Nasopulmonay Drug Delivery System Loaded via Nanocarrier

Intranasal administration is particularly beneficial for drugs with poor oral stability, such as peptides and proteins. Additionally, it offers a non-invasive and convenient method that enhances patient compliance¹. The nasal route also enables direct transport of drugs to the central nervous system via olfactory pathways, helping to overcome the blood–brain barrier. Due to these advantages, intranasal delivery has become an important focus in modern pharmaceutical research for both therapeutic and preventive applications^2-3.

For medications like proteins and peptides that have low oral stability, intranasal delivery is especially advantageous⁴. It also provides a convenient and non-invasive approach that improves patient compliance. Additionally, the nasal route helps to cross the blood-brain barrier by allowing medications to be directly transported to the central nervous system via olfactory pathways⁵. Because of these benefits, intranasal administration has gained significant attention in contemporary pharmaceutical research for both therapeutic and preventive uses⁶.

ANATOMY AND PHYSIOLOGY OF NASOPULMONARY DRUG DELIVERY   SYSTEM

Table 1: Anatomy and physiology of nasopulmonary drug delivery system^7-15

• There are three components to the nasal cavity area:

1. The nasal vestibule

The lobby is the first area of the airway that comes into contact with the external environment. In contrast to the rest of the nasal cavity, the vestibule is lined with stratified epithelium.

2. Breathing zone

The breathing zone is the part of the lungs (alveoli) where oxygen enters the blood and carbon dioxide is removed. It helps supply oxygen needed for Cellular Respiration in body cells. It also maintains proper balance of gases and supports normal body functioning¹⁶.

3. The olfactory region

The olfactory region is a specialized area in the upper part of the nasal cavity responsible for the sense of smell. It contains sensory receptors that detect odor molecules and convert them into nerve signals, which are then sent to the brain for identification. This process allows us to recognize different smells and also contributes to taste and environmental awareness.

• Vestibule

The nasal vestibule filters large particles using nose hairs and mucus. It also protects the airway by trapping dust and germs before they enter deeper respiratory parts. It contributes to the humidification and slight warming of incoming air, facilitating easier breathing¹⁷.

• Nasal valves

The nasal valve regulates airflow by controlling the resistance of air entering the nasal cavity. It helps direct and limit airflow to ensure efficient breathing and prevents the nasal passages from collapsing during inhalation.

• Nasal septum

The nasal septum separates the nasal cavity into two passages, ensuring even airflow through both nostrils. It provides structural support to the nose and helps direct incoming air for proper filtering, warming, and humidifying¹⁸.

• Nasopharyngeal region

The nasopharyngeal region allows air to move from the nasal cavity to the throat for respiration. It filters dust and microbes using mucus and cilia, helping keep the air clean. It also warms and moistens inhaled air for easy breathing. It provides immune defense through lymphoid tissue and helps clear mucus to maintain an open and healthy airway¹⁹.

• Trachea bronchial region

 The trachea conducts air between the larynx and the bronchi. It also filters, warms, and moistens the air before it enters the lungs²⁰.

• Lungs

The lungs help the body breathe by taking in oxygen and removing carbon dioxide. Oxygen from the air enters the blood in the alveoli, while carbon dioxide from the blood is released and breathed out. This process supports energy production in body cells and keeps the internal environment balanced²¹. Lungs act as organs that exchange gases between air and blood to keep the body alive and functioning properly.

• Pulmonary epithelium

The pulmonary epithelium forms a barrier that protects lung tissue from harmful substances and pathogens. It also facilitates gas exchange and helps maintain fluid balance in the lungs.

• The bronchi

 The bronchi conduct air between the trachea and the bronchioles in the lungs. They also filter, warm, and moisten the air before it reaches deeper parts of the lungs²².

• Bronchioles

Bronchioles are small air passages that carry air from the bronchi to the alveoli in the lungs. They regulate airflow by expanding or narrowing, ensuring proper distribution of air for gas exchange.

• Alveolar region

The alveolar region is responsible for gas exchange, allowing oxygen to enter the blood and carbon dioxide to leave it. It also helps maintain efficient respiration due to its thin walls and large surface area²³.

MECHANISM OF ACTION OF NASO DRUG DELIVERY SYSTEM

There are two main ways in which drug molecules pass through the nasal mucosa.

1. Trancellular pathway: This is the preferred route for lipophilic drugs because they can dissolve in the lipid bilayer of cells film. They pass directly through the epithelial cells of the nasal mucosa²⁴.
2. Paracellular pathway: Most drugs that use this route are hydrophilic, making it difficult for them to enter the body of the cell membrane. They move through the spaces created by epithelial cells^25-26.

