Intranasal Drug Administration in Alzheimer-Type Dementia

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1		Jesus Vicente de Julián-Ortiz	--	1514	2023-05-19 21:53:17	\|
2	format correct	Conner Chen	Meta information modification	1514	2023-05-22 04:44:54	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15051399

Alzheimer-type dementia (ATD) treatments face limitations in crossing the blood–brain barrier and systemic adverse effects. Intranasal administration offers a direct route to the brain via the nasal cavity’s olfactory and trigeminal pathways.

intranasal delivery Alzheimer blood–brain barrier

1. Nasal Cavity Anatomy

The main functions of the nasal cavity are breathing and smell, and, in addition, it exerts a protective action of filtering, warming and humidifying the inhaled air before it reaches the lower respiratory tract ^[1]. Likewise, it is composed of two symmetrical cavities that are divided by the nasal septum and lined with a layer of mucosa. These cavities in turn are divided into three regions:

Vestibular region: This is the most anterior area, and contains nasal hairs to filter inhaled particles and the main cell type is squamous epithelial cells. In this region, drug absorption is very limited ^[2].
Respiratory region: This is the area with the largest surface (about 130 cm²) and the most vascularity, which makes it an ideal place for the systemic absorption of drugs. It encompasses the lateral walls of the nostrils, including the protruding nasal turbinates. There are four main cell types: goblet, ciliated, non-ciliated columnar and basal. In addition, the respiratory region is innervated by the maxillary and ophthalmic branches of the trigeminal nerve (V1, V2) ^[3].
Olfactory region: This is located on the roof of the nasal cavity and covers only 10% of the total nasal area. There are different types of cells: basal cells, olfactory nerve cells, support cells, cilia and trigeminal neurons. In addition, the olfactory region facilitates the transport of drugs to the brain having a direct connection with the brain through the olfactory and trigeminal neurons ^[4].

Figure 1 illustrates the anatomy of the nasal cavity and provides a schematic representation of the olfactory region.

Figure 1. (a) Anatomy of the nasal cavity, adapted from ^[5]. (b) Schematic representation of the olfactory region, adapted from ^[6].

2. Intranasal Absorption

The first step in drug absorption from the nasal cavity is to cross the mucus layer. Mucin, which is the major mucus protein capable of binding solutes, hinders drug diffusion. Non-ionized, lipophilic and small particles easily pass through this layer of mucus. Thus, the molecular weight and lipophilicity of drugs can have a large impact on the rate and degree of nasal absorption of drugs. However, other physicochemical properties of the drug and the formulation must also be considered, as well as some physiological factors of the nose, which may also influence the bioavailability and transport of the drug from the nose to the brain ^[7].

Figure 2 summarizes the main factors that influence the nasal absorption of drugs administered by this route.

Figure 2. Factors affecting absorption through the nasal route ^[7].

Once through the mucus, different mechanisms of absorption can be followed through the nasal mucosa: transcellular diffusion, paracellular transport, endocytic vesicle-mediated transport and carrier-mediated transport. Transcellular diffusion is the main mechanism of absorption and is the most suitable for lipophilic and low molecular weight molecules ^[8]^[9]. Figure 3 schematically represents the different mechanisms of absorption through the nasal mucosa.

Figure 3. Mechanisms of drug absorption across the nasal epithelium ^[5].

3. Nose–Brain Absorption Pathways

(a): Direct Absorption Mechanism

Olfactory Sensory Neurons

The olfactory nerve pathway is a direct and primary route of drug transport from the nasal cavity to the brain, preventing its passage through the BBB. When the drug reaches the olfactory receptors after passing through the nasal mucosa, there are two transport mechanisms to the brain: the intracellular route, in which the drug is taken up by the olfactory neurons through a process of endocytosis, and the extracellular route, in which the drug crosses the nasal epithelium through the tight junctions between the olfactory nerves and the supporting cells ^[10].

In both cases, the molecules travel through the cribriform plate, which separates the brain from the nasal cavity, to enter the olfactory bulb and the CSF. Subsequently, the drug can be distributed from the CSF to the brain by mixing with the interstitial fluid of the brain. The intracellular route requires from hours to days for the active fraction to reach the different regions of the brain and is adequate for the passage of lipophilic molecules, while the extracellular route only requires a few minutes for the active fraction to reach the brain and is suitable for the passage of hydrophilic molecules ^[11]. Figure 4 schematically represents the intranasal transport of drugs through the olfactory route to the CNS by the intracellular and extracellular route.

Figure 4. Intranasal transport of drugs through the olfactory route to the CNS by intracellular and extracellular routes ^[10].

Trigeminal Neurons

Both the respiratory and olfactory epithelium are supplied with trigeminal nerves (Figure 5). Branches from the ophthalmic division (V1) of the trigeminal nerve innervate the dorsal and anterior part of the nasal mucosa, and those from the maxillary division (V2) innervate the turbinates.

Once the drug has diffused through the mucosa, it allows its transport directly to the brainstem at the level of the pons, avoiding its passage through the BBB. Transport through the trigeminal route can also occur intracellularly or extracellularly, as occurs with olfactory neurons ^[12].

