INTRODUCTION:

As drug delivery system is expanding its fundamental role to assist doctors to deliver therapeutic active substances to their aim sites , it is not supervising that a large amount of research lessons based on this domain were reported in many pharmaceutical papers.²Neurological disorder are the major cause of disability regulated lifecycle years and the additional important reason of passing worldwide representing 16.8% of global deaths.¹ Intranasal route for brain targeting is gaining much attention in the scientific world due to the particular anatomical and physiological functions of the nasal cavity.³

The burden of neurological disease is rising with unipolar and depressive disorders predicted to become the second largest cause of morbidity by 2030.⁴ The richly supplied vascular nature of the nasal mucosa coupled it its high drug permeation make the nasal routes of administration attractive for many drugs including proteins and peptides.⁵ In addition absorb ton of drug at the olfactory region of the nose provides a potential for a pharmaceutical compound to be available to the central nervous system.⁶ In Europe the societal cost of neurological disorder was estimated at 798 euros billion in 2010, a figure comprising direct medical as well as nonmedical cost and productivity loses.⁷ Condition such as dementia anxiety and addiction inflict the greatest cost on European health budget.⁸

Nose to Brain Mechanism of Deliverry: -

for the purpose of drug delivery, the nasal cavity is divided into the respiratory area and olfactory area, with the latter situated high up into the nares and former close to the nostrils.⁹ The feasibility by using olfactory neurons to serve as a direct drug transport route to the CSF and brain has been investigated extensively during the act decades. Now we understand the mechanism of drug uptake into the brain from the nasal cavity mainly through two different pathways. One is the systemic pathways by which by some of the drug is absorbed into the systemic circulator by rich vasculature of the respiratory epithelium and subsequently reaches the brain by crossing the BBB. The other side of the olfactory pathway by which the drug is directly delivered to brain tissue, bypassing the BBB. Drug across olfactory epithelial cells may simply move slowly through tight interstitial space of cells, or across the cell membrane by endocytosis or transport by vesicle carriers and neurons.^10,11 There are three likely mechanisms underlying the direct nose to brain drug delivery. there could be at least one intracellular transported mediated route and two extracellular transport mediated routes.¹²The exact mechanism by which compounds transfer from the nasal mucosa to the brain is not fully understood. However, it is known that absorption of molecules takes place at the olfactory and respiratory epithelia.¹³The routes of compound transfer through the olfactory area, of the nares, to the olfactory bulb are transcellular through either the sustentacular cells or the exposed olfactory sensory neurons.¹⁴The intracellular transport-based route is relatively slow process, taking hours for intranasally administered substances to reach the olfactory bulb. The olfactory neurons in the olfactory epithelium could uptake the molecules by such processes as endocytosis, which could reach the olfactory bulb by axonal transport. The two likely extracellular transport-based routes could underlie the rapid entrance of drug into the brain, which can occur within minutes of intranasal drug administration. In the first extracellular transport-based route, intranasally administered substances could first cross the gaps between the olfactory neurons in the olfactory epithelium, which are subsequently transported into the olfactory bulb. In the second extracellular transport-based route, intranasally administered substances may be transported along the trigeminal nerve to bypass the BBB. After reaching the olfactory bulb or trigeminal region the substances may enter into the other regions of brain by diffusion. In addition, intranasally administered drugs may also partially enter into the CNS the drugs enter into the systemic blood circulation from the nose.¹⁵A key advantage of the nose-to-brain route is the possibility of reducing plasma exposure, as has been demonstrated.¹⁶

Advantages of Nose to Brain Dug Delivery System:

· It is non-invasive, easy and convenient route of administration.

· Bypass the BBB and targets the CNS reducing systemic exposure and thus systemic side

· Rapid onset of action.

· No destruction by stomach acid.

· No first pass metabolism.

The Noval Approches Used to Improve the uptake of Drug Include:

1. Mucodhesive Formulation:-

The use of mucoadhesive polymers into nasal formulation can increase the mucosal contact time and prolong the residence time of the dosage forms in the nasal cavity. Using mucoadhesive polymers various formulations can be made like mucoadhesive powder, nasal gel, micro emulsion, nano emulsion etc.

Examples of mucoadhesive polymers

1. Cellulose derivatives- Carboxy methyl cellulose (CMC), hydroxyl propyl cellulose (HPC), Methyl cellulose (MC), Carboxy methyl cellulose(CMC) etc.

