1. INTRODUCTION:

1.1 Intranasal Drug Delivery System:^1,2,3,4,5

The intranasal drug delivery system represents a recent advancement in the field of drug administration technology. It offers a means of delivering drugs through the nasal route, allowing for both local and systemic delivery. In this system, the drug comes into contact with the submucosa of the nasal cavity, which is highly vascularized with large and fenestrated capillaries. This vascularization facilitates rapid absorption of the drug and bypasses processes such as first-pass metabolism, gut wall metabolism, and destruction in the gastrointestinal tract. The nasal mucosa, compared to the gastrointestinal tract, offers higher permeability to a wide range of compounds due to the absence of pancreatic and gastric enzymatic activity and minimal dilution by gastrointestinal contents. As a result, intranasal drug delivery has emerged as a reliable and beneficial alternative to oral and parenteral routes. It improves drug bioavailability by avoiding metabolism in the gastrointestinal and hepatic systems. Moreover, the intranasal route is non-invasive, increasing patient compliance, particularly among the elderly and children. The large surface area (approximately 150cm2) and high vascularity of the nasal mucosa allow for systemic distribution of the active compound. Additionally, the direct absorption of molecules through the trigeminal and olfactory pathways from the nasal cavity enables direct access to the brain, leading to favorable pharmacokinetic/pharmacodynamic profiles for drugs acting on the central nervous system. This route of administration also offers the potential for targeting the brain directly, as active pharmaceutical ingredients absorbed in the nasal mucosa can exert both local and systemic effects.

1.1.1 The Nose – Anatomy, and Physiology:^2,4

The nasal cavity in humans and other animals serves primarily for breathing and olfaction. However, it also plays a crucial role in protecting the respiratory system. It accomplishes this by filtering, warming, and humidifying the inhaled air before it reaches the lower airways. The nasal cavity is lined with a mucus layer and hairs that are responsible for these functions, effectively trapping particles and pathogens present in the inhaled air. Additionally, the nasal structures are involved in sound resonance, mucociliary clearance, immunological activities, and metabolism of endogenous substances, all of which are important functions. The human nasal cavity has a volume of approximately 15-20mL and a surface area of around 150 cm2. It is divided into two symmetrical halves by the middle septum, with each half opening at the face through the nostrils and extending posteriorly to the nasopharynx. The nasal halves consist of four distinct areas (nasal vestibule, atrium, respiratory region, and olfactory region) characterized by their unique anatomical and histological features as depicted in Figure 1. Top of Form

Figure 1: The nose anatomy

Anatomy of the nose⁵

1 Nasal vestibule:^4,6

The nasal vestibule, located at the most anterior part of the nasal cavity just inside the nostrils, occupies an area of approximately 0.6 cm2. This region is equipped with nasal hairs, also known as vibrissae, which play a crucial role in filtering inhaled particles. Histologically, the nasal vestibule is covered by a stratified squamous and keratinized epithelium, along with sebaceous glands. These characteristics of the nasal vestibule are beneficial as they provide significant resistance against toxic environmental substances. However, due to its specific features, drug absorption in this area is challenging. The nasal vestibule is considered the least favorable region for drug absorption among the four regions of the nasal cavity.

2 Atrium:^2,4

The atrium is the region that lies between the nasal vestibule and the respiratory region in the nasal cavity. Its anterior section is characterized by a stratified squamous epithelium, while the posterior area is composed of pseudostratified columnar cells that have microvilli.

3 Respiratory region:^2,5,6

The respiratory region is the largest and most permeable area within the nasal cavity, primarily responsible for systemic drug absorption. It plays a crucial role in filtering, heating, and humidifying the inhaled air. This region is divided into three sections known as the superior, middle, and inferior turbinates, which protrude from the lateral wall. These specialized structures contribute to the humidification and regulation of the temperature of the inhaled air. The spaces between the turbinates, called meatus, create pathways for airflow, ensuring close contact between the inhaled air and the respiratory mucosal surface. The inferior and middle meatus are associated with the reception of the nasolacrimal ducts and paranasal sinuses, which are air-filled cavities located in the facial bones surrounding the nasal cavity. The nasal respiratory mucosa, found in the respiratory region, is of particular importance for achieving systemic drug delivery. It consists of the epithelium, basement membrane, and lamina propria. Nasal mucus plays a crucial role in various physiological functions, including the humidification and warming of inhaled air, as well as providing physical and enzymatic protection to the nasal epithelium against foreign substances, including drugs. The presence of mucin in the nasal mucus layer is significant as it can trap larger molecules such as peptides and proteins. Below the mucus layer lies the lamina propria, which is richly supplied with blood vessels, including fenestrated capillaries that are highly permeable, as well as nerves, glands, and immune cells. These immune cells produce immunoglobulins and antibodies that offer immunological protection against bacteria and viruses.

