A Step Nearer to Orally-Delivered Insulin for Diabetes

0
594

Diabetes is a metabolic disease that causes blood sugar to rise, also known as hyperglycemia. The prevalence of this disease continues to increase with the World Health Organization (WHO). specification An increase from 108 million people affected in 1980 to 422 million in 2014 underscores the importance and importance of treatment. When combined with lifestyle changes, insulin therapy continues to play an important role in controlling and regulating blood sugar levels, with injection being the primary means of delivering the hormone. However, this route of administration is much more invasive compared to oral drug delivery, meaning that diabetic patients with fear of needles and / or self-injection may not be ready 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 benefits of oral insulin delivery. Benyettou and Trabolsi explain the intricacies of the imine-linked covalent organic scaffold (nCOF) nanoparticles they developed and discuss how this approach can help overcome the key barriers associated with oral delivery of the drug.

Q: What are some of the challenges associated with subcutaneous insulin delivery by injection?

A:
In conjunction with lifestyle changes, insulin therapy remains a key element in controlling and regulating blood sugar levels in diabetics. The main mechanism for this is the injection of insulin. However, studies have shown that the onset of insulin therapy is delayed in a large proportion of people with uncontrolled diabetes and those who ultimately undergo treatment. There is a delay of more than two years from the first administration.

Reasons people may not be ready to start insulin therapy may include fear of needles and self-injection, as well as pain and anxiety. Insulin pens alleviate some of these conditions and overcome dosing problems associated with vials and syringes. However, this method is not error-free.

Q: What are the main advantages of administering drugs orally, in particular, can you elaborate on the oral bioavailability of insulin?

A:
Orally administered insulin can enter the systemic circulation after passing through the liver, similar to physiological insulin secretion, while insulin injected subcutaneously can lead to peripheral hyperinsulinemia and associated complications.

A shift towards oral insulin delivery can improve insulin therapy uptake and revolutionize diabetes care as it is a non-invasive approach to therapy that does not cause the side effects caused by frequent subcutaneous injections.

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

By using prepared layers of nanosheets with insulin charged between each layer, it is possible to protect it. Using this technology, researchers have now developed gastro-resistant imine-linked covalent organic framework nanoparticles (nCOFs) that have insulin protection in the stomach even in diabetics whose sugar content is normal within two hours after ingesting the nanoparticles.

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

A:
To be considered an effective oral insulin delivery method, the delivery system must include a biocompatible, high load platform that provides insulin protection against external acidic environments and enzymatic degradation, in addition to targeted drug delivery in conjunction with stimulant drug release such as hyperglycemia.

Nanocarriers such as polymeric, inorganic, and solid lipid nanoparticles have been shown to be effective insulin transporters, circumventing many of the problems associated with oral insulin delivery. These aforementioned systems show promise for desirable biopharmaceutical and pharmacokinetic properties. However, recent clinical studies have resulted in nanoparticle failure due to toxicology, poor oral bioavailability, and increased intra-individual differences in insulin absorption – strong evidence that the challenges persist.

To date, two systems have been approved by the FDA for the oral delivery of insulin. The first developed by Oramed (ORMD-0801) contains both a species-specific protease inhibitor that protects the active ingredients and an effective absorption enhancer that promotes absorption via the intestinal epithelium. However, the system is not specific and prolonged use can damage the gastric membrane barrier and lead to toxicity. The second, HDV-I from Diasome, is based on hepatic targeting liposomes that suffer from instability in the GI tract, high cost, and drug release during storage.

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

A:
We developed nCOFs for glucose-responsive oral insulin delivery to overcome oral insulin 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 have a long-range ordered structure in which the organic building blocks are spatially controlled in two or three dimensions, resulting in regular pores with diameters that facilitate the loading and controlled release of large drugs and proteins / enzymes. In addition, due to their high flexibility in the molecular architecture and the functional design, they are versatile and therefore react uniquely to their environment.

Our technology has the potential to make oral insulin delivery safer, more effective and more patient-friendly. Relief of treatment limited to intravenous or subcutaneous administration.

Compared to the two FDA-approved technologies, our system is biocompatible, highly stable in the stomach, inexpensive, specific and responsive to glucose. It is therefore an advancement in the future of oral insulin delivery and a new way to treat type I diabetes by oral nCOF-based insulin delivery.

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

A:
In a hyperglycemic episode, blood sugar levels are high. The excess sugar penetrates the nanoparticles and weakens the interactions between the insulin molecules and the nanoparticle framework, thereby releasing them into the blood. The higher the blood sugar concentration, the more insulin is released. When the glucose level is normal, there are not enough sugar molecules to displace the insulin, which consequently remains safe and protected in the nanoparticle.

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

A:
The next step is to design and prepare a library of biocompatible nCOFs that have high insulin capacity while providing insulin protection against the harsh conditions of the stomach and a drug release mechanism induced by hyperglycemia.

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

Q: In addition to diabetes, are there any other diseases that you think the technology can be used to treat?

A:
Our system could have a much wider use than insulin delivery. People with various health conditions may benefit from this new method of drug delivery in the future. We envision a day when 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 importance of the proposed approach, the possible follow-up of the project would be the formulation of drugs against diseases with relevant social impacts such as cancer, Alzheimer’s and Parkinson’s disease, and dialysis-related amyloidosis. In the UAE, such diseases have become of particular concern and a major public health problem.

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