**1. Introduction**

Insulin is a hormone secreted from the β cells of the islets of Langerhans, specific groups of cells in the pancreas. Insulin is a protein consisting of two polypeptide chains, one of 21 amino acid residues and the other of 30, joined by two disulfide bridges. It was isolated in 1921 with its first clinical use in 1922 [1]. Insulin is prepared different techniques; One of these isolated from animals and the other is biotechnological preparation using with the recombinant DNA techniques [2, 3].

Insulin is a important player in the control of intermediary metabolism and profound effects on both carbohydrate and lipid metabolism. It has significant influence on protein and mineral metabolism [4, 5].

The traditional and most predictable method for the administration of insulin is by subcuta‐ neous injections. This method is often painful and hence, deterrent to patient compliance especially for those requiring multiple dose injections of four times a day. Also, there have been reports of hypoglycemic episodes following multi dose injections of insulin [6, 7]. Several new approaches to the method have been adopted to decrease the suffering of the diabetic patients including the use of supersonic injector, infusion pump, sharp needles and pens. Some insulin delivery routs so problematic way for example oral administration; Oral delivery eliminates the pain caused by injection, psychological barriers associated with multiple daily injections. Oral delivery of insulin as a non-invasive therapy for Diabetes Mellitus is still a challenge to the drug delivery technology, because insulin is degraded by the enzymes in the acidic environment of stomach. Otherwise insulin delivery via transdermal delivery is so popular way of insulin administration but there are some disadvantages of this route, for example insulin molecular size and application problems etc. While some of them eased the pain encountered by the diabetic patients, they offer incomplete convenience. Even though

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the ultimate goal would be to eliminate the need to deliver insulin exogenously and regaining the ability of patients to produce and use own insulin, new concepts are currently explored to deliver insulin using oral, pulmonary, nasal, ocular and rectal routes [8, 9].

The success of the route of administration is judged on the basis of its ability to elicit effective and predictable lowering of blood glucose level and therefore minimizing the risk of diabetic complications. It is clear that several difficulties have to overcome with the use of formulation and application devices technology [10, 11]. The various explored routes are reviewed in this chapter. On the other hand, the chapter is an attempt to illustrate the use of insulin drug delivery and their body route in diabetes management benefiting many diabetic patients with promising patient compliance.

Diabetes mellitus (DM) which is a metabolic disorder characterized by chronic hyperglycemia (increased blood and hepatic glucose levels) with disturbances in carbohydrate, fat and protein metabolism, resulted by diminished insulin secretion, impaired insulin action or both. It's expected to increase from 171 million in 2000 to 366 million by the year 2030 as predicted by the WHO so it continues to increase in prevalence and will become a serious threat of mankind health [12]. Insulin injections remain to be preferred approach for the treatment of insulindependent diabetes mellitus (T1DM) and for many patients non-insulin-dependent diabetes mellitus (T2DM) also. People with type 1 diabetes mellitus have an autoimmun mediated destruction of pancreatic islet beta-cells and insulin deficiency. T1DM usually occurs in children and young adults and require daily insulin administration by injection or an insulin pump for survival. On the other hand, insulin resistance (which is associated with excessive glucose production by the liver and impaired glucose utilization by peripheral tissue, espe‐ cially muscle) is observed in T2DM. They have an impaired endogenous insulin secretion to deal with the increased blood glucose level and majority needs oral antidiabetic drugs. As the disease progresses, the pancreas looses its ability to produce insulin and necessity of insulin therapy increases [12, 13, 14].

