Application or function of cyclodextrin in insulin and cell delivery for efficient diabetic treatment

Abstract

Diabetes mellitus (DM) poses a significant global health challenge, with escalating prevalence rates and associated complications necessitating urgent attention. Traditional insulin delivery methods, such as multiple daily subcutaneous injections, present challenges in terms of patient compliance and efficacy. Consequently, there is a growing interest in alternative insulin delivery systems. Cyclodextrins (CDs), owing to their unique molecular structure and adaptable properties, have emerged as promising excipients for insulin delivery. By forming inclusion complexes, CDs enhance the stability, solubility, and bioavailability of insulin formulations, thereby improving their efficacy in blood glucose regulation. Recent research has explored various routes of administration for cyclodextrin-complexed insulin formulations, including mucosal and oral delivery, offering novel strategies for enhanced glycemic control. Encapsulation of insulin within cyclodextrin-based carriers, such as mucoadhesive nanoparticles, represents a particularly innovative approach with the potential to revolutionize diabetes treatment. The utilization of cyclodextrins in insulin and cell delivery signifies a significant advance in pharmaceutical research, promising to optimize therapeutic outcomes and enhance the quality of life for individuals living with diabetes. As the global burden of diabetes continues to rise, the development of alternative insulin delivery systems becomes increasingly imperative, and cyclodextrins offer a promising avenue for addressing this pressing healthcare need.

Introduction

Diabetes mellitus (DM) is a widespread chronic, non-communicable metabolic disease that is caused either by insufficient insulin production by the pancreas or an inadequate response of the body’s cells to the insulin produced. It is characterized by a permanently elevated blood glucose level caused by impaired insulin secretion, impaired insulin action, or a combination of both factors [1]. According to the International Diabetes Federation (IDF), there are 537 million people with diabetes mellitus; this figure is expected to rise to 783 million by 2045 [2]. DM is primarily classified into different types according to its origin, such as type I DM, type II DM, and gestational DM. In type I, which is characterized by a complete lack of insulin production, the likelihood of a cure is particularly low. In addition, DM can lead to complications affecting the eyes, kidneys, cardiovascular system, and nervous system and in severe cases can lead to death [3]. As a result, in the twenty-first century, this illness has emerged as one of the global health emergencies requiring the most attention [4]. Therefore, the treatment of this disease is one of the most important issues in the world. Patients with early-stage type II DM may benefit from oral blood glucose-lowering medications such as metformin and α-glucosidase inhibitors, as well as a sensible diet and vigorous exercise. In the later stages of type II DM, however, patients’ blood glucose levels can only be controlled by administering insulin directly into the vein [5].

Table 1. The results of the modified CDs with some polymers.

Polymer	Method	Result	Ref.
Aryl piperazine/2-hydroxypropyl-β-cyclodextrin	Inclusion complex	Improve bioavailability and the aqueous solubility	[51]
Methyl-β-cyclodextrin- polymethacrylic acid	Hydrogel carriers	Reduce blood glucose level in diabetic animal models	[14]
Chitosan-carboxymethyl-β-cyclodextrin	Ionotropic gelation	Increase the stability and release of insulin	[73]
Hydroxypropyl cyclodextrin –polymethacrylic acid- chitosan	Inter-ionic gelation	To reduce proteolytic degradation of Insulin and increase the absorption

Table 2. Cyclodextrins for Insulin Delivery: A Summary of Current Status and Future Outlook.

Aspect	Details	Ref.
Advantages	Enhances solubility, stability, and bioavailability of insulin	[39]
	Reduces insulin aggregation and enzymatic degradation	[63]
	Provides sustained and controlled release of insulin	[63]
Challenges	Potential renal toxicity with high doses of unmodified CDs	[63]
	Mild immune responses with prolonged use	[84]
	Hemolytic activity of certain CD derivatives	[63]
Future Directions	Development of safer CD derivatives with reduced toxicity	[63]
	Long-term clinical trials to assess safety and efficacy	[85]
	Exploration of novel CD formulations for targeted insulin delivery	[63]

In recent decades, numerous insulin variants from different sources have been developed for the treatment of diabetes mellitus [6]. These exogenous insulin variants are processed into rapid-, short-, intermediate- and long-acting suspensions [7], [8]. Multiple daily subcutaneous insulin injections are standard protocol for insulin administration, but patient compliance is poor due to the inconvenience involved. In addition, repeated injections cause various skin problems, including bacterial sequelae [9]. In addition, parenteral administration of insulin cannot maintain blood glucose control in people with diabetes mellitus and does not resemble the natural release of insulin from the body [10]. Intestinal injection of insulin via the portal system, although similar to endogenous insulin, is associated with metabolic abnormalities [11]. However, the development of a suitable oral insulin delivery system can increase the bioavailability of insulin and successfully regulate blood glucose levels [12], [13]. Researchers have recently used polymers, MOFs, nanoparticles, and cyclodextrins for the oral administration of insulin [12], [14].

