ReviewStrategies for effective oral insulin delivery with modified chitosan nanoparticles: A review
Introduction
While insulin has been available for ninety years, it is not yet able to combat the diabetes pandemic that has developed in this century. Considering a predicted doubling in diabetes-related deaths between 2005 and 2030 [1] and the fact that the economic burden of diabetes represents approximately 6% of the total health budget of developed countries [2], it is surprising that insulin, the most effective diabetes treatment, has not gained widespread use. While insulin can be used alone in the therapy of diabetes without any oral antidiabetic drug, the reverse is not true [3]. Insulin therapy is commonly delayed despite the dire consequences, partly due to the inconvenience and complications associated with insulin administration by injection. Thus, in the last decade, the focus has shifted from the development of insulin alternatives to the development of alternative delivery methods.
Invasive parenteral (injected) insulin suffers from poor patient compliance due to needle phobia, pain, skin bulges, allergic reactions, common infections, and stress generated from the difficult long-term regimen of insulin therapy [4], [5]. Moreover, many patients still experience hypoglycemic episodes despite easier glucose monitoring options. Parenteral insulin is also associated with non-physiological delivery to the wrong target tissues, poor pharmacodynamics, non-ideal initiation and weight gain [3], [6]. Developments in biotechnology have led to the development of alternatives to parenteral delivery, although these developments have not been rapid enough to meet the pressing demand.
The goal of an alternative delivery route is to reach the bloodstream by noninvasive means, which is inaccessible for a protein drug due to the multiple physicochemical barriers. Including those arising in the innate immune system. Scientists are trying to evade these barriers efficiently through ocular, vaginal, rectal, oral (buccal, gastro-intestinal (GI), and sublingual), nasal, and other routes [7], [8]. The barriers to reaching the bloodstream are either physical, such as poor absorption at barrier surfaces, or chemical, such as pH inactivation and enzymatic degradation. Fig. 1 presents possible hurdles for oral insulin delivery. Lassmann-Vague and Raccah [7] reviewed the obstacles present for different delivery routes. Delivery of insulin via the ocular route was tested in animal models in combination with different absorption enhancers, with particular attention given to toxicity as polymers were added to overcome low absorption. Vaginal and rectal routes have also been investigated, but the absorption rate and bioavailability are poor due to the thick mucosal layers in these tissues. The use of absorption enhancers (bile salts, chelating agents, surfactants, cyclodextrins, and dihydrofusidate) does not help as they may cause local reactions with severe complications. Nasal delivery has also been evaluated because of the easy access, high vascularity and large absorption area associated with this route. Unfortunately, highly active mucociliary clearance in the nose hindered prolonged drug action resulting in poor bioavailability. Buccal and sublingual insulin administration provide better results due to the low levels of proteolytic enzyme activity, the high vascularization of the tissue, the large surface area for absorption and the ease of administration. However, the multiple layers of oral epithelial cells represent a significant barrier to drug penetration, which, coupled with the continuous flow of saliva, leads to poor efficacy. Taking all of this into account, the oral route is considered to be the most feasible and convenient method of drug administration to improve compliance among diabetic patients. In addition to the large surface available for absorption, orally administered insulin can mimic the physiological fate of insulin in the body [8], providing better glucose homeostasis [9], [10].
Orally administered insulin is absorbed directly from the intestine and then transported to the liver via portal circulation, where it inhibits hepatic glucose production [9]. Unlike other delivery routes, the gut is the natural route of nutrient absorption into the circulation. The fact that the gut presents the largest absorption surface of all routes provides better efficacy. However, the oral delivery of peptide drugs is hindered by the structural instability of proteins and peptide drugs in the harsh environment of the gut, i.e., the highly acidic environment in the stomach and the presence of proteolytic enzymes [11]. Fig. 2 presents a schematic diagram of the possible mechanisms by which chitosan nanoparticles improve insulin absorption. Both natural and synthetic polymers have been applied to the design of delivery vehicles capable of overcoming absorption barriers in the form of hydrogels, beads, microspheres, nanoparticles, and other formulations. Natural polymers such as agar, agarose, alginate, and chitosan and synthetic polymers including poly(lactic acid), poly(lactic-co-glycolic acid), poly(phosphoesters), and poly(є-caprolactone) have demonstrated efficacy as protein carriers [12], [13], [14]. Polymeric carrier systems for insulin delivery must be biodegradable, nontoxic and biocompatible, non-immunogenic, easy to synthesize and characterize, and preferably water soluble and inexpensive [15]. The polymer molecular weight, solubility, and structure also greatly influence drug delivery.
Unless the protein is protected, the oral bioavailability of proteins is usually less than 1–2% [16] due to the action of digestive proteases in the stomach and intestine, the acidic pH of the stomach and the physical barrier of the mucus, glycocalyx and protease-containing microvilli. In brief, effective delivery systems for oral protein delivery should fulfill the following criteria:
- i.
pH-sensitive behavior to protect the drug at the pH of the stomach and release it at intestinal pH.
- ii.
Release should be ‘site specific’, i.e., close to the absorption surface to avoid intestinal proteases.
- iii.
Selective and reversible opening of the tight junctions is preferable.
- iv.
Release should be controlled to achieve the physiological insulin concentration in blood.
- v.
