Nastya
Title: Diabetes mellitus: new formulation and delivery technologies for antidiabetic therapy
Abstract: With the increasing number of diabetes cases worldwide, there is a need to study and improve the formulation and delivery technologies of antidiabetic drugs for both prevention and control. Challenges emerge when conventional strategies, including diet and exercise, fall short of adequately controlling hyperglycemia. Despite the initial effectiveness observed in pharmacological interventions, they are burdened by notable limitations primarily arising from low bioavailability and immediate drug release. In response to these challenges, recent years have witnessed development of of innovative delivery modalities to enhance anti-diabetic approaches' effectiveness. Thus, in this review, we discuss new therapeutic perspectives on oral delivery of insulin with increased bioavailability, the use of biomarkers for type 2 diabetes and current advanced cell encapsulation technologies in diabetes therapy.
I. Introduction
Diabetes mellitus (DM) is a prevalent and intricate metabolic disorder characterized by either inadequate secretion of insulin from pancreatic cells or reduced binding efficacy of insulin to cell surface receptors. Globally, 537 million adults (20–79 years) were diagnosed with diabetes in 2021, responsible for 6.7 million deaths and expected to reach 783.2 million by 2045 (Berlin et al., 2024). An essential component in the control of type 1 diabetes (T1D) is insulin therapy, while patients with type 2 diabetes (T2D) can control their blood sugar with oral antidiabetic drugs. However, as their pancreatic function declines over the course of the disease, many T2D patients must also include insulin in their treatment regimen (American Diabetes Association Professional Practice Committee, 2022). Since its introduction as a medical treatment in 1921, insulin has been widely recognized as an effective therapeutic option for all forms of DM. Oral administration of insulin poses various challenges, including enzymatic metabolism in the liver and limited ability to cross the intestinal epithelium due to its hydrophilic properties. As a result, it tends to be retained within the mucous layer, requiring the implementation of enzymatic or physical barriers to overcome this hurdle (Pardhi et al., 2024).There are several strategies available to improve the oral bioavailability of different types of insulin such as the use of innovative biodegradable devices, the incorporation of insulin into particulate nanocarriers or the use of cellular encapsulation techniques. Another novel approach would be to use asprosin as a target for therapeutic intervention in the treatment of T2D.
II. Discussion
a. Oral insulin delivery systems
To date, subcutaneous insulin administration (needle injections or pump-based infusion) is still the primary clinical treatment for millions of people with diabetes worldwide, while extensive efforts have explored the feasibility of alternative insulin delivery strategies (such as be oral, transdermal, by inhalation and release on mucous membranes). However, painful and repetitive needle injections can cause trauma and side effects in people with diabetes, such as weight gain, hypoglycemia, and lipoatrophy, because subcutaneous insulin does not exactly mimic the action of physiological insulin secretion (Zhang et., 2023). Abramson and colleagues recently reported a innovative device for the systemic delivery of insulin with high bioavailability via injections into the stomach and small intestine. The first ingestible insulin capsule, called the luminal deployable microneedle injector (LUMI), contains multiple drug-loaded microneedles encapsulated in a matrix of poly(methacrylic acid-co-ethyl acrylate) and polyethylene glycol and is designed to dissolve at pH levels found in the small intestine (≥5.5) to propel LUMI out of the capsule. The authors tested microneedle penetration through ex vivo studies in humans and in vivo studies in pigs and observed that the device consistently delivered microneedles to tissue without animal discomfort, residual devices, and tissue perforation. After swallowing and reaching the intestine in the swine model, the capsule holding the spring dissolves due to the rise in pH, causing actuation that pushes the LUMI out of the capsule. LUMI is then deployed externally with a network of microneedles to penetrate the epithelial barrier, dissolve and release the encapsulated insulin or other macromolecule drugs (Abramson et al., 2019). In vivo study showed that the device can serve as a platform to orally deliver insulin, presenting a faster pharmacokinetic uptake profile and a systemic uptake >10% of that of a subcutaneous injection over a 4-h sampling period (Zhang et al., 2024).
Nanoparticle-based drug delivery platforms are another notable example of innovative oral insulin delivery technologies. These have received considerable attention because the unique physicochemical properties and high surface-to-volume ratio of nanoparticles enable high drug loading through encapsulation or the formation of physicochemical bonds with their functional groups (Li et al, 2022). Previous studies of nanoparticle-based oral insulin delivery platforms primarily use nanoparticles as carriers for the loading and transport of insulin via transcytotic and/or paracellular pathways. Specifically, mesoporous silica nanoparticles have been extensively studied as carriers for oral insulin administration due to their large surface area and pore volumes and excellent physicochemical stability. A discovery was recently reported that small, negatively charged inorganic silica nanoparticles can act as physicochemical permeation enhancers to facilitate oral insulin delivery by inducing tight junction relaxation. It was found that negatively charged nanoparticles of 50 nm in diameter can transiently (within 4 hours) and reversibly induce increased intestinal wall permeability. The novel use of silica nanoparticles could represent a new direction for nanoparticles in oral insulin delivery. Instead of drug carriers, they act as physicochemical permeation enhancers to facilitate oral insulin administration by inducing tight junction relaxation (Lamson et al., 2020).
