INTRODUCTION:

The burden of non-communicable diseases (NCDs) is increasing in developing nations, including India, as a result of a change in the environment and improved health care services in the preventive and promotion domains. Neurological illnesses make up a sizable component of the worldwide disease burden among NCDs.^1,2The World Federation of Neurology and the World Health Organization (WHO) both released significant documents that highlight the public health issues associated with treating neurological illnesses, particularly in resource-constrained poor nations.^3,4 Through house-to-house surveys, the prevalence of neurological illnesses was determined in six studies from various parts of the nation, all of which included rural populations and two of which included urban populations.

With an average of 2394 per 100000 people, the crude prevalence rate ranged from 967 to 4, 070 per 100000 people.^5-10 In India, where there are currently 1.27 billion people, it is believed that 30 million of them experience neurological problems.

The brain and spinal cord make up the central nervous system (CNS). The CNS's three main tasks are to receive sensory data, interpret data, and transmit motor signals. The brain serves as the CNS's headquarters and the body's processing centre. The forebrain, midbrain, and hindbrain are the three primary sections that make up its general organisation.¹¹

Diseases of Nervous System:

1. Alzheimer's disease: Alzheimer's disease is a brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks.

2. Bell's palsy: Bell's palsy is a condition that causes sudden weakness in the muscles on one side of the face. In most cases, the weakness is temporary and significantly improves over weeks.

3. Cerebral palsy: Cerebral palsy (CP) is a group of disorders that affect a person's ability to move and maintain balance and posture. CP is the most common motor disability in childhood. Cerebral means having to do with the brain. Palsy means weakness or problems with using the muscles.

4. Epilepsy: Epilepsy is a neurological disorder marked by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain.

5. Motor neurone disease (MND): Motor neurone disease (MND) is an uncommon condition that affects the brain and nerves. It causes weakness that gets worse over time.

6. Multiple sclerosis (MS): Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (the brain and spinal cord). MS occurs when the immune system attacks nerve fibers and myelin sheathing (a fatty substance which surrounds/insulates healthy nerve fibers) in the brain and spinal cord.

7. Neurofibromatosis: Neurofibromatoses are a group of genetic disorders that cause tumors to form on nerve tissue. These tumors can develop anywhere in the nervous system, including the brain, spinal cord and nerves.

8. Parkinson's disease: Parkinson's disease is a progressive disorder that affects the nervous system and the parts of the body controlled by the nerves. Symptoms start slowly. The first symptom may be a barely noticeable tremor in just one hand. Tremors are common, but the disorder may also cause stiffness or slowing of movement.¹²

Diagnostic tests may include:

· Blood tests

· Electroencephalogram (EEG)

· Magnetic resonance imaging (MRI)

· Computed tomography scan (CT scan.)

· Lumbar puncture (spinal tap)¹³

Complications occur during Neurological Disorders:

· Extrapyramidal syndromes

· Neuroleptic malignant syndrome

· Serotonin toxicity

· Drug discontinuation symptoms

· Seizures¹⁴

Treatment of Neurological Disorders:

In an emergency, parenteral delivery via the nasal route may be substituted. Neurological illnesses can be treated in a variety of ways, and these therapies can change depending on the ailment. Neurorehabilitation is typically the major form of treatment, with the goal of restoring, minimising, or compensating whatever functional deficiencies the patient may have while maintaining reasonable expectations for what is attainable.^15,16

1. Oral

2. Sublingual and Buccal Routes

3. Intravenous Route

4. Intramuscular Route

5. Intranasal Route¹⁷

Nasal Drug Delivery System:

The nose is a crucial organ in therapeutics since it allows for self-administration and faster, greater levels of medication absorption.¹⁸Nasal therapy, commonly known as "NASAYA KARMA, " is a recognised type of treatment in the Ayurvedic schools of Indian medicine.¹⁹ The nasal route was first introduced as a viable systemic delivery alternative to other traditional drug delivery routes in the early 1980s.²⁰ Because it is permeable to more compounds than the gastrointestinal tract and has a neutral pH and less dilution by gastrointestinal contents than the gastrointestinal tract, nasal mucosa has been considered as a potential administration route to achieve faster and higher levels of drug absorption.²¹

