REVIEW ARTICLE Year : 2023  |  Volume : 14  |  Issue : 1  |  Page : 14-19

The hidden obstacles to intranasal insulin delivery: A narrative review

Ujjawal Rawat, Ambika Choudhary, Piyush Mittal, Anurag Verma
Department of pharmacy practice, Teerthanker College of Pharmacy, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India

Date of Submission13-Oct-2022Date of Decision05-Dec-2022Date of Acceptance15-Dec-2022Date of Web Publication18-Feb-2023

Correspondence Address:
Mr. Ujjawal Rawat
Department of Pharmacy Practice, Teerthanker College of Pharmacy, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, 244001
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jod.jod_108_22

A large number of people are suffering with one or the other type of diabetes around the globe. Insulin has proven to be beneficial for the treatment of both types of diabetes. Due to the drawbacks (injection pain, needle phobia, lipodystrophy, noncompliance peripheral hyperinsulinemia, failure to deliver physiological pattern of insulin, and daily metabolic variability in glycemic control) associated with a conventional delivery system that is, the subcutaneous injection, a need to develop new insulin delivery system was felt strongly. A few noninvasive methods which are under process to deliver insulin include per-oral (enteric gastrointestinal route), intrapulmonary, buccal, intranasal, oropharyngeal, rectal, intrauterine, ocular, transdermal, oral, and vaginal. Intranasal insulin is fetching tons of importance as it provides multiple reasons to choose this method of delivery over other delivery systems. Certain factors are responsible for limiting the use of intranasal insulin for which various methods have been studied to overcome it. Many clinical trials are going on for launching intranasal insulin into the market.

Keywords: Diabetes, insulin, intranasal delivery, oral insulin, subcutaneous insulin

How to cite this article:
Rawat U, Choudhary A, Mittal P, Verma A. The hidden obstacles to intranasal insulin delivery: A narrative review. J Diabetol 2023;14:14-9
  Introduction 

Nearly 422 million people are suffering from diabetes around the globe, says World health organization.[1] It is also responsible for 1.6 million deaths each year and the number is increasing at a fast pace.[2] World health organization also mentions that over time diabetes mellitus can cause severe damage to blood vessels, kidneys, eyes, and heart.