b. Encapsulation
Currently, to avoid adverse immune response, encapsulation technology has been employed with cell therapy, which contributes to the clinical treatment of diabetes. At present, clinical trials using alginate encapsulated human β cells (NCT00790257) and human islets (NCT02064309) have been conducted or are under way to evaluate their safety, metabolic efficacy and immune response generated. In addition, the use of gene editing (such as CRISPR/Cas9) can also help donor xenocells achieve immune avoidance (Li et al., 2024). The Diabetes Research Institute of Miami has developed another technique that encapsulates islets in biomaterials. Named BioHub, it is a scaffold system made of thrombin and a gelatinous substance made from the patient's plasma. A stent containing islets was then implanted into the omentum, which is a more accessible and dense system of blood vessels than any other complement. The device is highly vascularized, and as the gel degrades over time, new blood vessels also form, supporting the survival and function of the islets. Studies in animal models have shown that metabolic function of encapsulated cells is improved in highly vascularized BioHub scaffolds, resulting in improved blood glucose levels (Berman et al., 2016). However, this strategy requires the administration of an immunosuppressive regimen. The methodological safety and long-term feasibility of this strategy will be determined in ongoing studies.
c. A perspective of targeted therapy with asprosin
Asprosin, a recently discovered adipokine, has been shown to be pathologically elevated in people experiencing insulin resistance, according to a study. The aim of this study was to evaluate the association between circulating levels of asprosin and type 2 diabetes. It was concluded that circulating levels of asprosin were significantly increased in patients with type 2 diabetes compared to controls. Therefore, there is potential to use asprosin as a target for therapeutic intervention in the treatment of type 2 diabetes (Mahat, Janthikar, Rathore & Panda, 2024).
III. Conclusion
Despite several recent technologies that have achieved some positive results in preclinical studies in rodents or pigs, including luminal deployable microneedle injector and encapsulation, discussed in this article, more research is needed to validate these technologies to make meaningful progress toward the clinics. Strategies developed to increase the bioavailability of oral insulin, the current advanced cell encapsulation technologies and discovering the potential of aspirin as a biomarker and therapeutic target in the management of type 2 diabetes represents promising and valuable future perspectives for diabetes therapy.
References
1. Abramson A, Caffarel-Salvador,E,Soares V, Minahan D, Tian RY, Lu X, Dellal D, Gao Y, Kim S, Wainer J. A luminal unfolding microneedle injector for oral delivery of macromolecules. Nat. Med., 2019; 25: 1512-1518.
2. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes. Diabetes Care 2022; 45:125–143.
3. Berlin I, Durlach V, Thomas D, Verges B, Le Faou AL. Tobacco smoking and diabetes. A comparative survey among diabetologists and smoking cessation specialists. Primary Care Diabetes, 2024.
4. Berman DM, et al. Bioengineering the endocrine pancreas: Intraomental islet transplantation within a biologic resorbable scaffold. Diabetes, 2016; 25: 1350-1361.
5. Eldor R, Francis BH, Fleming A, Neutel J, Homer K, Kidron M, Rosenstock J. Oral insulin (ORMD-0801) in type 2 diabetes mellitus: a dose-finding 12-week randomized placebo-controlled study. Diabetes Obes. Metab., 2023; 25: 943-952.
6. Lamson NG, Berger A, Fein KC, Whitehead KA. Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability. Nat. Biomed. Eng., 2020; 4: 84-96.
7. Li Y, He C, Liu R, Xiao Z & Sun B. Stem cells therapy for diabetes: from past to future. Cytotherapy;2023; 11: 1125-1138.
8. Li Y, Zhang W, Zhao R, Zhang X. Advances in oral peptide drug nanoparticles for diabetes mellitus treatment. Bioact. Mat., 2022; 15: 392-408.
9. Mahat RK, Janthikar AM, Rathore AR & Panda S. Circulating asprosin levels in type 2 diabetes mellitus: A systematic review and meta-analysis. Clinical Epidemiology and Global Health 2024; 25:101502.
10. Pardhi E, Bhor Y, Singh PK, Mehra NK. An apprise on novel drug delivery systems for management of diabetes mellitus.Journal of Drug Delivery Science and Technology, 2024; 9:105473.
11. Zhang E, Zhu H, Song Shi Y, Cao B. Recent advances in oral insulin delivery technologies. Journal of Controlled Release, 2024; 366: 221-23.
12. Zhang X, Chen G, Zhang H, Shang L, Zhao. Bioinspired oral delivery devices. Nat. Rev. Bioeng., 2023; 1: 208-225.