90% of primarily filtered glucose. SGLT-2 inhibitors inhibit glucose reabsorption in proximal renal tubule. It results glycosuria leads to a decline in plasma glucose level. A wide variety of SGLT-2 inhibitors are currently under development with Dapagliflozin, Canagliflozin, Empagliflozin being the most advanced substances. Excretion of approximately 40% of primarily filtered glucose translates to a loss of 50–100 g glucose every day. The consequential decline in fasting and postprandial glucose leads to an HbA1c reduction of approximately

**Figure 1.** The main administration routes for insulin delivery (Reproduced with permission from Ref. [20], Copyright

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239

Current therapy for diabetes mellitus through oral anti-diabetic drugs and subcutaneous administration of insulin suffers from serious disadvantages, such as patient noncompliance and occasional hypoglycemia. Moreover, these approaches don't mimic the normal physio‐ logical fate of insulin release and doesn't provide better glucose homeostasis. In normal human physiology when the blood glucose level increases insulin releases from the pancreas, reaches to the hepatic portal vein and goes to liver which is its primary site of action. Subcutaneous administration of insulin moves firstly peripheral tissues and can produce peripheric hyper‐ insulinemia. In order to overcome the problems associated with parenteral administration of insulin, substantial progress has been made for insulin route such as ocular, vaginal, rectal, oral, pulmonary, transdermal, intranasal, and other routes (Figure 1) [20]. 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. 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 of insulin have also been evaluated but the absorption rate and bioavailability are poor due to the thick mucosal layers in these tissues. Lots of absorption enhancers (bile salts, chelating agents, surfactants, cyclodextrins, and dihydrofusidate) used

0.8%. The loss of energy substrate reduces body weight approximately 3 kg.

2013 Elsevier)

but they couldn't prevent local reactions with severe complications.

Hyperglycemia, recurrence of ample fluctuation of blood glucose levels and insulin resistance can lead to long term complications such as micro and macrovascular. It is well known that improved metabolic control significantly reduces both microvascular (ie, retinopathy, nephr‐ opathy and neuropathy) or macrovascular [ie, cardiovascular disease (CVD), cerebrovascular accidents and peripheral vascular disease] complications in diabetes. The development of complications is a cause of considerable morbidity and increases disability and mortality for the individual with diabetes [15].

The conventional pharmacotherapies currently available for the treatment of type-2 diabetes include insulin sensitisers (metformin and thiazolidinediones), insulin secretagogues (sulpho‐ nylureas and glinides), alpha-glucosidase inhibitors, insulin and insulin analogues. Glucagon like peptide (GLP)-1 agonists and dipeptidyl peptidase (DPP)-4 inhibitors are the new therapies; that improve glycemic control have recently been developed [16, 17, 18, 19]. These therapies are proposed to treat the key metabolic abnormalities associated with T1DM and T2DM and minimize the side effects noted with conventional therapies. Also in development there are additional therapies that have effects on the kidney to promote glucose excretion [15]. SGLT-2 (proximal renal tubule) has high transport capacity for reabsorption of approximately

the ultimate goal would be to eliminate the need to deliver insulin exogenously and regaining the ability of patients to produce and use own insulin, new concepts are currently explored to

The success of the route of administration is judged on the basis of its ability to elicit effective and predictable lowering of blood glucose level and therefore minimizing the risk of diabetic complications. It is clear that several difficulties have to overcome with the use of formulation and application devices technology [10, 11]. The various explored routes are reviewed in this chapter. On the other hand, the chapter is an attempt to illustrate the use of insulin drug delivery and their body route in diabetes management benefiting many diabetic patients with

Diabetes mellitus (DM) which is a metabolic disorder characterized by chronic hyperglycemia (increased blood and hepatic glucose levels) with disturbances in carbohydrate, fat and protein metabolism, resulted by diminished insulin secretion, impaired insulin action or both. It's expected to increase from 171 million in 2000 to 366 million by the year 2030 as predicted by the WHO so it continues to increase in prevalence and will become a serious threat of mankind health [12]. Insulin injections remain to be preferred approach for the treatment of insulindependent diabetes mellitus (T1DM) and for many patients non-insulin-dependent diabetes mellitus (T2DM) also. People with type 1 diabetes mellitus have an autoimmun mediated destruction of pancreatic islet beta-cells and insulin deficiency. T1DM usually occurs in children and young adults and require daily insulin administration by injection or an insulin pump for survival. On the other hand, insulin resistance (which is associated with excessive glucose production by the liver and impaired glucose utilization by peripheral tissue, espe‐ cially muscle) is observed in T2DM. They have an impaired endogenous insulin secretion to deal with the increased blood glucose level and majority needs oral antidiabetic drugs. As the disease progresses, the pancreas looses its ability to produce insulin and necessity of insulin