The nasal cavity is used to transport medications, ranging in size from tiny micromolecules to massive macromolecules like peptide/proteins, hormones, and vaccinations.²²According to reports, lipophilic medications are typically well absorbed via the nasal cavity, with pharmacokinetic profiles frequently matching those observed after an intravenous injection and a bioavailability that frequently approaches 100%.²³ Fast medication absorption is facilitated by the nasal cavity's wide absorption surface area and high vascularization.²⁴ Following intranasal delivery, drugs are swiftly absorbed from the nasal cavity, leading to fast systemic drug absorption. Improved nasal drug absorption may be the outcome of a strategy to prolong the duration that drug formulations stay in the nasal cavity. The medicine to be breathed needs to be adjusted for particle size, concentration, and chemical form depending on whether a local or systemic pharmacological effect is required.²⁵

ANATOMICAL AND PHYSIOLOGICAL CONSIDERATION FOR INTRANASAL DELIVERY:

The human skull is divided into two functional parts to safeguard the sensitive inside tissues. One of them is the viscerocranium, which is made up of many bones that make up the skeleton of the face and sections of the jaw and protects the eyes, mouth, and nasal cavity.^26,27 The nasal vestibule, atrium, respiratory area, olfactory region, and nasopharynx are the five anatomically distinct areas of the nasal cavity as in Table 1.^28-30,81

Fig. no. 1 Anatomy and Physiology of Nasal Cavity

Table 1: Structural features of various regions and their impact on the permeability of nasal cavity

Region	Structural Features	Permeability
Nasal vestibule	Nasal hairs (vibrissae) Epithelial cells are stratified, squamous, and keratinized Sebaceous glands present	Least permeable due to the presence of keratinized cells, very resistant to hydration and can withstand insults from noxious substances of the environment
Atrium	Transepithelial region Stratified squamous cells present anteriorly and pseudostratified cells with microvilli present posteriorly	Less permeable as it has small surface area and stratified cells are present anteriorly
Respiratory region (inferior turbinate middle turbinate superior turbinate)	Pseudostratified ciliated columnar cells with microvilli (300 per cell), large surface area Receives maximum nasal secretions due to the presence of seromucous glands, nasolacrimal duct, and goblet cells	Most permeable region due to large surface area and rich vasculature
Olfactory region	Specialized ciliated olfactory nerve cells for smell perception	Direct access to cerebrospinal fluid
Nasopharynx	upper part contains ciliated cells, and the lower part contains squamous epithelium	Receives nasal cavity drainage

MECHANISM OF NASAL ABSORPTION:

a) First mechanism - It involves an aqueous route of transport, which is also known as the paracellular route but slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble compounds. The molecular weight greater than 1000 Daltons having drugs shows poor bioavailability.

b) Second mechanism - It involves transport through a lipoidal route and it is also known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drug also cross cell membranes by an active transport route via carrier-mediated means or transport through the opening of tight junctions.^31-32

Fig. no. 2Absorption mechanism of drug through nose to brain

Advantages:

· Drugs that are not absorbed orally can be delivered into nasal cavity

· Enhanced patient compliances.

· Decrease risk of overdose.

· Fast onset of therapeutic action.

· Increased retention time of drug as compared to nasal spray

· Avoid hepatic first-pass metabolism

· Rapid drug absorption and quick onset of action can be achieved easily.^{33-38, 48, 82}

Disadvantages:

· The nasal cavity provides a smaller absorption surface area when compared to gastrointestinal tract.

· High-molecular-weight compounds cannot be delivered through this route (mass cut off ~1 kDa).

· May cause nasal irritation

· Small amount of drug can be administered.^33-35

FACTORS INFLUENCING THE NASAL DRUG ABSORPTION:

A) Factors Related to Drug:

1. Molecular Weight: The physicochemical characteristics of the substance have little effect on the penetration of drugs with molecular weights lower than 300 Dalton.

2. Polymorphism: It is well established that polymorphism has an impact on a drug's solubility, rate of dissolution, and ability to pass through biological membranes. Therefore, research on the polymorphic stability and purity of medications for nasal powders and/or solutions is crucial.

3. Solubility and Dissolution Rate: Drugs should dissolve for greater absorption. Absorption is somewhat harder if there are particles present.

4. Lipophilicity: As lipophilicity rises, the nasal mucosa is more permeable to the substance. Since they can diffuse into and move through the cell in the cytoplasm as well as partition into the lipid (bilayer) of biological membranes, lipophilic substances frequently easily penetrate biological membranes via the transcellular route. Drugs like testosterone have already demonstrated nasal absorption in animal studies.