2. Poly acrylates - Carbopol 971 P, Carbopol 934 P, Carbopol 974 P.

3. Starch (maize starch)

4. Chitosan

Various mucoadhesive formulations can be made for delivery of drugs through nasal route like mucoadhesive powder, gel, microemulsion, nano emulsion, microspheres etc.

A. Powders:

Powder dosage forms of drugs for nasal administration offer several advantages over liquid formulations. In the powder form, the chemical stability of the drug is increased, a preservative in the formulation is not required, and it is possible to administer larger doses of drugs. Powder form is suitable for number of non-peptide drugs and is well suited for peptide drugs.¹⁵

B. Nasal gel:

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.¹⁷

Microemulsions:

Microemulsion formulations of clonazepam incorporated with mucoadhesive agents exhibited faster onset of action followed by prolonged duration of action in the treatment of status epilepticus.¹⁸

D. Nanoemulsion:

Nano emulsion based intranasal delivery of Rizatriptan benzoate (antimigraine drug) for nose to brain targeting has been developed using pseudo ternary phase diagrams of lipophilic- hydrophilic surfactants and water and different ratio of mucoadhesive polymers i.e. HPMC and Carbopol 980.¹⁹

2. Liposomes:

Liposomes are spherical microscopic vesicles composed of one (uniflagellar) or more (multilamellar) concentric lipid bilayers, arranged around a central aqueous core. They are made of natural, biodegradable, nontoxic, and natural constituents such as phospholipids and may mimic naturally occurring cell membranes. They may contain cholesterol as a membrane stabilizer and may include trace amounts of charging agents. Having these desirable structure features, liposomes can encapsulate drugs with widely varying lipophilicities, with the lipophilic ones being located in the lipid bilayer and the hydrophilic ones being retained in the aqueous core. Amphiphilic drugs can be adsorbed at the head group region of the bilayers. Liposomes have been investigated as carriers of various pharmacologically active agents such as antineoplastic, antimicrobial drugs, chelating agents, steroids, vaccines, and genetic materials. Liposomes provide an efficient drug delivery system because they can alter the pharmacokinetics and pharmacodynamics of the entrapped drugs. Liposomes can also be coated with several thousand strands of polyethylene glycol (PEG) to extend the circulation time in the blood.²⁰

3. Nanoparticles:

Nanoparticles may offer an improvement to nose-to-brain drug delivery since they are able to protect the encapsulated drug from biological and/or chemical degradation, and extracellular transport by Pep efflux proteins. This would increase CNS availability of the drug. A high relative surface area means that these vectors will release drug faster than larger equivalent, a property desirable where acute management of pain is required. Their small sizes potentially allow nanoparticles to be transported transcellularly through olfactory neurons to the brain via the various endocytic pathways of sustentacular or neuronal cells in the olfactory membrane, as described above. Surface modification of the nanoparticles could achieve targeted CNS delivery of a number of different drugs using the same ‘platform’ delivery system which has known and well characterized biophysical properties and mechanism(s) of transit into the CNS.16 Research showed that surface modified nanoparticles enhanced trans nasal delivery and gene therapy to target cancer cells.²¹

Clinical Use of Nose-to-Brain Delivery:

It is clear from the foregoing account that utilizing the nose to- brain route is a suitable method of achieving brain delivery of actives. As such, a variety of clinical trials have been reported that use this route. The first report of nose-to-brain delivery was made in 2002 by Born et al. (2002), in which insulin along with melanocortin (4–10) and vasopressin was administered as intranasal solutions to humans, and elevated levels of all three drugs detected in the CSF 10 minutes after dosing with peak levels were observed 80 minutes after dosing. This breakthrough study has paved the way for a variety of clinical studies using the nose-to-brain rout for various disease indications.²²

Polymers Used in Nasal Drug Delivery:

Cellulose Derivatives

Different cellulose derivatives are seen to be effective on enhancing the intranasal absorption of drugs such as Hydroxypropyl Methylcellulose (HPMC), Hydroxypropyl Cellulose (HPC), Methylcellulose (MC), and Carboxymethyl Cellulose (CMC), and insoluble cellulose derivatives such as Ethyl cellulose and Microcrystalline Cellulose (MCC).²³

Polyacrylates:

Polyacrylates have been investigated very frequently in many drugs administration’s routes, like nasal drug delivery systems, due to their excellent mucoadhesive and gel-forming capability. Among the pharmaceutical polyacrylates, carbomers, and polycarbophil, which differ in the cross-linking condition and viscosity, are widely used in the nasal mucoadhesive drug delivery systems. Polyacrylates, capable of attaching to mucosal surfaces, can offer the prospects of prolonging the residence time of drugs at the sites of drug absorption, and ensure intimate contact between the formulation and membrane surface. Studies by Awoke in rabbits reported that the use of Carbopol 971P in nasal dosage forms increases their residence time in the nasal cavity. The percentages of the formulations cleared from the nasal cavity at 3 hours were 24% for Carbopol 971P, while it was 70% for lactose. Prolonged release of drugs can also be obtained by using polyacrylates in nasal formulation, which result in a more stable blood concentration-time curve.^24,25

Chitosan:

Chitosan is a linear polysaccharide biopolymer produced by deacetylation of chitin, the main component of crustacean’s exoskeleton. Due to its biodegradability, biocompatibility and bio adhesive properties associated to a low toxicity, Chitosan is widely used in intranasal formulations. It is believed that it interacts with the protein kinase C system and opens the tight junctions between epithelial cells increasing Para cellular transport of polar drugs. Moreover, it interacts strongly with nasal mucus layer enhancing the contact time for the transfer of the drug across the membrane. Finally, Chitosan also enhances the dissolution rate of low water-soluble drugs. Consequently, Chitosan is used in several intranasal pharmaceutical forms, including powders, liquids, gels, microparticles and microspheres. For some drugs, it is well documented that the addition of Chitosan to nasal formulation increases drug bioavailability.²⁶

Cyclodextrins:

Cyclodextrins are cyclic oligosaccharides composed of glucose units joined trough α-1, 4-glycosidic bonds resulted from bacterial digestion of cellulose. Structurally, they take in a hydrophilic counter surface and a lipophilic central cavity where polar drugs can be included. Cyclodextrins are used as complexing agents to improve nasal drug absorption by increasing the drug solubility and stability. They can work as absorption enhancers, since they interact with the lipophilic components of biological membrane changing their permeability. Although widely used in intranasal medicinal preparations; Cyclodextrins present some local and systemic toxicity. Moreover, alterations of nasal morphology, ciliary beat frequency, erythrocyte hemolysis and cytotoxic effects have also been reported.²⁷

Lectins:

Lectins are classified as a group of structurally diverse proteins that are found in plants as well as in the animal kingdom. Lectins have the capacity to identify and bind to specific sugar moieties. The sugar binding moiety of most lectins is only a small part of the lectin, i.e., a major portion of lectin is not involved in the recognition and binding to the receptor. Lectins also cause agglutination due to their ability to cross link sugar containing macromolecules. The various lectins which have shown specific binding to the mucosa include lectins extracted from Ulex europaeus I, soybean, peanut and Lens culinarians. Lectins have the ability to stay on the cell surface or become internalized via a process called endocytosis if the adhesion is receptor mediated. Lectins have potential to be used in Nasal Drug Delivery; especially where internalization of the drug encapsulated nanoparticles is of particular importance such as DNA delivery.

Thiomersal:

Thiomersal are mucoadhesive polymers that have side chains carrying thiols which lead to the formation of covalent bonds between the cysteine groups in the mucus and the polymer by thiol/desulphated exchange reactions or simple oxidation process. These adhesions are also known as desulphated bridges. These bridges sometimes improve cohesion by 100 congregations. They also have a permeability enhancing effect and the ability to control the rate at which drugs are released. This property and increased cohesion lead to higher residence time of the drugs administered in combination with thiomersal, hence improving their bioavailability. Thiolate polymers display in situ gelling properties due to the oxidation of thiol groups at physiological pH-values, which results in the formation of inter- and intramolecular disulfide bonds. This increases the viscosity of the formulation coupled with extensive crosslinking due to formation of desulphated bonds with the nasal mucosa, which increases the residence time of the formulation tremendously.

