Diabetes is a serious chronic disease and metabolic disorder of glucose. Insulin is one of the hormones for regulating blood glucose level in the blood. Diabetes is caused by the low secretion of insulin in the body, also sometimes the body properly does not respond to the insulin [1]. Insulin is a type of hormone which is released from the pancreas and controls the blood glucose level in the body. The treatment for diabetes mellitus varies according to its different types. Diabetes mellitus are a group of metabolic diseases which is identified by the failure of blood glucose level regulation mechanisms. In 2012, around 1.5 million deaths were caused by the diabetes mellitus. The WHO classifies diabetes mellitus into: type 1 (T1DM), type 2 (T2DM), gestational diabetes and intermediate conditions. Type 1 diabetes mellitus is also known as early-onset, juvenile or insulin-dependent diabetes mellitus, which is caused by absolute insufficiency of insulin as an outcome of autoimmune demolition of insulin-producing cells in the pancreas. Unconstrained DM in the short-term can result in threatening problems, such as hypoglycemia (<4 mmol/l), hyperosmolar hyperglycemic state (often >40 mmol/l) and diabetic ketoacidosis. If the patient is having DM for the long time then he or she can often experience other medical problems such as cardiovascular disease, kidney failure, loss of vision and neuropathy leading to possible leg amputation. Type 2 Diabetes Mellitus is the most customary form of diabetes and it is also known as late-onset or non-insulin-dependent Diabetes Mellitus, which is responsible for nearly all the other cases of Diabetes Mellitus and it is a result of insulin resistance and relative insulin deficiency in the body [2]. In treatment of diabetes mellitus insulin has usually been administered subcutaneously. Possible routes for the delivery of insulin are expected to overcome some limitations, on the whole it is concerned with the risk of episodes of hypoglycemia, weight gain and inadequate post-meal glucose control, in order to lead a better patient compliance. The subcutaneous injections of insulin have been considered the main treatment for insulin replacement after its discovery, although, there are several barriers which is related to the weak patient consent [3]. The conventional care of the patients with type 2 diabetes frequently requires monitoring of blood glucose levels and insulin therapy to maintain normoglycemia. The self-administration of the insulin causes the pain and it needs injections over his or her whole life. There are various alternative routes for the non-injectable insulin delivery which comprise rectal, intrapulmonary, ocular, oral, nasal, dermal and buccal have thus been considered for the administration of insulin [4]. Nanoparticles which are biodegradable have been often used as insulin transdermal delivery vehicles because of its grand bioavailability, better encapsulation, controlled release and less noxious properties. There is worldwide growth in the prevalence of diabetes mellitus is a serious public health problem. Patients who are having the diabetes, the recent development in the administration of the insulin has improved their quality of life, recent efforts of the scientists in the past ten years have focused on developing different strategies based on nasal, oral, pulmonary and transdermal delivery routes. Among these different strategies oral insulin delivery is the most convenient route of administration of insulin has emerged as one of the most convenient administration routes.

Structure of Insulin

The human insulin, comprises 51 amino acids, chain A has 21 amino acids and chain B has 30 amino acids. Two disulfide bonds connect the chain A and B and from this two sulfide bonds one is between 7th amino acids of chain A and B and the another sulfide bond is between 20th amino acid of chain A and 19th amino acids of chain B. There is also one disulfide bond which is present between 6th and 11th amino acids of chain A [2] (Figure 1).

Figure 1: Structure of Insulin

Source: CNX OpenStax [CC BY 4.0 (http://creativecommons.org/licenses/by/4.0)], via Wikimedia Commons