5. Partition Coefficient and pKa: Since pH partition theory states that unionised substances are absorbed better than ionised, it follows that nasal absorption likewise occurs in the same way.^35-39

B) Factors Related to Formulation:

1. pH: Both the formulation's pH and the pH of the nasal surface can have an impact on how well a medicine permeates. The pH of the nasal formulation should be adjusted to 4.5-6.5 to prevent nasal discomfort.

2. Viscosity: A formulation with a higher viscosity increases the amount of time the drug is in touch with the nasal mucosa, extending the time it takes for permeation.

3. Osmolarity: Optimal osmolarity should be maintained since it reduces the nasal epithelial mucosa's size and affects how medications permeate the nasal mucosa.

4. Buffer Capacity: Nasal formulations are typically given in tiny volumes between 25 and 20 L. Therefore, nasal secretions may change the dose's administered pH. The concentration of unionised drugs that are available for absorption may be impacted by this. In order to maintain the pH, a sufficient formulation buffer capacity may be needed.

5. Drug Concentration, Dose, and Dose Volume: These three interrelated factors affect the effectiveness of nasal delivery. They are drug concentration, dose, and dose volume. In nasal perfusion tests, it was demonstrated that L-Tyrosine nasal absorption increased with drug concentration.⁴⁰

C) Physiological Factors:

1. The effect of deposition on absorption: A longer nasal residence period is provided by deposition of the formulation in the anterior of the nose. While the posterior section of the nose, where drug permeability is often higher, offers shorter residence duration, the anterior portion of the nose has low permeability.

2. Nasal Blood Flow: Because the nasal mucosal membrane has a high concentration of blood vessels and is essential for controlling the air's temperature and humidity, how well a medicine will be absorbed will rely on how the blood vessels dilate and contract.

3. Effect of Enzymatic Activity: A number of enzymes that are found in the nasal mucosa may have an impact on the stability of medications. At the mucosal membrane, for instance, proteases and amino peptidases degrade proteins and peptides. Compared to the gastrointestinal tract, there is a significantly smaller amount of amino peptidase present.

4. Mucociliary Clearance Effect: The residency (contact) period between the medication and the epithelial tissue affects how well a drug is absorbed. The residency time has an inverse relationship with mucociliary clearance, which has an inverse relationship with drug absorption.

5. Effect of Physical Condition: Nasal mucociliary transport and/or nasal absorption ability may be impacted by intranasal diseases. The mucosa can occasionally be dry, bleeding, or compressing. One can have sinusitis, rhinorrhea, or a nasal infection.⁴¹

DIFFERENT METHODS TO IMPROVE NASAL ABSORPTION:

1) Permeation enhancers: A number of permeation enhancers, including fatty acids, bile salts, phospholipids, surfactants, cyclodextrin, etc., have been studied to increase nasal absorption. These enhancers act through a variety of mechanisms, including inhibition of enzyme activity, reduction of mucus viscosity, reduction of muco-ciliary clearance, opening tight junctions, and solubilizing or stabilising the drug.

2) Prodrug strategy: Prodrugs are chemical moieties that are inactive but become active when administered to a target spot. This method is mostly used to enhance the formulation's physicochemical qualities, such as flavour, solubility, and stability.

3) In-situ gel: With chemicals like carbopol, cellulose derivatives, lecithin, chitosan, etc., it is possible to transform a solution into a gel under the impact of stimuli like temperature, pH, and ionic concentration. These formulations typically alleviate the issue of nasal cavity retention time.

4) Nasal enzyme inhibitors: Protease and peptidase inhibitors are employed in the production of peptide and protein molecules. Bile salts, amastatin, bestatin, boroleucine, fusidic acids, etc. are further examples.

5) Structural alteration: Drug structures can be changed to enhance nasal absorption without altering their pharmacologic properties. The majority of alterations are chemical to alter the medication's physicochemical composition so that it has better nasal absorption.

6) Mucoadhesion: The state in which two materials are stuck together for a protracted amount of time is referred to as mucoadhesion. After making physical contact with the biological membrane, mucoadhesive polymers permeate the tissue's surface. In addition to having a high production cost, synthetic polymers pollute the environment while being created.^41,86

INTRANASAL DRUG DELIVERY SYSTEM:

The intranasal route of drug delivery has been taken into consideration more frequently in recent years when creating new chemical entities or enhancing the therapeutic profile of already-approved medications. However, a number of techniques should be taken into consideration when evaluating the therapeutic feasibility of intranasal drug administration, particularly the nature of the pathologic state (acute or chronic) and the expected consequences of medication treatment (local, systemic or at CNS).^35,40,85

• Nasal drops: Of all the formulations, nasal drops are one of the easiest and most practical delivery techniques. The lack of dose precision in this technique is its biggest drawback.