3. Table 2: List of mechanisms of nasal drug delivery systems^27-28

CONTROLLED RELEASE DRUG DELIVERY SYSTEM

Controlling medicine concentrations, reducing the number of doses, maximising drug use, and enhancing patient adherence are all made possible by controlled release drug delivery systems. However, compared to conventional pharmaceutical formulations, they may also have drawbacks such material toxicity, biocompatibility problems, unwanted product degradation, the need for surgery, patient discomfort, and greater prices²⁹. A zero-order release profile indicates consistent drug release, and controlled drug delivery is the regulated administration of a medication over a predefined period of time. Conversely, sustained release dosage forms are administered in a certain way that ensures a prolonged but erratic therapeutic concentration. The first dose is administered quickly, and the remaining dose is released gradually³⁰. The effectiveness of nasal and pulmonary drug delivery channels, which are widely utilised for both local and systemic therapy, is greatly improved by Controlled Drug Delivery Systems (CDDS). These pathways have special benefits, such as a large absorptive surface area, a quick beginning of action, and avoidance of first-pass metabolism.

Fig 1: Controlled Release Drug Delivery System

BENEFITS OF CONTROLLED RELEASE DRUG DELIVERY SYSTEM

1. Sustained drug release: Systems for controlled release offer a steady and prolonged pharmaceutical release over an extended duration, guaranteeing a steady and therapeutic drug concentration in the body.
2.  Fewer frequent doses: CDDS often allows for less frequent dosing regimens than formulations for immediate release, which improves patient convenience and compliance.
3. Decreased side effects: By carefully releasing the medicine, peak plasma concentrations can be decreased, potentially reducing adverse side effects and enhancing the treatment's safety profile.
4.  Enhanced efficacy: These systems may increase a medication's efficacy and potentially improve treatment outcomes by optimising drug delivery to the intended site.
5. Better bioavailability: Controlled release formulations, which keep drug levels within the therapeutic range, can provide longer-term drug absorption and bioavailability.
6.  Reduced administration frequency: Extended-release formulations can improve patient comfort and adherence by reducing the daily dosage requirements.
7. Targeted medication delivery: Certain controlled release systems can reduce off-target effects and improve medication delivery efficacy by concentrating on specific tissues or cells^31-32.

Commonly Used Nanocarriers for Nasopulmonary Delivery

Table 3: Commonly used nanocarriers for nasopulmonary delivery ^33-37

1. LIPOSOMES

Liposomes are spherical nanocarriers that contain phospholipid bilayers and an aqueous core. They protect hydrophilic and lipophilic medications from deterioration and improve absorption through the mucosa of the nose and lungs. Sprays, nebulisers, and inhalers are used in nasopulmonary delivery³⁸. By adhering to the respiratory epithelium, liposomes (50–500 nm) improve drug stability and efficacy and reduce systemic side effects while facilitating targeted delivery to lung tissues^39-40.

2. MICELLES

Amphiphilic molecules in water self-assemble to create micelles, which are tiny transporters. They allow for targeted drug administration and range in size from 10 to 100 nm⁴¹. They administer medications through sprays or inhalation in nasopulmonary systems, avoiding first-pass metabolism and guaranteeing quick absorption⁴². They are helpful for medications that are poorly soluble in water, such as anticancer, anti-inflammatory, and antibiotics⁴³.

Mechanism of micelles nanocarrier used in nasopulmonary system

Figure 2 :- Mechanism of micelles nanocarrier used in nasopulmonary system

3. GOLD NANOPARTICLES

Gold nanoparticles (AuNPs) are exceedingly small gold particles, typically ranging in size from 1 to 100 nm⁴⁴. They are commonly used as drug delivery nanocarriers due to their biocompatibility, large surface area, and ease of surface modification. Gold nanoparticles facilitate the direct administration of medications to the respiratory tract or systemic circulation through the nasopulmonary drug delivery system, utilising the nose and lungs⁴⁵.

4. DENDRIMERS

Synthetic, highly branched nanocarriers called dendrimers are utilised in nasopulmonary medication administration by inhalation or nasal sprays. Drugs might be linked to surface groups or contained within the core due to their structure. PAMAM and PPI dendrimers are common varieties⁴⁶.  They improve the bioavailability, stability, and solubility of medicines, particularly those that are unstable or poorly soluble. Targeted and regulated drug delivery to the respiratory system is made possible by dendrimers⁴⁷.  They are being researched for the treatment of lung conditions such as cystic fibrosis, cancer, asthma, and tuberculosis. Dendrimers also enhance nasal mucosal absorption, which increases therapeutic efficacy by facilitating quicker drug delivery to lung tissues or systemic circulation⁴⁸.

