a glucose-triggered release mechanism, will be selected as candidates for the in vitro and in vivo treatment of diabetes.

Q: Are there other diseases – in addition to diabetes – for which you expect the technology could be used to treat?

Our system could have a much wider use than insulin delivery; people with various health conditions may benefit from this new drug delivery method in the future. We envision a day in which a wide variety of biologics could be administered orally.

Antibodies could be delivered this way, or routine vaccinations if the device were loaded with antigens. In addition to the scientific significance of the proposed approach, the potential follow-up of the project would be the formulation of drugs against diseases of relevant social impact such as cancer, Alzheimer’s and Parkinson’s disease and dialysis-related amyloidosis. Within the UAE, such diseases are of particular concern and have become major public health issues.

Farah Benyettou and Ali Trabolsi were speaking to Molly Campbell, Science Writer and Laura Lansdowne, Managing Editor for Technology Networks.