Cyclodextrins (CDs) are a unique family of molecules that are formed when starch molecules are spontaneously degraded [15]. They possess characteristic truncated-cone morphology, with primary and secondary hydroxyl groups positioned outwardly from the exterior of the cavity, situated on its narrower and wider edges, respectively. Conversely, hydrogen atoms and glycoside oxygen bridges face inward toward the interior of the cavity, imparting a lipophilic nature to it [16]. Researchers are increasingly interested in CDs because of the many advantages they offer. They are capable of forming a wide range of supramolecular structures and complexes that are useful in many different scientific fields. In the pharmaceutical industry, they are mainly used as complexing agents to increase the water solubility and bioavailability of poorly soluble drugs [17], [18]. Based on the quantity of glucose units present, the most common types of CDs available on the market are α-, β-, and γ-CD [19].

Recently, Trotta et al. [20] have introduced a novel cyclodextrin-calixarene-based drug delivery system, demonstrating robust anti-fibrotic effects in diabetic models. Notably, this system resulted in a 60 % reduction in cardiac fibrosis in animal models. Furthermore, the therapeutic efficacy of this system was reported to be threefold greater compared to formulations utilizing individual components. Wang et al. [21] designed β-cyclodextrin/dialdehyde glucan-coated keratin nanoparticles for oral insulin delivery, which enhanced insulin stability in gastrointestinal conditions. This drug delivery system is not only suitable for insulin delivery but also has the potential for application in colorectal cancer therapy. In an animal model, these nanoparticles exhibited good biocompatibility and improved the oral bioavailability of insulin to 12.27 %.

As cyclodextrins increase the stability and bioavailability of insulin formulations, they are effective adjuvants in the administration of insulin. Cyclodextrins serve as effective auxiliary agents in the administration of insulin by forming inclusion complexes (An inclusion complex is a molecular structure where a guest molecule is encapsulated within a host molecule’s cavity, stabilized by non-covalent interactions) that protect insulin molecules from enzymatic degradation in the gastrointestinal tract, particularly in the acidic environment of the stomach. Additionally, they enhance the solubility of insulin, thereby facilitating its more efficient absorption. Research has shown that insulin formulations containing cyclodextrin complexes can be administered via different channels, e.g. orally and via the mucous membranes, and that they prove versatile in improving the effectiveness of insulin delivery [4], [14]. Researchers have made significant advances in pharmaceutical research by encapsulating insulin in cyclodextrin-based carriers, such as mucoadhesive nanoparticles, which have the potential to effectively control blood glucose levels in diabetes models. The use of cyclodextrins in insulin delivery can optimize therapeutic efficacy and patient outcomes in the treatment of diabetes [14].

Alternative insulin delivery systems need to be developed as diabetic mellitus (DM) is becoming more common worldwide and conventional insulin delivery methods are causing difficulties. With their unique molecular structure and adaptable properties, cyclodextrins (CDs) have become a viable excipient for insulin delivery. CDs improve the stability, solubility, and bioavailability of insulin formulations, thereby increasing their efficiency in blood glucose regulation. This is achieved through the formation of inclusion complexes. Recent studies have demonstrated the potential of cyclodextrin complex-containing insulin formulations for various routes of administration, including mucosal and oral delivery, offering new approaches for improved glycemic control. By encapsulating insulin in cyclodextrin-based carriers, such as mucoadhesive nanoparticles, researchers have paved the way for innovative oral insulin delivery strategies that could completely transform the treatment of diabetes. The use of cyclodextrins in insulin delivery is an important advance in pharmaceutical research and has the potential to maximize treatment outcomes and improve the quality of life for people with diabetes. As well as, regional disparities in diabetes prevalence, such as high rates in the Middle East and North Africa region and rapid growth in Africa, significantly impact the demand for insulin delivery systems. These differences underscore the urgent need for developing both cost-effective and advanced systems for low- and high-income regions, respectively.

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Siamak Javanbakht, Hossein Poursadegh, Sima Darvishi, Ali Mohammadzadeh, Ayda Saboury, Marjan Joulaie, Reza Mohammadi, Application or function of cyclodextrin in insulin and cell delivery for efficient diabetic treatment, Hybrid Advances, 2025, 100462, ISSN 2773-207X, https://doi.org/10.1016/j.hybadv.2025.100462.

Application or function of cyclodextrin in insulin and cell delivery for efficient diabetic treatment

Abstract

Introduction

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