Review on Naso-Pulmonary Drug Delivery System

The most convenient and favored method of medicine delivery is oral administration due to its simplicity in manufacturing and administration. Inadequate gastric absorption prompted research on alternative medication delivery systems. The term “Nasya” refers to the ancient Indian ayurvedic medical system use of the nasal route for medicament administration. This day intranasal drug delivery is thought to be more reliable and successful than parental and oral medicine delivery techniques. Without a doubt intranasal Drug administration has been used widely for a very long time to treat, prevent or alleviate the symptoms of topical nose illness [2].                                                                                   The medication being given and The intended place of action determine the kind of device that is used Breathold dilation, Leukotriene inhibitors and inhaled corticosteroid are among the several treatment that are Frequently given utilizing NPPDS for treatment of asthma Nasal Decongest: you can use Nasal spray that contain decongestant to treat nasal congestion brought on by allergies or Other like common cold; prescription drug for migranes such as the nasal spray, harmone Replacement therapy such as the administration of estrogen and testosterone is used for Harmone replacement therapy in the form of nasal spray . It has been suggested that using the nasal mucosa as an administration route could Increase and speed drug absorption. The reason for this is Because of its big surface area, porous endothelium membrane, high blood flow overall, ability to evade first pass metabolism, and convenient accessibility. Recent year have seen a significant amount of research on the nasal delivery of medication for systemic treatment, including peptide and protein medicines, among many other molecules [4]. Many researchers have recently tried to deliver medication to the central nervous system via the nose. However, the formulation inadequate contact with the nasal mucosa is the main drawback of administrating medication via the nasal route. In an attempt to improve nasal drug absorption numerous attempts have been undertaken recently to lengthen the duration of drug formulation residence the duration of drug formulation residence in the nasal cavity. Because of nasal mucosa high degree of permeability and vascularization researchers have been interested in using the nasal route for systemic pharmaceutical distribution. Numerous scholars have examined the vascular Nature and structural features of the nasal membrane in reaction to drug administration. The septum divides the nose into two nasal chambers. Each cavity has a surface area of roughly 75cm² and a capacity of around 7.5ml. The vestibular, respiratory and olfactory region of nose are its three distinct function regions. The respiratory area is the most crucial for systemic medication distribution among them. Basal mucus containing goblet, ciliated columnar and non-ciliated columnar cell type make up the respiratory epithelium. To transfer particle to the pharynx area for ingestion, the cilia move in wave-like manner. Furthermore, almost 300 microvilli cover the cell in these area, offering a sizable surface area for absorption. The lamina propria lies behind the epithelium, blood vessels, nerves, mucus secretary gland, and Serous gland may be located here [1].                                                                                                                                    

A layer of mucus covers the nasal tube epithelium, this layer is replaced ever ten to fifteen minutes. In adult, the PH of mucosal secretion ranges from 5.5- 6.5, while in children it ranges from 5.0 to 6.7. Particular are caught in mucus layer and subsequently expelled from the nasal cavity by the cilia. Every 20 minutes, the mucus in the nose clear the particle moving through the pace of about 5-6mm/min. Numerous enzymes are also found in nasal cavity. These isoforms of cytochrome P450 enzyme have been found in human-CYPIA, CYP2A, CYP2E Additional enzyme found in human nose include glutathione s-transferase and carboxylesterase. In recent years, a workable solution for administering drugs through the nose has emerged: the Nasopulmonary drug delivery system. This comprehensive review looks into the potential applications and benefits of the drug delivery system as well as its future prospects [3]. A nasal-pulmonary drug delivery system is one non-invasive method of getting medication into the lungs through the nose (NPDDS). These systems have the following advantages over traditional oral and injectable drug delivery methods: rapid absorption because of the large surface area and high vascularity of the nasal and pulmonary mucosa; first-pass metabolism avoidance drugs administered through the NPDDS bypass the liver, which can lower the bioavailability of certain drugs targeted delivery [5].

2. ADVANTAGES: _-

• Fast on set of Action: -

Compare to oral administration nasal medication delivery has a speedier therapeutic impact and faster absorption because of nasal cavity thin mucosal barrier.

• Avoidance of first pass Metabolism: -

When are administered by the nasal route, they avoid the liver first pass Metabolism, which increases their bioavailability and maintain more stable plasma concentrations than when that are administered orally.