4 Olfactory region:^2,4,5,6

The olfactory region is situated in the upper part of the nasal cavity and is closely connected to the brain. It has a surface area of approximately 10 cm2 and plays a crucial role in facilitating the transport of drugs to the brain and cerebrospinal fluid (CSF). The human olfactory region consists of a thick connective tissue called the lamina propria, which serves as a foundation for the olfactory epithelium. Within the lamina propria, there are axons, Bowman's bundle (a bundle of nerve fibers), and blood vessels. The olfactory epithelium itself is composed of three types of cells: basal cells, supporting cells, and olfactory receptor cells. Neurons are interspersed among the supporting cells. Notably, the neuroepithelium in the olfactory region is the only part of the central nervous system (CNS) that is directly exposed to the external environment.

Similar to the respiratory epithelium, the olfactory epithelium is pseudostratified, but it contains specialized olfactory receptor cells that are crucial for the perception of smell. Within this region, there are also small serous glands known as glands of Bowman, which produce secretions acting as solvents for odorous substances.

1.1.2 Mechanism for Absorption of Drugs Through Intranasalroute:^3,7

The absorption of drugs from the nasal cavity involves passing through the mucus layer, which serves as the initial barrier. Small and uncharged drugs can easily traverse this layer, while larger and charged drugs face difficulties in crossing. Mucin, the main protein in mucus, tends to bind to solutes, impeding diffusion. Moreover, the structure of the mucus layer can undergo changes in response to environmental factors such as pH and temperature. Various absorption mechanisms have been proposed in the past, but three primary mechanisms have been widely recognized:

1. The first mechanism is the aqueous or paracellular route, which involves the transport of drugs through the aqueous spaces between cells. This route is passive and relatively slow. There is an inverse relationship between the molecular weight of water-soluble compounds and their intranasal absorption, with poor bioavailability observed for drugs exceeding 1000 Daltons in molecular weight.

2. The second mechanism is the lipoidal or transcellular route, which allows for the transport of lipophilic drugs. This process is dependent on the lipophilicity of the drug and exhibits rate dependency.

3. Active transport is another route by which drugs can cross cell membranes. It involves carrier-mediated transport or passage through the openings of tight junctions between cells.

These three mechanisms represent the primary pathways for drug absorption in the nasal cavity.

1.1.3 Factors Influencing Intranasal Drug Delivery System and Bioavailability:

1-Physicochemical Properties of Drugs:

A. Molecular weight and size: ^3,8

The absorption of drugs through the nasal route is influenced by the molecular size of the drug. Lipophilic drugs show a direct relationship between molecular weight and drug permeation, meaning that larger lipophilic drugs tend to have lower permeation rates. On the other hand, water-soluble compounds exhibit an inverse relationship, where smaller molecules have higher permeation rates. For compounds with a molecular weight equal to or greater than 300 Daltons, the rate of permeation is particularly sensitive to molecular size. Absorption significantly decreases when the molecular weight exceeds 1000 Daltons, unless absorption enhancers are used. These enhancers can help overcome the limitations imposed by large molecular size and improve the absorption of high-molecular-weight drugs through the nasal route.

B. Lipophilic-hydrophilic balance:⁸

The hydrophilic and lipophilic nature of the drug also affects the process of absorption. By increasing lipophilicity, the permeation of the compound normally increases through the nasal mucosa. Although the nasal mucosa was found to have some hydrophilic character, it appears that these mucosae are primarily lipophilic in nature and the lipid domain plays an important role in the barrier function of these membranes.

C. Solubility:²

A major factor in determining the absorption of the drug through biological membranes is drug solubility. As nasal secretions are more watery in nature, a drug should have appropriate aqueous solubility for increased dissolution. Lipophilic drugs have less solubility in the aqueous secretions. Water-soluble drugs are absorbed by passive diffusion and lipophilic drugs via active transport depending on their solubility.

D. PKa and partition coefficient:²

As per the pH partition theory, unionized species are absorbed better compared with ionized species and the same fact is true in the case of nasal absorption. There is a constant relationship between pKa and nasal absorption of drugs. With an increase in lipophilicity of the partition coefficient of the drugs its concentration in biological tissues increases.

