ReviewStrategies for the delivery of antidiabetic drugs via intranasal route
Graphical abstract
Introduction
Diabetes is a complex chronic endocrine disorder identified by higher blood glucose levels with the addition of a risk of developing life-threatening health problems that include higher medical care costs, reduced quality of life, and larger chances of mortality (Cho et al., 2018). According to the World Health Organization, 422 million people were affected and around 1.6 million deaths were reported due to diabetes in 2020. Diabetes mellitus is categorized into 3 types: Type 1 (insulin-dependent diabetes mellitus), Type 2 (non-insulin-dependent diabetes mellitus) and gestational diabetes. Type 1 Diabetes Mellitus (T1DM) occurs when there is less production of insulin in the body due to the autoimmune destruction of the β-cells of the pancreas whereas in Type 2 Diabetes Mellitus (T2DM) the body becomes resistant to insulin and causes a relative deficiency of insulin and it is the 90% of the total diabetic cases. Also, gestational diabetes occurs when females become glucose intolerant during pregnancy and this is attributed to the hormonal changes in the body. This condition is harmful to the foetus, neonates as well as the mother and leads to adverse outcomes if the blood glucose level is not maintained properly (Diabetes, 2013, Shende et al., 2017). The drugs in the management of diabetes are classified according to their effect on insulin resistance, rise in the level of insulin in the body, enhancement in insulin sensitivity, and some other miscellaneous ways to control the glucose level in the blood as shown in Fig. 1. Administration of insulin is used to maintain the blood glucose level in T1DM and also in the lateral stages of T2DM when the oral antidiabetic drugs are ineffective. It is administered in the form of subcutaneous injections and not by conventional oral route because peptides are unstable in the gastrointestinal environment. The subcutaneous route shows low patient compliance because of frequent administration and pain at the site of injection (Khair et al., 2020, Wong et al., 2016). Other routes for administration like transdermal, pulmonary and inhalation are considered as alternatives to the subcutaneous route. The transdermal route is difficult due to the low permeability of insulin through the skin, the pulmonary and inhalation delivery require optimum lung physiology because it directly affects the delivery of insulin. Amongst all the methods inhalation shows more effective delivery providing optimum absorption, stability and higher bioavailability. The drawbacks of inhalation formulations that limit their acceptance are low patient compliance, lack of safety profile, and cost-effectiveness (Wong et al., 2016).
The drugs used in the management of T2DM administered via the oral route are biguanides, thiazolidinediones, α-glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) agonists, sulfonylureas, meglitinides, dipeptidyl peptidase 4 inhibitors (DPP-4Is), bile acid sequestrants, and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is). Biguanides reduce glucose production in the liver, absorption in the gastrointestinal tract (GIT) and improve insulin sensitivity by higher peripheral uptake of insulin. Metformin is the only commercially available biguanide and shows a higher incidence of side effects like nausea, anorexia, weight loss and taste disturbance by the large dose required for the oral route and low bioavailability of 50–60%. Other routes for the delivery of these drugs are in the process of development (Cetin and Sahin, 2016, Tran et al., 2015). Thiazolidinediones like pioglitazone and rosiglitazone activate peroxisome proliferator-activated receptor-γ (PPAR-γ) and reduce insulin resistance in the liver and periphery (Tran et al., 2015). GLPs are a recently developed class of drugs that inhibit the production of glucagon and restores insulin secretion. The peptides are large hydrophilic molecules and generally undergo degradation in the gastric environment which leads to low bioavailability. Therefore, it is difficult to transport such drugs through the gastrointestinal epithelium by paracellular or transcellular route (Gallwitz, 2019, Ismail and Csóka, 2017). The drugs are administered in the form of subcutaneous and intravenous injections consequently the limitation is the administration of multiple injections depending on the dosing requirements. To overcome this issue, other routes of administration like oral, transdermal, and intranasal routes are widely adopted and tested. DPP-4 inhibitors are the gliptins (sitagliptin, linagliptin, gemigliptin) that act by increasing the levels of incretins such as GLP-1 and insulin secretion in the blood (Gallwitz, 2019, Poudwal et al., 2020). Sulfonylurea (glyburide, glipizide, and glimepiride) drugs bind to specific β-cells of the pancreas and increase secretion of insulin. From the two generations of sulfonylureas, the second-generation drugs are more commonly used than the first generation due to the improved adverse reaction profile. The class of meglitinides (nateglinide, and repaglinide) inhibits the ATP-dependent potassium channels and raises the secretion of insulin in the blood. The α-Glucosidase inhibitors acarbose and miglitol are used in prevention of diabetes by reducing hydrolysis of polysaccharides in the small intestine. This class requires the presence of polysaccharides in the consumed food to be effective but no physiological change is observed in their absence. Bile acid sequestrants such as colesevelam reduce the blood glucose levels without affecting the body insulin levels but its mechanism of action remains unclear. SGLT-2 causes