Hyperglycemia, recurrence of ample fluctuation of blood glucose levels and insulin resistance can lead to long term complications such as micro and macrovascular. It is well known that improved metabolic control significantly reduces both microvascular (ie, retinopathy, nephr‐ opathy and neuropathy) or macrovascular [ie, cardiovascular disease (CVD), cerebrovascular accidents and peripheral vascular disease] complications in diabetes. The development of complications is a cause of considerable morbidity and increases disability and mortality for

The conventional pharmacotherapies currently available for the treatment of type-2 diabetes include insulin sensitisers (metformin and thiazolidinediones), insulin secretagogues (sulpho‐ nylureas and glinides), alpha-glucosidase inhibitors, insulin and insulin analogues. Glucagon like peptide (GLP)-1 agonists and dipeptidyl peptidase (DPP)-4 inhibitors are the new therapies; that improve glycemic control have recently been developed [16, 17, 18, 19]. These therapies are proposed to treat the key metabolic abnormalities associated with T1DM and T2DM and minimize the side effects noted with conventional therapies. Also in development there are additional therapies that have effects on the kidney to promote glucose excretion [15]. SGLT-2 (proximal renal tubule) has high transport capacity for reabsorption of approximately

deliver insulin using oral, pulmonary, nasal, ocular and rectal routes [8, 9].

promising patient compliance.

238 Application of Nanotechnology in Drug Delivery

therapy increases [12, 13, 14].

the individual with diabetes [15].

**Figure 1.** The main administration routes for insulin delivery (Reproduced with permission from Ref. [20], Copyright 2013 Elsevier)

90% of primarily filtered glucose. SGLT-2 inhibitors inhibit glucose reabsorption in proximal renal tubule. It results glycosuria leads to a decline in plasma glucose level. A wide variety of SGLT-2 inhibitors are currently under development with Dapagliflozin, Canagliflozin, Empagliflozin being the most advanced substances. Excretion of approximately 40% of primarily filtered glucose translates to a loss of 50–100 g glucose every day. The consequential decline in fasting and postprandial glucose leads to an HbA1c reduction of approximately 0.8%. The loss of energy substrate reduces body weight approximately 3 kg.

Current therapy for diabetes mellitus through oral anti-diabetic drugs and subcutaneous administration of insulin suffers from serious disadvantages, such as patient noncompliance and occasional hypoglycemia. Moreover, these approaches don't mimic the normal physio‐ logical fate of insulin release and doesn't provide better glucose homeostasis. In normal human physiology when the blood glucose level increases insulin releases from the pancreas, reaches to the hepatic portal vein and goes to liver which is its primary site of action. Subcutaneous administration of insulin moves firstly peripheral tissues and can produce peripheric hyper‐ insulinemia. In order to overcome the problems associated with parenteral administration of insulin, substantial progress has been made for insulin route such as ocular, vaginal, rectal, oral, pulmonary, transdermal, intranasal, and other routes (Figure 1) [20]. 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. 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 of insulin have also been evaluated but the absorption rate and bioavailability are poor due to the thick mucosal layers in these tissues. Lots of absorption enhancers (bile salts, chelating agents, surfactants, cyclodextrins, and dihydrofusidate) used but they couldn't prevent 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. 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 multiple layers of oral epithelial cells represent a significant GI barrier to drug penetration, which, coupled with the continuous flow of saliva, leads to poor efficacy.