E. Polymorphism:^2,3,9

Polymorphism is an important parameter in nasal drug product development which is administered in particulate form. Polymorphism is known to affect the dissolution of drugs and their absorption through biological membranes is affected by polymorphism. This factor should be carefully considered in the dosage form development for the nasal delivery

F. Chemical state of drug:²

The absorption of the drug is determined by the chemical form of the drug in which it is presented to the nasal mucosa. Chemically altering a drug molecule by adding a bio-cleavable lipophilic moiety is the alternative for improving absorption of the drug which is not have desired absorption properties. The prodrug approach provides many additional challenges which need to be overcome in the drug product developmental process. The toxicity of the prodrug itself needs to be fully evaluated.

2 Physicochemical Properties of Drugs Formulation:

A. Viscosity:^4,8,9

As formulation viscosity increases, the contact time between drug and nasal mucosa enhances, and, thereby, the potential of drug absorption increases. At the same time, the high viscosity of formulations interferes with normal ciliary beating and/or mucociliary clearance and, thus, increases the permeability of drugs.

B. pH:²

The extent of drug ionization is determined by the pH partition hypothesis hence it is related to formulation pH. The nasal formulation should be adjusted to the appropriate pH to avoid irritation, obtain efficient absorption, and prevent the growth of pathogenic bacteria. Ideal formulation pH should be adjusted between 4.5 and 6.5.

C. Osmolarity:^2,3

Formulation tonicity substantially affects the nasal mucosa generally, an isotonic formulation is preferred. Drug absorption can be affected by the tonicity of the formulation. Shrinkage of epithelial cells has been observed in the presence of hypertonic solutions. Hypertonic saline solutions also inhibit or cease ciliary activity. Low pH has a similar effect as that of a hypertonic solution.

3 Physiological Factors:

A. Blood supply:⁴

The nasal mucosa is richly supplied with blood and presents a large surface area making it an optimal local for drug absorption. The blood flow rate influences significantly the systemic nasal absorption of drugs so that as it enhances more drug passes through the membrane, reaching the general circulation. Vasodilatation and vasoconstriction may determine the blood flow and, consequently, the rate and extent of the drug to be absorbed.

B. Nasal secretions:²

Nasal secretions are produced by anterior serous and seromucous glands. The permeability of drug through the nasal mucosa is affected by:

• Viscosity of nasal secretion: The viscous surface layer will inhibit the ciliary beating if the sol layer of mucus is too thin and mucociliary clearance is impaired if the sol layer is too thick because of contact with cilia is lost. Permeation of the drug is affected due to impairment of mucociliary clearance by altering the time of contact of the drug and mucosa.

• Solubility of a drug in nasal secretions: For permeation of drug solubilization is necessary. A drug needs to have appropriate physicochemical characteristics for dissolution in nasal secretions.

• PH of nasal cavity variation in pH is observed between 5.5–6.5 in adults and 5.0

7.0 in infants. Permeation of drug is greater if the nasal pH is lower than pKa of a drug because under such conditions the penetrant molecules exist as unionized species.

C. Mucociliary clearance (MCC) and ciliary beating:⁹

Whenever a substance is nasally administered, it is cleared from the nasal cavity in 21 min by Mucociliary clearance because mucociliary clearance is the normal defense mechanism of the nasal cavity which clears substances adhering to the nasal mucosa and cleared in GIT by draining into the nasopharynx. Drug permeation is enhanced by increasing the contact time between drug and mucus membrane because of reduced Mucociliary clearance.

D. Pathological conditions:²

Mucociliary dysfunctional, hypo or hyper secretions, irritation of the nasal mucosa occurs due to diseases such as the common cold, rhinitis, atrophic rhinitis, and nasal polyposis, and drug permeation is affected by this.

E. Environmental conditions:^2,8

The environmental pH plays an important role in the efficiency of nasal drug absorption. A moderate reduction in the rate of MCC occurs at the temperature of 24ᵒC, it has been predicted that a linear increase in ciliary beat frequency occurs with an increase in temperature.

F. Membrane permeability:²

Absorption of the drug through the nasal route is affected by membrane permeability which is the most important factor. The large molecular weight drugs and water-soluble drugs like peptides and proteins have low membrane permeability hence absorbed through endocytic transport in fewer amounts.