• Non-invasive Administration: - Because nasal drug delivery is generally well tolerated and non-invasive, it is appropriate for individual who may have trouble swallowing pills or who need to take their medication frequently.
• Administration Ease: -Nasal medication delivery is easy to use and convenient, frequently requiring little effort from the patient and no special equipment to administer, which can enhance patient compliance 
• Localized Drug Delivery: - By delivering medication specifically to certain area of lungs or nasal cavity, nasal drug delivery minimizes systemic exposure and lower the possibility of systemic side effects.

3. DISADVANTAGES: -

1. Pathological disorder as allergic or cold can drastically change the nasal bioavailability
2. It is currently unclear whether the absorption enhancer utilizes in nasal drug delivery systems are histologically harmful.
3. Comparatively inconvenient for patients in comparison to oral administration method due to potential for nasal discomfort
4. In comparison to GIT, the nasal cavity offers a lower surface area for absorption.                        

4.Anatomy and Physiology of Nasal 

• Nasal Vestibule: -This area of nasal cavity, which is the most anterior, is coated with skin that has sebaceous gland and hair follicles. Hair serves as the filter to remove bigger particles from inspired air.
• Nasal Septum: - Made of bone posteriorly and cartilage anteriorly, the nasal septum divides the nasal cavity in half. There are blood artery and a mucus” membrane lining the septum.
• Nasal Turbinate’s (conchae): - Each side of nasal cavity contain three pairs of nasal turbinates (superior, middle, inferior). The nasal cavity surface area is increase by this bony projection coated in vascular mucosa, which also aid in filtering, heating and humidifying inspired air.
• Nasal Mucosa: - Pseudotratified ciliated columnar epithelium makes up the respiratory mucosa that lines the nasal cavity. This mucosa is made up of ciliated cell, brush cell, basal cell, and goblet cell, which produces mucus, foreign objects and pathogens are captured and eliminated by mucus layer, and are then propelled into the pharynx for expectoration or swallowing by ciliary action.
• Blood flow: - The internal and exterior carotid artery branches provide the nasal cavity with a plenty blood flow. The nasal mucosa large vasculature makes it easier for medication to be absorbed quickly when taken internally.
• Nerves: - The trigeminal nerves (CNV), which control feeling (touch, pain, temp) and reflexes like sneezing and nasal congestion, has branches that innervate the nasal cavity.
• Olfactory region: - It is located in superior aspect of nasal cavity, is home to olfactory receptor that are important for smell perception Specialized olfactory epithelium containing olfactory sensory neuron line this area.
• Nasopharynx: - It connects the nasal cavity to the throat, is formed by the posterior portion of nasal cavity opening into it. This area facilitates the flow of food and air as well as drainage of nasocrimal duct [11-12].

5. Mechanisms of Drug Delivery in Nasal Drug Delivery System

• Transcellular pathway: - lipophilic medication preferentially take up space in lipid bilayer of cell membrane where they breakdown path. They go straight through the nasal mucosa lining epithelial cell.
• Paracellular pathway: - This pathway is mainly used by hydrophilic medicine, which have difficulty passing through the cell membrane. They traverse the gap in between epithelial [20,21].

Table 1: - Mechanism of Pathways6. A) Factors Influencing Drug Absorption and Bioavailability:

Factors Related to Drug

Lipophilicity: - The compound usual rise in penetrations through the nasal mucosa corresponds with an increase in lipophilicity. The nasal mucosa has been seen to possess certain hydrophilic characteristics; nonetheless it seems that these mucosa are predominantly lipophilic in nature, and the lipid domain is crucial for the barrier function of these membrane [3].

Chemical Form: - A drugs chemical Form may play a significant role in influencing absorption. The drugs absorption may change, for instance if it is transformed into an ester or salt. Huang etal’s study looked at how a drug structural alteration affected absorption. It was shown that in-situ nasal absorption of L-tyrosine carboxylic acid ester was considerably higher than that of L -tyrosine itself [3].

Polymorphism: - Drug solubility and dissolution rate, consequently the medication absorption across biological membranes is known to be impacted by polymorphism [3].

Molecular weight: - When it comes to lipophilic molecule, the molecular weight and drug penetrations have a direct relationship, while the relationship for water soluble compounds is inverse yammato et. Al and fisher et. Al suggests that the physicochemical properties do not have impact on drug permeation of less than 300 Da [3]. Drug solubility and dissolution rate: - When it comes to measuring nasal absorption from powder and suspension, solubility and dissolution rate play a significant role. Before being absorbed, the particle that have lodge in nasal cavity must be dissolved. No absorption occurs if a medication is eliminated or stay in form of particle [3].