The drug delivery vehicle should be biocompatible.
To summarize, a multi-functional drug carrier is required to surmount the multiple hurdles between orally delivered insulin and the systemic circulation. Specific performance criteria need to be met to make oral insulin formulations successful. Insulin absorbed in the intestinal environment is usually transported to the portal circulation via the liver, which is responsible for controlling hepatic glucose production [9], [17]. The rapid pre-systemic destruction of orally delivered insulin coupled with poor absorption in the intestinal region results in low bioactivity [9], [11]. In contrast, injection via the portal vein mimics endogenous insulin, improving the bioavailability [18].
Ensuring adequate bioavailability of oral insulin, preserving its bioactivity, and maximizing the desired effects in the body are the most essential criteria for successful insulin delivery. To fulfill these criteria, the preliminary objective is the effective protection of insulin in the harsh acidic stomach environment. Controlled release of the drug requires a prolonged residence time in the intestinal milieu for better absorption, which is usually achieved by enhancing the permeability of the drug carrier though the mucosal epithelial layer of the intestine. Various strategies for improving drug absorption have been investigated, including the use of pH-responsive polymeric vehicles [19], [20], [21], enzyme inhibitors [22], [23], permeation enhancers, absorption enhancers [22], [24] and the introduction of chemical modifications [25] to insulin. The polymers used in these vehicles must be biocompatible, biodegradable, nontoxic and provide significant bioadhesion to achieve the oral administration of insulin to the systemic circulation. This review discusses these and other possible methods for improving oral insulin delivery.
Section snippets
Chitosan, the starting point
As summarized in Table 1, chitosan is biocompatible, non-immunogenic, nontoxic and biodegradable, making it an excellent choice as a component of oral drug delivery systems and making it highly attractive for biomedical and drug delivery applications.
Chitosan, a natural biopolymer prepared by N-deacetylation of chitin as shown in Fig. 3, is a major component of the shells of crustaceans and can be obtained at low cost. Chitosan is a biocompatible [26], [27], [28], mucoadhesive [29],
Nanoparticles for insulin delivery
The field of “nanomedicine,” so named in 2004 by the European Science Foundation, represents a new era in the field of drug delivery research in which nanoparticles are applied as drug delivery vehicles. Nanoparticles have several advantages for oral drug delivery. Generally, these particles are small in size (within the micro or nano range) and are capable of encapsulating proteins or peptide drugs such as insulin and protecting them from enzymatic degradation in the adverse GI environment,
Passage through the harsh environment of the stomach
From the beginning of studies on insulin-loaded nanoparticles, the main goal has been to protect the drug from the harsh acidic pH of the stomach. In 2002, Pan et al. [41] proposed using chitosan nanoparticles to improve insulin delivery by synthesizing pH-responsive chitosan nanoparticles, which initially showed a burst release of insulin in vitro. The release was found to be rapid at pH 4.0, whereas slower release was observed at pH 5.8. The isoelectric point (pI) of insulin is 5.3, which may
The second barrier: the intestine, mucus layer and tight junctions and intestinal proteolytic enzymes
The intestine is considered the second major obstacle for oral protein delivery. The huge sulfated mucopolysaccharide layer, the glycocalyx and mucus, intestinal microvilli, the finger-like projections and tight junctions in between the closely packed intestinal epithelial cells collectively represent a physical hindrance to absorption, while intestinal enzymatic deactivation poses a chemical obstacle, limiting proper absorption and desired action. These challenges can be overcome by the use of
The pharmacological bioavailability, drug physiology and biocompatibility (immune tolerance, degradation, toxicity) of chitosan nanoparticles
After administration of insulin, achieving a good pharmacological bioavailability is the primary criterion to allow it to exert its desired action within the body. The oral delivery of a protein drug involves a high risk of conformational changes that may easily impact the drug's bioactivity. Pan et al. [41] formulated chitosan nanoparticles by an ionotropic gelation method using tripolyphosphate. After administration of 21 IU/kg of insulin–chitosan nanoparticles, a prolonged hypoglycemic effect
Food interaction and variable rates of gastric emptying—a particular problem in diabetic patients
Advanced studies in diabetes research have shed light on food interaction and clinical disorders of gastric emptying in some diabetic patients. An important issue regarding medicine intake is to ensure proper timing (on an empty stomach or with food) to treat and alleviate the particular disease [105]. The food–drug interaction is highly complex and requires intense research to maximize the bioavailability of the administered drugs. Previous studies showed that the food–drug interaction may
Future directions
This review mainly focuses on the nanoparticles of either native chitosan or its derivatives and their application to improved oral insulin delivery. The primary goal of these vehicles is to protect the insulin from the harsh acidic environment while passing through the GI tract and residing in the stomach for almost an hour. Generally, nanoscale polymeric drug formulations are reported to reach the intestine after residing in the stomach for an hour. Enteric coating may provide sufficient
Conclusions
This detailed review of oral insulin delivery demonstrates that chitosan nanoparticles can serve well as oral delivery vehicles and improve the biological activity of the drug after administration. Several published reports state that certain modifications protect insulin from the acidic environment and help to protect it from proteolytic deactivation in the stomach. Following the oral route, the insulin is destined to reach the systemic circulation, crossing over intestinal barriers such as
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