G. Enzymatic degradation:⁴

Drugs nasally administered circumvent gastrointestinal and hepatic first-pass effects. However, they may be significantly metabolized in the lumen of the nasal cavity or during the passage across the nasal epithelial barrier due to the presence of a broad range of metabolic enzymes in nasal tissues. Carboxylesterase, aldehyde dehydrogenases, epoxide hydrolases, and glutathione S-transferases have been found in nasal epithelial cells and are responsible for the degradation of drugs in the nasal mucosa

H. Effect of deposition on absorption:^3,10

Deposition of the formulation in the anterior portion of the nose provides a longer nasal residence time. The anterior portion of the nose is an area of low permeability, while the posterior portion of the nose is where the drug permeability is generally higher and provides shorter residence time.

1.1.4 Advantages Of Intranasal Drug Delivery System:⁸

1) Drug degradation that is observed in the gastrointestinal tract is absent.

2) Hepatic first-pass metabolism is avoided.

3) Rapid drug absorption and quick onset of action can be achieved.

4) The bioavailability of larger drug molecules can be improved by means of an absorption enhancer or other approach.

5) The nasal bioavailability for smaller drug molecules is good.

6) Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal drug delivery.

7) The nasal route is an alternative to the parenteral route, especially, for protein and peptide drugs.

8) Convenient for the patients, especially for those on long-term therapy, when compared with parenteral medication.

9) Drugs possessing poor stability in gastrointestinal fluids are given by nasal route.

10)Polar compounds exhibiting poor oral absorption may be particularly suited for this route of delivery.

1.1.5 Limitations of Intranasal Drug Delivery System:^2,8,12

1) The histological toxicity of absorption enhancers used in nasal drug delivery systems is not yet clearly established.

2) Relatively inconvenient to patients when compared to oral delivery systems since there is a possibility of nasal irritation.

3) Nasal cavity provides a smaller absorption surface area when compared to GIT.

4) There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa, both from the substance and from constituents added to the dosage form.

5) Certain surfactants used as chemical enhancers may disrupt and even dissolve membranes in high concentrations.

6) There could be a mechanical loss of the dosage form into the other parts of the respiratory tract like lungs because of the improper technique of administration.

7) Dose is limited because of the relatively small area available for the absorption of the drug.

8) Time available for drug absorption is limited.

9) Diseased condition of nose impairs drug absorption.

1.1.6 Delivery System-Based Approaches for Intranasal Drug Delivery:^3,5,11

1. Nasal spray:

Both solution and suspension formulations can be formulated into nasal sprays. Due to the availability of metered-dose pumps and actuators, a nasal spray can deliver an exact dose from 25 to 200µm. The particle size and morphology (for suspensions) of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.

2. Nasal drops:

Nasal drops are one of the most simple and convenient systems developed for nasal delivery. The main disadvantage of this system is the lack of dose precision and therefore nasal drops may not be suitable for prescription products. It has been reported that nasal drops deposit human serum albumin in the nostrils more efficiently than nasal sprays.

3. Nasal gels:

Nasal gels are high-viscosity thickened solutions or suspensions. The advantages of a nasal gel include the reduction of post-nasal drip due to high viscosity, reduction of taste impact due to reduced swallowing, reduction of anterior leakage of the formulation, reduction of irritation by using soothing/emollient excipients, and target to mucosa for better absorption.

4. Nasal powder:

This dosage form may be developed if solution and suspension dosage forms cannot be developed e.g., due to lack of drug stability. The advantages to the nasal powder dosage form are the absence of preservatives and superior stability of the formulation. However, the suitability of the powder formulation is dependent on the solubility, particles size, aerodynamic properties, and nasal irritancy of the active drug and /or excipients.

5. Microspheres:

Microspheres are carriers that can protect the drug from enzyme degradation and release it according to a determined time schedule, increasing the time of permanence of the drug in the nasal mucosa compared to an aqueous solution. They are formed by a monolithic polymeric structure where the drug is homogeneously dispersed. The matrix is insoluble in the water but absorbs water resulting in swelling or progressive erosion of the particle, with consequent release of the entrapped drug molecules. Intranasal microspheres have been proposed for the delivery of water-soluble drugs but also for carrying peptides and proteins.

6. Microemulsions:

Microemulsions consist of an aqueous and an oily phase with the addition of one or more surfactant agents that stabilize the interfacial film, and a coactive agent that facilitates its spontaneous formation. These colloidal carries are thermodynamically stable and can help to reduce the systemic toxicity of drugs, improve their bioavailability, and increase their solubility and absorption through the nasal mucosa. An important technological feature is that they can host both hydrophilic and lipophilic drugs.