B) Factors Related to Formulation

1] Physicochemical properties of formulation

• pH and mucosal irritancy: - A drug penetration may be impacted by the PH of the nasal surface as well as the formulation. The pH of nasal formulation should be adjusted to 4.5-6.5in order to prevent nasal irritation. This is not only preventing irritation but also efficient drug penetration and inhibit the growth of bacteria [3].
• Osmolarity: - Rats’ absorption of secretin was examined by Oliwaki et., who discovered that at 0.462 M sodium chloride concentration, absorption reached its maximum, as it was noted that at this salt concentration, the nasal epithelial mucosa shrank [51]. This leads to increased compound penetration as a result of structural alterations, and the use of sorbitol as an osetoregulatory drug further supported this. Because of the consequent decrease in 52) anal permeability of secretin, as reported by the authors, isotonic solutions are typically recommended for administration [3].
• Viscosity: - The longer the medication is in touch with the nasal mucosa due to the increased viscosity of the formulation, the longer the time it takes for permeation. In addition, very viscous formulations change a drug’s capacity to pass through the body by interfering with regular processes such ciliary beating and mucocilliary clearances [3].

7. The Theories of Nasopulmonary Drugs Delivery System: -

The term “Nasopulmonary drug delivery” describes the administration of medications via the nasal canal, which targets the lungs and the upper respiratory system. This method has a number of benefits, including non-invasive delivery, a quick start of action, and avoidance of first-pass metabolism. The pulmonary medication delivery mechanism is the subject of five theories. For the pulmonary drug delivery route, the following 5 theories are taken into consideration for the delivery of the medication:

•Electronic Theory

•Adsorption Theory

•Wetting Theory

•Diffusion Theory

• Fracture Theory

Nasopulmonary drug delivery systems are based on a number of theories that optimize medication deposition, absorption, and effectiveness in the nasal and pulmonary areas. The idea of mucocilliary clearance, which controls the passage of mucus and other particles through the respiratory epithelium, is one well-known theory. While pulmonary drug delivery systems must take into consideration clearance mechanisms in the lungs to achieve optimal drug deposition and retention, nasal drug delivery systems must overcome application this clearance mechanism to ensure sufficient drug retention and absorption in the nasal cavity. Particle size and aerodynamic behavior are the focus of another hypothesis, which highlights the need of maximizing particle size distribution and aerodynamic characteristics to enable effective medication delivery to both the nasal and pulmonary areas. 13–16, There is discussion on these theories [1]. Tablet The list of description of theory of pulmonary drug delivery systems with its application.

Table 2:  The Theories of Nasopulmonary Drugs Delivery System

These are the five theories for medication distribution and absorption for treating a specific condition, along with a few commercially available drug items listed in Table 2 above. Furthermore, Nasopulmonary drug delivery is greatly influenced by theories of drug solubility, permeability, and formulation properties, which direct the creation of formulations that can improve drug solubility and penetration. Targeted distribution to particular respiratory tract areas and via mucosal barriers.

8.  Advancement in Nasopulmonary Drug Delivery System

8.1. Formulation strategy for enhanced drug delivery: -

The various dosage forms available for the delivery of drugs to treat specific Diseases, Medical devices known as inhalers are used to administer medication directly to the lungs. This allows for the targeted and efficient treatment of a number of respiratory disorders, including cystic fibersis, asthma, and chronic obstructive pulmonary disease (COFD). Compared to oral or injectable drugs, they provide a number of benefits, such as a quicker onset of action, fewer systematic side effects, and better patient compliance.

There are various varieties of inhalers, each having a unique mode of action, benefits, and drawbacks.

Type of inhaler formulation: - They are of 3 types

Metered Dose inhaler: -MDI use a propellant to propell a pre-measured dosage of medication They are frequently used in the treatment of asthma and chronic obstructive Pulmonary disorder (COPD).

Nebulizer: - L A fine mist of suspension or solution nebulizer and inhaled over a sufficient period of time. They are usually prescribed for those who are unable to successfully use MDI or DPI for patient with severe respiratory disorder. Below list the various formulation types together with their respective doses form and modes of action.

Table 3: Type of Inhalers

There are some important marketed products with different types of inhalers in formulation as per table 3 will discuss briefly.