the reabsorption of glucose from renal tubules and excretes it when the resorptive capacity is attained. The drugs belonging to this class are dapagliflozin, canagliflozin and empagliflozin used either in mono- or in combinational therapies with other classes of drugs that inhibit the SGLT-2 function and reduce glucose levels in the body (Tran et al., 2015). The oral route is preferred for administration of antidiabetic drugs over conventional because of the ease of dosing, lower risk of hypoglycaemia, efficacious and safe delivery but due to the disadvantages such as frequency of administration and low bioavailability (metformin shows a bioavailability of 65%) to overcome the setbacks of oral route other pathways of administration are developed one of them is the intranasal route (Stein et al., 2013). The intranasal drug delivery is a non-invasive method traditionally used for local diseases such as nasal allergy, congestion, and infections. Apart from the local diseases, nasal delivery is effective for systemic delivery of the drug in crisis treatments, long-term treatments, vaccine delivery of antigen, and DNA vaccines. The drug delivery intranasally is not complicated and all types of formulations solutions, suspensions, powders, in-situ gels and ointments are administered by the route (Kaur et al., 2016). The scope of intranasal delivery ranges from the products of small molecular weight drugs (sumatriptan, desmopressin, non-steroidal anti-inflammatory drugs oestradiol) to large proteins and peptides (insulin, calcitonin, leuprolide, interferon) by using different enhancement methods (Duan and Mao, 2010, Illum, 2002). Various formulations used in the administration via nasal route transported and absorbed by paracellular or transcellular route in the forms of drops, sprays, gels, powders, inserts, ointments, microemulsions, and particulate system (Kaur et al., 2016). This review article depicts the strategic transportation of drugs via intranasal route with the advantages and drawbacks in comparison to other routes like oral, parenteral, transdermal, etc and modifying the delivery through the nasal route by using polymers (chemical modifiers and absorption enhancers), temperature-sensitive gels, smart insulin delivery systems and deep eutectic mixtures.
Section snippets
Mechanisms of intranasal drug delivery
The nasal cavity is recognised by a large surface area (150 cm2) for the absorption of a drug due to the presence of numerous microvilli and cilia on the surface of the nasal epithelium. The nasal epithelium contains long thin projections (4–6 µm) moving with a speed of 1000 S per minute. This propels the mucus to move towards the posterior part of the nasal cavity to increase the rate of transfer of drug towards the portion of the cavity from where the drug gets absorbed inside the body (
Intranasal route in diabetes
The intranasal route for its advantages over the parenteral routes of administration is used for diabetes in the delivery of insulin and GLP-1 agonists. The easy accessibility of the nasal cavity makes it possible for the patients to self-medicate for long-term therapies and reduce the frequency of administration that increases the patient compliance (Duan and Mao, 2010). When insulin is administered by intranasal route it provides better control in postprandial hypoglycaemia in
Strategies for intranasal delivery for antidiabetic drugs
Several methods tried and tested for the delivery of drugs by the intranasal route and the different barriers are eliminated by the improvement in the half-life of the drugs, higher mucoadhesion and retention time, protection from the degradation of enzymes, polymers that enable delivery through the tight junctions of the nasal epithelium and enhanced potency of the drugs administered. All these methods as shown in Fig. 3 and several others presently are adopted for a common achievement to
Challenges
Lipophilic drugs (alprenolol and propranolol) are entirely absorbed with 80–100% bioavailability in contradiction to the polar and high molecular weight therapeutics (such as peptides and proteins) like insulin, shows the bioavailability less than 1%. Drugs cross the nasal mucosa by paracellular (through tight junctions between the cells) or transcellular (receptor-mediated transport or vesicular transport mechanism) route where the delivery of hydrophilic drugs is limited due the low
Toxicity
The use of the nasal route for delivery of the number of drugs is limited due to potential toxicity via the nasal membrane either by use of permeation enhancers, enzyme inhibitors or even by individual drugs (Bae et al., 2019). Despite this situation and its possibilities, the delivery of antidiabetic drugs intranasally is not toxic to the body. A formulation of intranasal GLP-1 containing permeation enhancers increased the bioavailability of the drug in rabbits by 5 fold but resulted in a low
Conclusions and future perspectives
In the last two decades, the nasal delivery of antidiabetic drugs was extensively studied and tested. The conventional methods of delivery require modifications to improve patient compliance and therapeutic effect of the drugs. Intranasal delivery is capable of providing the required therapeutic level of the drug for management of T1DM and T2DM with adequate safety and efficacy. The delivery of insulin and GLPs are under research but the other antidiabetic drugs need to be analysed. The
CRediT authorship contribution statement
Jheel Dholakia: Writing – original draft. Bala Prabhakar: Writing – review & editing. Pravin Shende: Conceptualization, Writing – review & editing, Visualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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