Insulin successfully treats type 1 as well as type 2 diabetes mellitus.[3] Insulin hormone, first discovered in 1921, successfully treated symptoms of diabetes mellitus, is a 51 amino acid protein, constituted of two chains, chain A (it is constituted of 21 amino acids) and chain B (it is constituted of 30 amino acids) and joined by a disulfide bond.[4],[5] Initially insulin is present as pre-pro-insulin, which is converted into pro-insulin by the removal of a signal peptide, followed by cleaving c peptide and producing the mature form of insulin.[6],[7] For persistent maintenance of blood sugar levels in the target range, insulin is the best basic therapeutic option for insulin-dependent/juvenile diabetes/type 1 diabetics as well as for patients with long-standing noninsulin-dependent/type 2 diabetes.[8],[9],[10],[11] Attributed to high molecular weight and short half-life, insulin is administered with the aid of subcutaneous injections.[8],[12] Being a peptide hormone, insulin cannot be taken orally as it is immediately degraded by gastric acid.[13] Delivery of insulin via the standard route, that is, the subcutaneous route is associated with lipodystrophy, noncompliance peripheral hyperinsulinemia, needle phobia, injection pain, failure to deliver a physiological pattern of insulin, daily metabolic variability in glycemic control, slow absorption, and hypoglycemia.[14],[15],[16] A regular pattern of basal and nutrient-linked insulin secretion could not be achieved with subcutaneous insulin due to pharmacokinetic parameters.[17],[18] Furthermore, the inconvenience connected with insulin injections on daily basis has led to the need to establish efficient and reliable noninvasive and noninjectable methods for the administration of insulin.[19] Few noninvasive methods which are under process to deliver insulin include per-oral (enteric gastrointestinal route),[20] oral buccal,[21] oropharyngeal,[22] intrapulmonary,[23] intrauterine,[24] transdermal,[25] intranasal,[26],[27] ocular, rectal and vaginal.[28] Inhaled insulin was the first alternative form of delivering insulin which was noninvasive and to be licensed but later was withdrawn from the market. In the current scenario, intranasal insulin is the focused route of noninvasive insulin administration as it is possibly the maximum feasible and beneficial for persistent systemic medication.[29],[30],[31],[32] On comparing the pharmacokinetic parameters with the subcutaneous route, the intranasal route proves to be highly efficient[33],[34]. Intranasal insulin is fetching importance as it provides multiple reasons to choose this method of delivery such as quick systemic absorption as it has a large epithelial surface area, extensively vascularized nasal mucosa (approx. 160 cm2), unwanted entero-hepatic metabolism of the drug can be avoided, and most importantly patient adherence is increased.[35],[36],[37] Also, the nasal route is superior to the conventional subcutaneous route (noninvasive and painless), oral route (bypass gastro-intestinal peptidases), and inhalational route (lung function not needed). In healthy individuals, pharmacokinetic tests on insulin nasally administered revealed that the onset of action was 10 min of administration. Within 10 min of administration, the glucose-lowering effect reached a dose-dependent peak[38],[39],[40],[41],[42]. On comparing with the time action profile of subcutaneous-administered normal insulin, this profile tends to be more suitable for postmeal insulin substitution. As a result, nasal insulin administration is an appealing route for administration in diabetic patients. Under experimental conditions, giving insulin nasally to type 1 patients resulted in a greater reduction in postprandial glucose than giving it subcutaneous, however, the results have not been confirmed yet in the performed double-blinded studies. Subcutaneous insulin depicted a slow elevation of insulin in the blood, whereas nasal insulin showed a rapid and short-lived increase. A sudden rise and dip in serum insulin concentration characterizes the pharmacokinetic profile of insulin-containing spray.[43]

Nasal insulin has also been reported to affect the cognitive function as it crosses the blood-brain barrier. In a study conducted with 104 adults with cognitive impairment, it improved memory.[44],[45],[46],[47],[48] Even with tremendous benefits, supplying insulin correctly via this route is a tough undertaking because of low delivery payload which results in terrible reproducibility, high volume liquid dosages as well as mucosal irritation.[49],[50],[51] Also, on comparing the bioavailability achieved by intranasal dose administration, it was significantly lower than the parenteral route.[52],[53],[54],[55],[56]

Limitations in intranasal delivery

The intranasal route is well known for its excellent ability to deliver protein and peptide drugs for systemic medications, but the usual anatomy of nasal space affords some limitations to protein and peptide drug absorption. There are certain factors responsible for delayed insulin absorption through the nasal route and act as barriers. These include:

Deposition of drug and clearance of nasal cavity

Infiltration/permeability across the mucosal coating and epithelial membraneEnzymatic degradation by proteolytic enzymes [Figure 1].[2],[3],[57],[58]

Also, nasal mucosal damage and long-term safety is a concern.[59],[60] Inter and intraindividual variability in bioavailability is also depicted.[61],[62]

Deposition of drug and nasal cavity clearance

Particles which might be deposited within side the nasal hollow space will have a tendency to be unexpectedly cleared through mucociliary mechanisms. The expected half-life of clearance is approx. 15–30 min.[63] Thus, being a major drawback mucociliary clearance restricts the duration available for the drug’s systemic absorption. This is particularly important in the case of insulin absorption, which does not exhibit optimal absorption characteristics.[64],[65] There are certain factors on which it depends, where will the drug be deposited and how much time it will take to clear it from the cavity.

Few of the reported factors are

type of delivery system

type of administration devicedroplet or powder particle size[66],[67],[68]

Upto what extent deposition will be there depends on the aerodynamic diameter of the particle of formulation. If the particle diameter is more than 10 micrometers it will entirely be trapped inside the nasal cavity and will not be delivered to the lower respiratory tract whereas if the particle size with a diameter of less than 10 micrometers it will pass through the cavity and be delivered into the lower respiratory tract. Factors such as turbulence of airflow and velocity of the air stream come into play if particle size ranges from 1 to 10 micrometers.