Alginate poly-ethylene glycol acrylate:

Alginate Polyethylene glycol Acrylate is also recognized by the acronym Alginate-Peck. It has an alginate backbone with acrylate polyethylenglycol groups attached to it. This polymer meshes the properties of alginates (strength, simplicity and gelation) with characteristics specific to the acrylate functionality of PEG like cohesion. PEG’s have the ability to penetrate the mucus surface while the acrylate group of the polymer reacts with the sulphone group of glycoproteins present in the mucus. This solution in a potent interaction between the mucus and the polymer. It is expected to be cross-linkable by two different paths: chemically via the acrylate end groups and physically through the alginate backbone. Alginate is a mucoadhesive polysaccharide of 1 → 4 linked α-l-glucuronic acid and β-d mannuronic acid which binds to the glycoproteins in the mucus through carboxyl–hydroxyl interactions. It is anionic in nature. It is known to undergo ionic sol to gel transition (gelation) upon interaction with multivalent ions such as Ca2+, Fe2+, thus reducing its adhesion to mucosal tissues.²⁸

Poloxamer (Pluronic’s):

Poloxamers are made up of non-ionic difunctional triblock copolymers containing a centrally located hydrophobic polypropylene oxide between hydrophilic polyethylene oxides. Aqueous solutions of poloxamers are extremely stable in the presence of acids, alkalis and metal ions. These polymers are readily soluble in aqueous, polar and non-polar organic solvents. Hence, they are commonly chosen choice as excipients in formulations. Poloxamers are said to contain thermoreversible property and will convert from a liquid to a gel at body temperature, thus, causing in situ gelation at the site of interest preventing the drug to be removed from the nasal cavity due to conciliary clearance. This vastly progresses the bioavailability of the drug administered.²⁹

Intranasal Drug Delivery System:

Intranasal administration of NAD+ is found to be neuroprotective as it reduces transient focal ischemia.³⁴ Similarly, intranasal administration of the PARG inhibitor gallotannin also reduce ischemic brain injury in rats.³⁵ Such representative abolishes activation of poly (ADP-ribose) polymerase-1 (PARP-1), which plays a significant role in ischemic brain damage. Further, NAD+ was observed to reduce infarct formation by up to 86% even when administered at 2 hours after ischemic onset.³⁵ Similarly, intranasal administration of antiporters or NMDA receptor blockers supply neuroprotection against the more upstream events of global ischemia such as membrane depolarization and excitotoxicity.³⁶ Similarly, nasal administration of EPO (erythropoietin) is a prospective, novel, neurotherapeutic detain in the treatment of acute ischemic stroke in humans. It is one of the most successful techniques that show neuroprotective capacity in the treatment of patients with acute stroke and other neurodegenerative disorders. No doubt that this new therapeutic approach could revolutionize the treatment of neurodegenerative disorders in the 21^stcentury.³⁷

Clinical Uses:

As such, a variety of clinical assessments have been reported that use this route. The first report of nose-to-brain delivery was made in 2002 by Born et al. (2002), in which insulin along with melanocortin (4-10) and vasopressin was allotted as intranasal solutions to humans, and upraised levels of all three drugs were recognized in the CSF 10 minutes after dosing with peak levels were noticed 8 minutes after dosing with peak levels were observed 80 minutes after dosing.³⁰

Nanoparticulate systems for brain delivery of drugs:

Nanoparticles vary in size between about 10 and 1000 nm (1 mm). These interrelate with biological barriers and easily pass through it and are used for drug targeting and biodistribution of pharmaceuticals in a controlled method. Drugs can bound in form of a solid solution or dispersion or adsorbed to the surface or chemically attached on nanoparticles support carrier loading.³⁸

Applications of nose to brain drug delivery:

Mucoadhesive microemulsion for the antiepileptic drug clonazepam has been formulated.³¹ The aim was to provide quick delivery to the rat brain. Brain/blood ratio at all sampling points up to 8 hours following intranasal administration of clonazepam mucoadhesive Microemulsion carrying valproic acid resulted in fractional diffusion capability and better brain bioavailability efficiency.³² Hence microemulsions are the promising approach for delivery of valproic acid for treatment of epilepsy. Clobazam microemulsion formulations were also evaluated for the average onset of seizures in pentylene tetrazole treated mice. This study showed high brain targeting regulation of prepared clobazam microemulsion and detain onset of seizures persuade by pentylene tetrazole in mice after intranasal administration of developed formulation.³³

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Received on 06.09.2021 Modified on 19.09.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(4):335-340.

DOI: 10.52711/0975-4377.2021.00054