Conventional Insulin Delivery and Microneedles

Insulin is a protein which is produced by β-cells of pancreas and it is the only blood glucose lowering hormone which is present in organism ant that is essential for DM. Usually the oral administration of the insulin is the most advantageous route for patients to take medicine. But, insulin cannot orally have administered due to its partially instability and degradation in the GI tract. The molecular weight of insulin is about 5800 Dalton, which leads to a low absorption of drug by epithelial cells of intestine. The above factors are responsible for extremely low oral bioavailability of insulin. Exubera, it was the first insulin inhaled formulation and it was introduced by the Pfizer to the market in 2006, but finally it got failed in the market because of its high variation in insulin absorption. The other reason due to which it was a failed formulation because it was having the complex inhalation technique and also there was low acceptance by the patient. Adding to this, microneedle-based insulin delivery systems is there which has also attracted the attention of researchers. Insulin in microneedles can be administered over the skin to the systemic circulation by the help of invasive patches and that leads to greatly increased patients’ compliance. There are various structures of microneedles, for instance hollow, solid, degradable, dissolved and phase transition microneedles. However, there are some of the microneedle-based insulin delivery systems (hollow systems) which had entered the clinical trials, but none of them formulation has become commercially available in the market so far. There are some concerns, which includes the safety of materials, the specific insulin delivers and the intricated production process of microneedles, should be further studied and improved until its application in clinic. There are subcutaneous injections which are still the dominating route for administration of insulin in most of the hospitals. Although, the insulin has short half-life which requires repeated injections of insulin in a single day to effectively benchmark the glucose level in blood, which causes bother to patients. Just to reduce the inconvenience to the patient for frequently administration of insulin and to enhance the patient compliance, prominent attempts have been made to evolve a advanced insulin delivery systems and in which NPs-based insulin delivery systems are the major research fields [5].

Insulin Delivery Systems Based on Nanoparticles

Sustained and controlled delivery of various theranostic agents nanoparticals has shown the considerable prospectives. NPs are commonly utilized due to its capacity to control the release of insulin, protect insulin from degradation and enhance its bioavailability [5].

Subcutaneous Delivery Systems

Insulin-Loaded Long-Term Delivery Systems: After the failure of the Exubera (it is an insulin formulation administered by inhalation) then the subcutaneous injection of insulin is the only possible route of administration for insulin. To control the glycemic level in the blood effectively, the frequent and repeated injections of insulin are required for diabetic patients. However, we all know that, repeated injections of insulin cause pain and inconvenience to the patient and which results in the low patient compliance. Insulin delivery systems based on NPs have been considered as the promising formulations for sustained and controlled delivery of insulin. For example, Shilo et al. which is a coated insulin onto gold NPs (INS-GNPs) for controlled and extended glucose control [5].

Oral Insulin Delivery Systems

Oral administration is widely acknowledged as the most convenient and tolerated drug delivery route for patients. However, due to the harsh conditions of the GIT the insulin generally given by subcutaneous injection, as insulin is a protein drug. Several functional NPs-based systems have been developed, to solve the above mentioned problem of insulin administration through oral route [5]. Numerous developmental challenges have been related with providing effectiveness of the oral route for insulin delivery. These developmental challenges include poor epithelial permeability and enzymatic degradation of insulin in the gastrointestinal (GI) tract, which leads to inadequate bioavailability of insulin. Pepsin from the stomach, pancreatin from the small intestine, aminopeptidases from the brush border membrane are the enzymes which are involved in the degradation of the proteins in the GIT mainly. In the past ten years so much progress has been done to the NPs-based insulin delivery systems due to which absorption barriers have been removed and the oral bioavailability of insulin has been increased. There is insulin loaded PEGylated calcium phosphate nanoparticles which do not release its insulin in the gastric acidic condition but releases the insulin in the neutral pH of intestine and it is prepared by Ramachandran et al. Yu et al. have made a complicated system, in which the insulin-loaded polymer-lipid hybrid NPs were converted into microparticles by spray freeze-drying and it is loaded in enteric capsules. These enteric capsules could avert the insulin from the harsh conditions of GIT and the NPs released in the intestine could increase the cellular permeability and uptake [5].

Nasal Insulin Delivery System

Intranasal insulin-delivery route is more advantageous than the oral insulin delivery route, because it has the ability to avoid the GI peptidases. It has some other advantages also such as it is non-invasive, painless, also it has no potential side effects associated with lung function. CPEX Pharmaceuticals Inc. has evolved an intranasal insulin spray, it containes regular short-acting human recombinant insulin and they have given the trade name is Nasulin™.The main excipient in this product formulation is cyclopentadecalactone (CPE-215), according to the company, it is there to enhance absorption. CPE-215 is obtained from a plant Angelica archangelica and this CPE-215 is a naturally occurring compound. There are some other components also of this formulation include polysorbate 20, sorbitan monolaurate and cottonseed oil [2]. There is another company Nastech Pharmaceuticals that developed a fast-acting intranasal insulin formulation, which is presently a property of Marina Biotech [3].