8.2. Novel Drug Delivery device and Technologies

The several novel drug delivery devices and technologies have been developed to enhance drug delivery to the nasal and pulmonary regions. The some of them as examples discussed below followings

Nasal Spray with Microfluidic Systems: -

Microfluidic systems integrated into nasal spray devices allow for precise control aver droplet size and distribution, optimizing drug deposition and absorption in the natal cavity.

Nasal powder inhaler: -

These devices offer benefits like increased patient satisfaction and drug stability by directly delivering powdered formulation to the nasal mucosa Ease of use in contrast to conventional liquid doses Spray.

Nasal Drug delivery systems with Nanotechnology: -

Nasal Drug Delivery System based on nanoparticles provide targeted and regulated drug administration to certain areas of the nasal cavity, increasing the availability and Effectiveness of treatment.

Nasal implant and insert: -

these are inserted inside. he nasal cavity to deliver prolonged, sustained medication release, providing a practical, noninvasive substitute for regular dosing.

Nasal Aerosol Device with vibrating mesh: -

Vibrating mesh technique in nasal Aerosol devices produces small Aerosol particles with a restricted size distribution, enhancing medication deposition increasing medication absorption and the nasal cavity.                                                                                                                   

Nasal pump with smart inhaler technologies: -

intelligent inhaler utilising technology built into nasal pumps, customized treatment plans are made possible by real-time monitoring of drug delivery parameters like dosage, frequency, and patient adherence. In contrast to others, nasal grace devices connected to nasal spray pumps aid in improving medicine administration by regulating the spray pattern and lowering variability in nasal.

Deposition, guaranteeing reliable and effective drug absorption. Mucoadhesive formulations in nasal administration systems stick to the nasal mucosa, optimizing contact time and boosting medication absorption to improve therapeutic effects.Pulmonary drug delivery devices vices with a dry powder inhalers (DPIs), DPis deliver drug formulations directly to the lungs in the form of dry powder, offering improved stability and ease of use compared to traditional nebulizers and nasal delivery. Systems with inhaled corticosteroids (ICS), HS S formulations delivered via nasal sprays or inhalers are used to treat respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), providing localized anti- Inflammatory effects with reduced systemic side effects These novel drug delivery devices and technologies hold great promise for improving the efficacy, safety, and patient adherence of nasal and pulmonary drug delivery systems, offering innovative solutions for the treatment of various respiratory and Systemic diseases [14].

8.3. Formulation Approaches in Nasopulmonary Drug Delivery System

The following are the most popular formulation approaches used in Nasopulmonary drug delivery systems:

1)Nasal Gels

2) Nasal Drops,

3) Nasal Spray

4) Nasal powder,

5) Liposomes

6) Microspheres

The goal of these formulation approaches is to maximize patient compliance and drug efficacy by addressing the particular difficulties involved in delivering medications to both the nasal and pulmonary regions. One approach is to create multifunctional formulations that can effectively target both sites of delivery. For example, formulations based on nanoparticles can be designed to encapsulate drugs and facilitate their transport across mucosal barriers in the nasal cavity while also enacting deposition and absorption in the hings upon inhalation.

1)Nasal Drops: -One of the easiest and most practical nasal administration systems ever created is nasal drops. Because of this system’s primary drawback—its lack of dose precision— nasal drops might not be appropriate for use with prescription medications. [53] According to reports, albumin from nasal drops deposits Baxman’s nose more effectively than nasal spray [6].

irritation [7]

Table 4:- Formulation Approach

8.4. The Evaluation of Nasopulmonary drug delivery

The various assessments that were carried out for the Nasopulmonary medication dose forms. A comprehensive method is employed to appraise Nasopulmonary drug delivery systems in order to determine their clinical applicability, safety, and effectiveness. To guarantee the best possible aerosolization and deposition of the medication inside the respiratory tract, the physicochemical parameters of the formulation are examined first. Aerodynamic and particle size distribution are characterized using methods like cascade impaction. Behavior, which are essential factors in determining lung penetration and deposition efficiency, Second, preclinical research is done to look at the given drug’s pharmacokinetics and Pharmacodynamics. To evaluate drug clearance, tissue distribution, and systemic absorption after nasal delivery, animal models are used. Furthermore, effectiveness research in pertinent illness models provide light on the prospective therapeutics potentials of the drug delivery systems. Table 5. The several list of evaluation of Nasopulmonary Drug Delivery System.

Table 5: - Evaluation Parameter