• Nasal sprays: Nasal sprays can be made from formulations that are either solutions or suspensions. Because metered dose pumps and actuators are readily available, a nasal spray can provide a precise amount between 25 and 200 L.

• Nasal emulsions and micro emulsions: Nasal emulsions benefit local application mostly because of their viscosity.

• Nasal gels: High-viscosity, thickened liquids or suspensions are known as nasal gels. A nasal gel's benefits include a decrease in post-nasal dripping due to its high viscosity, a decrease in flavour effect due to less swallowing, and a decrease in anterior formulation leakage.

• Nasal powders: If solution and suspension dosage forms cannot be established, mostly due to a lack of drug stability, powder dosage forms may be developed. However, the solubility, particle size, aerodynamic properties, and nasal irritancy of the active ingredient and/or excipients determine whether the powder formulation is appropriate.^{19, 42}

Applications of Intranasal Drug Delivery:

1. Delivery of non-peptide pharmaceuticals:

Despite the lack of a permeation enhancer, tiny, non-peptide medicines with low molecular weights (less than 1000 daltons) are effectively absorbed via the nasal mucosa.⁴³

2. Delivery of peptide-based pharmaceuticals:

Because of their physico-chemical instability and vulnerability to hepatogastrointestinal first-pass elimination, peptides and proteins often have a limited oral bioavailability.⁴⁴

3. Delivery of Drugs to Brain:

The percentage of drugs that reach the CNS following nasal delivery will rise with the development of nasal delivery systems for the brain. Certain molecules may be able to cross the blood-brain barrier and enter the brain through the olfactory area, which is situated in the upper distant regions of the nasal passages. Human studies have shown that proteins like AVP, CCK analogue, MSH/ACTH, and insulin are transported straight from the nasal cavity to the brain.^45,87

4. Delivery of Vaccines:

Nasal secretions mostly contain immunoglobulins (IgA, IgG, IgM, and IgE), protective proteins such complement, neutrophils, and lymphocytes in the mucosa.⁴⁶

5. Delivery of diagnostic drugs:

The delivery of diagnostic substances for the diagnosis of various diseases and disorders in the body through the nasal drug delivery system is also highly essential. Because the intranasal route allows for a more rapid and less harmful systemic release of the medication into the bloodstream. A diagnostic tool used to determine a patient's kidney function is phenolsulfonphthalein. The "Secretin" was used to diagnose pancreatic problems in diabetic patients.⁴⁷

Nanomaterial delivery via nasal route for the treatment of neurological disorders:

The twentieth century has undergone a transformation thanks to advancements in nanotechnology and its applicability to the fields of drugs and medicine. Greek word "nano" means "dwarf" and is used as the prefix. Nano refers to a very small or minuscule size.^49,50

Pharmaceutical nanoparticles are solid, submicron-sized drug carriers with a diameter of less than 100 nm that may or may not be biodegradable. In order to create materials and gadgets with unique features, nanotechnology incorporates individual atoms, molecules, or compounds into structures. In nanotechnology, work is done either from the bottom up, which more closely mimics chemistry and biology, or from the top down, which entails shrinking the size of huge structures to the tiniest structures, such as photonics applications in nano electronics.^51,53,54

Novel Drug Formulation via Nasal Route:

There have been a number of arguments in favour of creating liposome-, microsphere-, and nanoparticle-based nasal formulations for intranasal medication delivery. Enzymatic inhibitors, nasal absorption enhancers, or mucoadhesive polymers may also be present in these systems in addition to the medicine to increase stability, membrane penetration, and retention time in the nasal cavity.^90,91

1. Metallic nanoparticles: These particles can be created by manipulating their size and shape, and they can attach to different kinds of chemical functional groups.⁵⁶ They can adhere to and bind with different ligands, such as medicines, antibodies, peptides, and polymers, thanks to their alterations and linkings. For brain-targeted therapy, various kinds of metallic nanoparticles are used as carriers. FeONPs, AgNPs, Gadolinium metallofullerene NPs, Ultrasmall gadolinium oxide NPs, Ce2O3 NPs, ZnONPs, AuNPs, and PtNPs are some of these nanoparticles. Metallic nanoparticles are additionally employed for CNS imaging.^{55,57,58,84,87,88}