5. QUANTUM- DOTS

Quantum dot–polymer materials are hybrids where very small semiconductor particles are combined with polymer substances. The quantum dots provide special light and electronic properties, while the polymer acts as a flexible, protective support. This combination makes the material stable, easy to shape, and useful in devices like displays, sensors, and medical tools⁴⁹.

Mechanism of action of loaded drug via nanocarrier

Fig 3: Mechanism of action of loaded drug via nanocarrier

 NASO-PULMONARY MEDICATION DELIVERY SYSTEMS'S DOSAGE  FORMS

1. Nassal drops

They represent the simplest and most effective nasal drug delivery system currently available. Nose drops can be applied using a pipette or a squeezy bottle. For the treatment of local issues such as microbial growth, mucosal malfunction, and nonspecific loss of the nose or lower back, these medication formulations are often recommended. Nasal drops may not be useful for prescription drugs because the system's primary flaw is its lack of dosing precision. Nasal drops have been shown to deposit human serum albumin in the nostrils more successfully than nasal sprays ^50-51.

Table 4:- Method of nasal drops  loaded via nanocarrier

2. Nasal sprays

Nasal sprays are composed of suspension and solution. A nasal spray can accurately deliver a dose between 25 and 200 μm when metered dose pumps and actuators are available⁵².  The drug's morphology, formulation viscosity, and particle size (for suspensions) all influence the choice of pump and actuator assembly^53-54.

Table 5 :- Method of nasal spray drug loaded via nanocarrier

3. Nasal gels

Nasal gels were not very popular prior to the recent development of an exact dosing device. Nasal gels are highly viscous liquids or solutions that have been thickened⁵⁵. The benefits of nasal gels include reduced post-nasal drip due to their high viscosity, a diminished flavour effect from less swallowing, decreased anterior formulation leakage, and increased comfort from soothing and emollient ingredients⁵⁶.

Table 6:- Method of nasal gel drug loaded via nanocarrier

4. Nasal powders:

This dosage form may be developed if solution and suspension dosage forms cannot be made, for example, due to a drug's instability⁵⁷.  The benefits of the nasal powder dose form include the absence of an improved stability and preservative in the formulation. However, whether the powder formulation is suitable depends on the solubility, particle size, aerodynamic properties, and nasal irritation of the active drug and excipients⁵⁸. The drug's local application is another advantage of this approach, as it allows for targeted delivery to the nasal mucosa, potentially enhancing therapeutic effects while minimising systemic side effects⁵⁹.

5. DPIs, or dry powder inhalers

Depending on the source of airflow for powder aerosolisation, there are two types of dry powder inhalers: passive and active. Additionally, they come in single-use, multi-dose, and reusable varieties⁶⁰. They are classified into various categories based on the method of powder dispersion, the capacity of the dose, and the level of patient involvement during the powder aerosolisation process. DPIs are separated into three categories based on dose capacity: medium-dose capacity aerosolisation, low-dose capacity devices, and powder dispersion mechanisms⁶¹. These devices can be categorised as single-unit dose, multi-unit dose, and multi-dose reservoirs in terms of dose capacity. They have been used to treat diabetes mellitus as well as conditions like asthma, bronchitis, emphysema, and COPD^62-63.

Table 7:- Method of dry powder inhalers drug loaded via nanocarrier

6. Metered dose inhalers (MDI)

A metered-dose inhaler (MDI) is a device that allows patients to self-administer a certain amount of medication by inhaling a brief burst of aerosolised drug into their lungs⁶⁴. A pressurised medication container that fits into a mouthpiece is a feature of the Meter Dose Inhaler (MID). By inserting the container into the mouthpiece, a dose

of medication is released into the lungs⁶⁵.

Table 8 :- Method of Metered Dose Inhaler Drug Loaded via Nanocarrier

7. Nebulizers

The two nebulisers available differ in the force used in the creation of the aerosol from the corresponding liquid. Depending on the model and manufacturer, nebulisers produce droplets with a diameter of 1-5 μm. These devices do not demand coordination of the patient with inhalation and actuation of the device. Therefore, nebulisers are used in paediatric patients, elderly patients, ventilated patients, non-conscious patients, or those incapable of using pMDIs or DPIs^66-67.

Table 9: Nasopulmonary medication delivery system dosage form