Figure 5. Innervation of the trigeminal nerve in the nasal cavity ^[13].

(b): Indirect Absorption Mechanism: The Systemic Route

When a drug is deposited in the nasal cavity and depending on its residence time, a part of it can be absorbed and enter the systemic circulation due to the rich vasculature of the respiratory epithelium and reach the brain through the BBB. This is a secondary route of drug transport to the brain after nasal administration ^[14].

Small lipophilic molecules gain access to the bloodstream and penetrate the BBB much more easily than high molecular weight and hydrophilic molecules. In addition, the active substances that use this route undergo renal and hepatic metabolism, so that the amount of drug that finally reaches the brain is very low and depends on the partition coefficient (0.5–6.0) and the molecular weight of the drug (<500 Da). It also leads to a higher incidence of unwanted side effects in other peripheral organs ^[15].

Figure 6 schematically represents the structure of the nasal cavity and the different mechanisms of drug transport through the nasal mucosa to the brain.

Figure 6. Schematic representation of the structure of the nasal cavity and the mechanisms of drug absorption through the nasal mucosa to the brain. (A) Direct absorption mechanism through olfactory nerve and trigeminal route. (B) Indirect absorption mechanism by systemic route ^[16].

4. Advantages and Disadvantages of the Nasal Route

To date, numerous techniques have been developed to circumvent the BBB and improve drug delivery to the brain, including invasive techniques, such as surgical exposure or intrathecal and intraventricular routes of administration.

The intranasal route offers a non-invasive strategy to bypass the BBB and provide direct drug access to the brain in a short period of time, as it has a direct connection to the brain through neural channels. In addition, the nasal cavity has a large number of blood vessels with rapid blood flow and has a large available surface area for absorption. For this reason, it offers other advantages such as rapid drug absorption, avoidance of hepatic metabolism and easy administration, which increases patient compliance ^[17].

However, there are several obstacles that can limit absorption of drug through this pathway, such as poor drug permeability from the nasal mucosa, mucociliary clearance, enzymatic degradation of the drug, low drug residence time and possible toxicity that the formulation or drug can produce on the nasal mucosa. In addition, due to the limited volume of application through this route, the dose of the drug may be limited depending on its solubility in the vehicle, so it will only be applicable to potent drugs that allow obtaining sufficient pharmacological effect at low doses or by using dry powders. Likewise, it would be convenient to reserve this route for those active principles with a wide therapeutic margin due to the possible inaccuracy of the dosage after administration. All these characteristics make it difficult to obtain bioavailability into the brain via the intranasal route ^[2]. For this reason, numerous technological strategies have been investigated to overcome these drawbacks and improve the bioavailability of drugs administered intranasally, which will be detailed later.

Table 1 indicates the main advantages and disadvantages associated with the administration of drugs through the nose.

Table 1. Advantages and drawbacks of nasal drug administration.

Advantages	Disadvantages
Non-invasive, safe and painless Lower risk of infections Easy administration and better patient compliance Alternative to parenteral route of administration, especially for protein and peptide drugs Large absorption area and extensive network of blood and lymphatic vessels Rapid absorption and excellent bioavailability for low molecular weight drugs Prevents first-pass hepatic metabolism and drug degradation in the gastrointestinal tract Possible direct delivery to the brain bypassing the BBB via the olfactory and trigeminal nerves	Only applicable to potent drugs with a wide therapeutic margin Small volumes of administration (25–200 μL) Mucociliary clearance and low residence time Enzymatic degradation Low permeability of hydrophilic drugs Need for absorption promoters that can cause toxicity in the nasal mucosa Epithelial mucous pH 5–6.5 Interindividual variability Runny nose influences absorption Possible inaccuracy in dosage due to improper administration technique Some drugs and excipients can cause irritation to the nasal mucosa

Advantages

Disadvantages

Non-invasive, safe and painless
Lower risk of infections
Easy administration and better patient compliance
Alternative to parenteral route of administration, especially for protein and peptide drugs
Large absorption area and extensive network of blood and lymphatic vessels
Rapid absorption and excellent bioavailability for low molecular weight drugs
Prevents first-pass hepatic metabolism and drug degradation in the gastrointestinal tract
Possible direct delivery to the brain bypassing the BBB via the olfactory and trigeminal nerves

Only applicable to potent drugs with a wide therapeutic margin
Small volumes of administration (25–200 μL)
Mucociliary clearance and low residence time
Enzymatic degradation
Low permeability of hydrophilic drugs
Need for absorption promoters that can cause toxicity in the nasal mucosa
Epithelial mucous pH 5–6.5
Interindividual variability
Runny nose influences absorption
Possible inaccuracy in dosage due to improper administration technique
Some drugs and excipients can cause irritation to the nasal mucosa

References

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Subjects: Neurosciences

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Raquel Taléns-Visconti

Jesus Vicente de Julián-Ortiz

Ofelia Vila-Busó

Octavio Diez-Sales

Amparo Nácher

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Update Date: 22 May 2023

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