Among these approaches nanoparticular sysytems have attracted special interest because of providing the protection to the highly acidic medium in the stomach (preventing enzymatic degradation), prolonging intestinal residence time, increasing the permeability of drugs to systemic circulation (increasing absorption) and providing controlled-release properties for encapsulated drug [12, 28]. For the conventional medicine it is well understood the nanosize along with other characteristics does play an important role as evident from the improved bioavailability/pharmacological availability [29, 30]. Owing to the high surface area to volume ratio of NPs the window of absorption is also high in comparison with microparticles, this is an added advantage in improving the bioavailability of the administered drug [31, 32].

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Insulin therapy is effectively used in treatment of diabetes mellitus. Insulin is a key player in lowering blood glucose levels for type 1 diabetes and also required at later stages in type 2 diabetes patients. The widely accepted route for delivery of insulin is by parenteral adminis‐ tration but this delivery of insulin usually requires at least three or four daily insulin injections for good glycemic control. Consequently more acceptable different routes of insulin delivery have been searched to decrease suffering from discomfort, local pain, irritation, infection, immune reactions and lipoatrophy at the injection site of insulin. Oral delivery of insulin would deliver the drug directly into the liver through portal circulation and could mimic the phys‐ iological fate of endogenously secreted insulin [33, 34, 35]. However polypeptides, like insulin are degraded in the stomach pH and undergo proteolysis by enzymes in the gastrointestinal tract [22, 36]. Moreover the gastrointestinal mucosa has low permeability for large hydrophilic

In order to overcome the problems associated with parenteral administration of insulin several strategies that are based on nanotechnology has been developed to enhance the intestinal absorption of different protein and peptides. NPs consist of naturally occurring biodegradable polymers are widely investigated in this regard. They have emerged as potential carriers of several therapeutic agents for controlled drug delivery as well as the oral route of insulin. Various natural hydrophilic and hydrophobic polymers used as carrier of oral insulin such as

Over the past few decades, enhancing attention has been paid to the use of polymeric NPs either hydrophilic or hydrophobic as carriers for insulin delivery. Hydrophilic polymers are of particular interest due to their non-toxic, biocompatible, biodegradable and natural polymers. Among them, chitosan is widely used because of its ease of chemical modification

chitosan, alginate, dextran sulphate, etc. are commonly used to prepare NPs.

*2.1.1. Polymers used as matrices for oral insulin delivery*

and promising biological properties.

**2. Delivery route of insulin**

**2.1. Oral delivery**

peptides.

Taking all of this account oral administration is considered to be the most safest and convenient which delivers the drug directly into the liver through portal circulation, where it inhibits hepatic glucose production. Hence by oral delivery to a greater extent the natural physiological route of insulin can be mimicked (Figure 2) [21]. The highly acidic environment in the stomach and the presence of proteolytic enzymes cause structural instability of the oral delivery of protein and peptide drugs including in the harsh environment of the gastrointestinal system [22, 23, 24]. These drugs should overcome some various GI barriers such as chemical, enzy‐ matic and absorption barriers to obtain adequate bioavailability [25]. Different formulation of polymers for insulin delivery such as liposomes, microspheres, microemulsion and nanopar‐ ticles (NPs) have been investigated to circumvent these GI barriers [26, 27].

**Figure 2.** Schematic diagrams illustrating the absorption, distribution and elimination of aspart insulin following oral or subcutaneous (s.c.) administration to rats (Reproduced with permission from Ref. [21], Copyright 2013 Elsevier).

Among these approaches nanoparticular sysytems have attracted special interest because of providing the protection to the highly acidic medium in the stomach (preventing enzymatic degradation), prolonging intestinal residence time, increasing the permeability of drugs to systemic circulation (increasing absorption) and providing controlled-release properties for encapsulated drug [12, 28]. For the conventional medicine it is well understood the nanosize along with other characteristics does play an important role as evident from the improved bioavailability/pharmacological availability [29, 30]. Owing to the high surface area to volume ratio of NPs the window of absorption is also high in comparison with microparticles, this is an added advantage in improving the bioavailability of the administered drug [31, 32].