2. Dendrimers: Optical dendrimers excel in the application of neuroscience because they offer the advantages of a particle-defined structure mixed with a functionalized surface. It is significant to note that the most recent dendrimer-based discovery is the MRI contrast agent, which enhances the ability to see the bloodstream.^59,62

3. Polymeric Nanoparticles: Polymer materials have good qualities since they are stable, allow for various agents, and allow for managing the kinetic energy of the medications, whereas lipids and carbon nanotubes are also used to make nanocarriers. Humans can safely use polymers. Polysaccharides, proteins, amino acids, and polyesters are just a few examples of the various polymers that are utilised to create nanoparticles for drugs to be delivered to the central nervous system.^{63,89, 92}

4. Liposomes: The spherical vesicles known as liposomes are made of lipid bilayers. The benefits of liposomes are their excellent biocompatibility, low toxicity, and lack of any negative side effects throughout the drug delivery process. Phosphatidylcholine and cholesterol make form liposomes.^64,65,83

5. Micelles: Angle copolymers inject new life into the stale tale of polymeric micelles by showing a variety of chain arrangements. A few uncommon features in micelle designs are brought about by the angle chain structure, which also leads to exceptional fundamental developments that could result in novel properties and applications. Therefore, the development of slope copolymer micelle structures and their applications is seen from the viewpoint of delicate matter physics.^66-68

Advantages of Nanoparticles via Nasal route for the treatment of CNS disorder:

1. Biodegradable

2. Adjustable surface modifications

3. Use for hydrophilic and hydrophobic drugs

4. Ease of ligand conjugation to improve blood circulation

5. Increased bioavailability of drug with better absorption

6. Reduction of dose of drug

7. Increased uptake due to ionic interaction with BBB.⁶⁹

Future scope of Nanomaterial deliver through Nasal Route for CNS Disorder:

A number of applied therapeutic polymers in the treatment ofcancer and other diseases are under investigation for clinical used in Fig. no. 4 present the development of new NPs-based approaches and strategies targeted toward drug delivery to the brain.^{70, 89}

Fig. no. 3 Applications of nanotechnology in drug delivery to the central nervous system

RESULT:

In modern industrialised environment, CNS problems are one of the most severe issues. The science of nanotechnology has proven to be quite advanced and promising, enabling the delivery of drugs to the brain with high precision. To assess their dynamic behaviour in biological science, we still need to learn more about their characteristics. There is currently no multifunctional medication for the various CNS illnesses that can originate from various distinct biochemical pathways. Nanodrugs may help to find a solution to this issue. Although the use of nanotechnology alone is unlikely to be able to complete the challenging process of CNS repair, it does have a significant potential to influence clinical neuroscience treatment options. The most successful uses of nanoparticles in the treatment of CNS disorders have paired the effectiveness of nanoscale interventions with growth factors or cells that improve the total impact of the nanoscale therapy, underscoring the significance of a combined approach to nanotherapeutics. Furthermore, improvements in our biology understanding of the mechanisms behind these illnesses can only increase the utility of nanotechnology applications in CNS disease. The molecular foundation of neurological illnesses is now more understood, and this knowledge, along with the multifunctional powers of nanotechnology, has the potential to significantly alter how neurology is practised.

DISCUSSION:

An introduction to some of the most significant uses of nanotechnology for CNS imaging has been given in this paper. The reader is urged to study the cited publications in order to understand more about this significant and fascinating area of research since the issues are covered here in a limited amount of depth by necessity. Neuroradiologists shouldn't be deterred from taking a serious interest in nanotechnology-related imaging topics by the fact that many of the topics discussed here are still in the discovery stage. Little doubt can be entertained that some of the general ideas discussed here will be therapeutically relevant, even though the applications of nanotechnology are not yet ready for clinical translation. After all, many methods used in neuroradiology today were once thought of as purely theoretical concepts with no real-world applications, similar to how nanotechnology applications are now seen.

ACKNOWLEDGMENTS:

Author is thankful to Principal and Management of Kamla Nehru College of Pharmacy Butibori, Nagpur for proving a research facility.

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Received on 06.04.2023 Modified on 18.08.2023

Asian J. Pharm. Res. 2024; 14(1):53-61.

DOI: 10.52711/2231-5691.2024.00008