A study was conducted to study the distribution of nasal insulin formulation labeled with 99mTc -human serum albumin. Nasal liquid insulin formulation containing didecanoyl-l-alpha-phosphatidylcholine was added to 99mtc-HSA which was administered by four different methods with a help of a novel pen spray device. The results were indirectly analyzed by measuring the blood sugar concentration. The scenographic data revealed about the deposition of insulin stating that the complete dose was not accumulated in the nasal cavity nor the lungs and regardless of the methods used all four methods give similar results and blood glucose concentrations were similar.[69]

Pathological conditions such as chronic sinusitis, nasal polyps, atrophic or allergic rhinitis, and infection such as common cold are clearly important factors to be considered which tend to reduce the clearance of nasal drug formulations.[70],[71],[72],[73] Diminished mucociliary clearance and also reduced nasal absorption were reported in patients suffering from chronic sinusitis, atrophic rhinitis, allergic rhinitis, and nasal polyposis[71],[72],[73],[74] whereas in patients with rhinorrhea associated with common cold increased mucociliary clearance has been documented.[74],[75] According to a report by Bascom et al., patients exposed to tobacco smoke had increased mucociliary clearance.

Mucus layer and epithelial membrane penetration

Mucus layer has a significant role in shielding the epithelial layer present just under it and is important for the mechanism of mucociliary clearance. For the drugs which are accumulated in the nasal cavity, mucus acts like a physical barrier.[76],[77] Nasal epithelium is an extremely effective barrier to peptide and protein drugs absorption as compared to mucus layer which is not a significant barrier. The drug molecule will be absorbed if it is capable of crossing the mucosal layer as well as the epithelial layer. There are two routes for the absorption of molecules of drug from the epithelial membrane—transcellular or paracellular. When the molecule passes through the tight intracellular junctions between two adjoining cells, it is the paracellular route, whereas in the transcellular route there may be passive diffusion or an actively mediated process or uptake through vesicles.[78] Whether the drug will choose the paracellular route or the transcellular route depends on the characteristics of the drugs as well as the barrier.[79] Highly lipid soluble compound crosses the biological membranes easily via the transcellular route whereas the hydrophilic polar compounds choose the paracellular routes.

Multiple drugs such as propanol,[80] naloxone, buprenorphine, testosterone[81], and 17 alpha ethinyl estradiol[82] show complete nasal absorption in the animal models. Unionized molecules show more absorption across the mucosal membranes than the ionized species.[83] Also, nasal insulin shows complete nasal absorption as per multiple studies.

Enzymatic degradation

Though the first-pass metabolism is avoided when the formulation is administered via the intranasal route, enzymatic deterioration inside the nasal cavity also represents a major barrier to peptide absorption. When insulin was administered intranasally to rats, it showed rapid deterioration (approx. 9% of insulin remained after infusion for 10–60 min.[84] According to a study after taking nasal insulin in humans, it was reported that during the absorption period, local enzymes are likely to destroy 0.5% of insulin given intranasally.

Within 20–30 min of intranasal administration, almost all of the insulin will have reached the pharynx and been swallowed. Aside from insulin loss, the anatomic structures of the nose limit the amount of aerosol volume that can be delivered effectively, restricting the amount of insulin that can be administered at a go. Furthermore, the bioavailability of insulin is limited by the use of more concentrated insulin preparations.