7. Nanoparticles:

Nanoparticles may offer several advantages due to their small size, but only the smallest nanoparticles penetrate the mucosal membrane by the paracellular route and in a limited quantity because the tight junctions are in the order of 3.9 - 8.4 Å. Controversial results are found when using nanoparticles in intranasal drug delivery

8. Liposomes:

Liposomes are phospholipids vesicles composed of lipid bilayers enclosing one or more aqueous compartments and wherein drugs and other substances can be included. Liposomal drug delivery systems present various advantages such as the effective encapsulation of small and large molecules with a wide range of hydrophilicity and pKa values. They have been found to enhance nasal absorption of peptides such as insulin and calcitonin by increasing their membrane penetration. This has been attributed to the increasing nasal retention of peptides. Protection of the entrapped peptides from enzymatic degradation and mucosal membrane disruption.

4. Evaluation of Nasal drug formulations:¹³

In vitro studies on nasal permeation: Several methods are employed to examine the diffusion of drugs through the nasal mucosa from a formulation. There are two distinct approaches for studying the drug's diffusion profile. (A) In vitro diffusion studies: A glass nasal diffusion cell is constructed. It consists of a water-jacketed recipient chamber with a total capacity of 60ml and a flanged top of approximately 3mm. The lid of the chamber has three openings for sampling, thermometer, and a donor tube chamber. The donor chamber, which is 10cm long with an internal diameter of 1.13cm, also has a total capacity of 60ml and a flanged top of about 3mm. Its lid has three openings for sampling and thermometer. The nasal mucosa of a sheep is separated from the underlying bony tissues and soaked in distilled water containing a few drops of gentamicin injection. After removing all traces of blood from the mucosal surface, it is attached to the donor chamber tube. The donor chamber tube is positioned in a way that it barely touches the diffusion medium in the recipient chamber. Samples (0.5ml) are withdrawn from the recipient chamber at predetermined intervals and transferred to amber-colored ampoules. The withdrawn samples are appropriately replaced. The drug content in the samples is then determined using suitable analytical techniques. The temperature is maintained at 37°C throughout the experiment.

(B) In vivo nasal absorption studies: Animal models are used to investigate nasal absorption. There are two types of animal models: whole animal or in vivo models and isolated organ perfusion or ex vivo models. These models are discussed in detail below.

Rat model: The surgical preparation for in vivo nasal absorption study in rats is conducted as follows: The rat is anesthetized by intraperitoneal injection of sodium pentobarbital. An incision is made in the neck, and a polyethylene tube is cannulated into the trachea. Another tube is inserted through the esophagus towards the back of the nasal cavity. The nasopalatine tract is sealed to prevent the drug solution from draining out through the mouth. The drug solution is administered to the nasal cavity through the nostril or cannulation tubing. Blood samples are collected through the femoral vein. Since all possible drainage outlets are blocked, the drug can only be absorbed and transported into the systemic circulation by penetration and/or diffusion through the nasal mucosa.

Rabbit model: The rabbit is advantageous as an animal model for nasal absorption studies for several reasons: 1. It allows pharmacokinetic studies similar to large animals such as monkeys. 2. It is relatively inexpensive, easily obtainable, and simple to maintain in a laboratory setting. 3. The rabbit has a sufficiently large blood volume (approximately 300ml) that permits frequent blood sampling (1-2ml) for a comprehensive characterization of absorption and determination of a drug's pharmacokinetic profile. Rabbits weighing approximately 3kg are either anesthetized or kept conscious depending on the study's objectives. In the anesthetized model, a combination of ketamine and xylazine is intramuscularly injected into the rabbit to induce anesthesia. The rabbit's head is held upright, and a nasal spray of the drug solution is administered into each nostril. The rabbit's body temperature is maintained at 37°C using a heating pad. Blood samples are collected through an indwelling catheter in the marginal ear vein or artery.

CONCLUSION:

Nasal drug delivery represents a promising alternative to the injectable route of administration and is considered a novel platform. In the near future, it is expected that more drugs will be introduced to the market in the form of nasal formulations for systemic treatment. The development of drugs with a drug delivery system is influenced by various factors. Additionally, for the management of chronic conditions such as diabetes, osteoporosis, and fertility treatment, innovative nasal products are anticipated to be commercialized. However, the bioavailability of nasal drug products poses a significant challenge in their development. Despite this challenge, pharmaceutical companies are investing substantial resources in the development of nasal products due to the growing demand in the global pharmaceutical market. To enhance the effectiveness and minimize side effects of nasal products, it is crucial to focus on fundamental research in nasal drug delivery.

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Received on 02.07.2023 Modified on 12.08.2023

Research J. Science and Tech. 2024; 16(1):51-58.

DOI: 10.52711/2349-2988.2024.00009