Buccal Insulin Delivery System

Being in a joint partnership MonoSolRx Midatech have developed a new buccal formulation. Both the companies have combined their speciality to form this formulation, MonoSol combined its Pharmfilm drug delivery technology and Medatech has combined its gold nanoparticle technology and they called the formulation MidaForm Insulin PharmFilm. In this formulation, recombinant human insulin in this formulation is bound to glycan-coated GNP through noncovalent binding and inserted in a polymeric mucoadhesive film for the delivery of insulin through the buccal mucosa [2]. The administration of insulin through buccal route helps to bypass the GI degradation and in this way it enhances bioavailability of the delivered biomolecules. As buccal insulin delivery system is safe and efficacious, as a result of this, it can be used for both T1DM and T2DM patients and also it is considered as an alternative to SC injections. In India this system has been marketed, with the brand name Oral Recosulin, although the Phase III clinical trials have been performed around the world [3].

Transdermal Delivery Systems

In human body the skin is the largest organ and like insulin it has been used as route of administration for the macroneedles. This non-invasive route of administration provides a good way for absorption of insulin until the bloodstream, allow a good control of diabetes and also circumventing the pain of using needles. Although, the skin is a functional barrier of human body, but it has low permeability due to which it prevent the movement of the hydrophilic macromolecules such as insulin. And to overcome this problem of low permeability of skin for insulin, some techniques have been evolved that permit the transdermal insulin delivery system.

Microneedles, is a insulin delivery system based on the use of microneedles and it is a novel approach to enlarge the transdermal insulin delivery. It has needles, forged in a microscale, with a diameter of 1 micron and the length ranges from 1-100 micron. Microneedles are incorporated with a transdermal patch, which dispensing a minimum invasive transport of insulin until bloodstream [3]. Ultrasonic strip(U-Strip), it is the non-invasive transdermal patch and it is designed by Transdermal Specialities and it can be used by patients who are having either T1DM or T2DM. This U-Strip is a two-component system, containing an insulin patch, which uses an absorbent pad containing up to 150 U of insulin, attached to the second component, the U-Strip controller, which is a transducer device that generates a unique alternating ultrasonic transmission [2].

In diabetic patients, to rule their blood glucose level the Insulin therapy has the great importance. However, frequent injections to the diabetic patients bring inconvenience and pains. For past many years, great attempts have been made to upgrade the insulin delivery to diabetic patients. However, scientists have attained certain improvement, the present treatment is still unsatisfying enough [5]. Search for different insulin-delivery methods that should have minimum invasiveness, convenient, safe, effective and tailored for children and adolescent patients are considered of huge importance. For insulin delivery, various non-invasive methods have been designed. These non-invasive methods of insulin delivery, promise to provide a greater diabetes care by offering enhancement in blood glucose level control in blood and reducing the weight gain, peripheral hyperinsulinemia, hypoglycemic events and late diabetic complications [3]. The microneedles obliged non-invasive delivery is lately believed to be the most efficient method among the numerous insulin delivery techniques. Mostly, the combination of nanoparticles and microneedles is very attractive, which has engaged immense heed from both academia and clinical medicine. The Dance-501 handheld insulin inhaler device and the U-striptransdermal insulin patch system are the two promising non-invasive products. The unique thing about this U-Strip system is that transdermal delivery of insulin is upgraded by combining two types of ultrasonic waveform [2]. 

Each route and delivery method has its own potential advantages and limitations and maybe a universal suitability of a system cannot be possible. Around the world, DM is a disease which affects thousands of people and a single satisfactory pharmacological profile or public adherence is not sufficient to confirm the success of a novel insulin delivery system [3].

1. Jin, Xuan et al. “Insulin delivery systems combined with microneedle technology.” Advanced Drug Delivery Reviews, 2018, https://doi.org/10.1016/j.addr.2018.03.011.

2. Easa, Najma et al. “A review of non-invasive insulin delivery systems for diabetes therapy in clinical trials over the past decade.” Drug Discovery Today, 2018, https://doi.org/10.1016/j.drudis.2018.11.010.

3. Soares, Sandra et al. “Novel non-invasive methods of insulin delivery.” Expert Opinion on Drug Delivery, vol. 9, no. 12, 2012, pp. 1539–1558, https://doi.org/10.1517/17425247.2012.737779.

4. Zhang, Pei et al. “Polymeric nanoparticles based on carboxymethyl chitosan in combination with painless microneedle therapy systems for enhancing transdermal insulin delivery.” RSC Advances, vol. 10, no. 41, 2020, pp. 24319–24329, https://doi.org/10.1039/d0ra04460a.

5. Zhang, Ting et al. “Can nanoparticles and nano-protein interactions bring a bright future for insulin delivery?” Acta Pharmaceutica Sinica B, 2020, https://doi.org/10.1016/j.apsb.2020.08.016.