  Methods to Overcome the Barriers to Nasal Insulin Absorption 

The numerous restrictions or obstacles should be removed for insulin to be successfully absorbed through the intranasal route. The marketing of intranasal insulin and many other peptidases is highly restricted because of their very low bioavailability. One of the methods to overcome this obstacle is the utilization of absorption enhancers. Absorption enhancers is the term referred to any substance which can modify the nasal absorption and without the use of absorption enhancers the absorption of intranasal insulin is trifling. There are certain properties required for any substance to act as an absorption enhancer which includes it should be rapidly acting, short-lived and reversible modification of absorptive properties and physiologically of the nasal mucosa and not be absorbed systemically. It should be safe for long-term nasal use and should not damage the nasal mucosa. Bile salts and derivatives cyclodextrins, phospholipids, chitosan, laureth 9, and enzyme inhibitors are well-documented absorption enhancers. Out of the reported enhancers till date, many are found responsible for damaging the nasal mucosa at the concentrations which are required to effectively promote nasal delivery. Hence studies are going on for achieving better substances for the same.

The other way round is the alteration of the structure of insulin itself. Alteration in the structure of insulin will result in enhanced absorption and other pharmacokinetic characteristics along with stability to enzymatic degradation.

Few examples are palmitoyl derivatives of insulin which depicted more lipophilicity than the parent insulin,[85] by modification with fatty acids improved absorption across intestinal membranes.[86],[87] However, unfortunately, enhancement of lipophilicity is associated with decreased pharmaceutical availability, but some derivatives also had equivalent activity as that of the parent insulin.

Another technique to increase the absorption of insulin through nasal mucosa is via the formation of nano-sized emulsions, designated as microemulsions. Microemulsion formulation has given tremendous results with clonazepam[88] and diazepam,[89] contributing the success to low globule size of nanoemulsion.

Various other strategies have also been employed such as glycosylation or PEGylation, the use of enzyme inhibitors, and absorption enhancers (gelatin, cyclodextrin and its derivatives, chitosan and its derivatives, and cell penetrating enhancers) [Figure 2].

Current innovations

Currently, two intranasal innovations are being investigated

Nasal insulin by NASTECH pharmaceuticals companyNasulin (CPEX pharmaceuticals)

The two compositions show bioavailability of nearly 15–25% and the onset of action around 10–20 min.

Nasulin, an intranasal spray constituted of recombinant human insulin depicted fast onset of action (peak at 40 min) and rapid insulin absorption, making it appropriate as after-meal insulin but was unluckily discontinued. More nasal insulin delivery devices are on the way.

A PINIT randomized phase 2 clinical trial (clinicaltrials.govidentifier:NCT03182322) is currently evaluating the safety and immune efficacy of intranasal insulin (440IU) therapy in islet autoimmunity negative children having age between 1 and 7 years who are highly at risk of developing type 1 diabetes. However, a randomized controlled phase 2 trial (clinicaltrials.govidentifier:NCT003366741) has reported the preventive effect of intranasal insulin (440IU) in children and adults (4–30 years) who were at risk of acquiring type 1 diabetes

The 440IU intranasal insulin, which includes recombinant human insulin, benzalkonium chloride glycerol, and water, is administered using nasal spray Pfizer actuators in both clinical trials. The outcomes of phase 2 clinical trials on the other hand are still awaited.

  Conclusion 

Insulin successfully treats type 1 as well as type 2 diabetes mellitus. Apart from the treatment of diabetes, using the intranasal route has also seen to be beneficial in conditions related to cognitive decline. Due to certain factors, the conventional insulin delivery system constitutes a tremendous challenge in the management of diabetes. Intranasal insulin is a great option to deal with it. But there are certain obstacles in intranasal insulin delivery that hinder its utilization. These include deposition of drug in the nasal cavity and nasal cavity clearance, infiltration/permeability across the mucosal coating and epithelial membrane, nasal mucosal damage, inter and intraindividual variability in bioavailability, and enzymatic degradation by proteolytic enzymes. Certain methods to overcome these barriers are enlisted which includes altering the structure of insulin, PEGylation, glycosylation, microemulsion formulation, use of enzyme inhibitors, and use of absorption enhancers.

Acknowledgement

None.

Ethical approval

ethical approval was not needed.

Financial support and sponsorship

No funding sources were provided for conducting this study.

Conflicts of interest

All the authors declare no conflict of interest.

 

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