Nose to Brain Drug Delivery System: A Review
P.R. Modi*, G.V. Patel, D.J. Daslaniya, U.L. Patel, B.V. Bhimani
Arihant School of Pharmacy and Bio- Research Institute, Uvarsad Cross Road, Adalaj, Gandhinagar 382421, Gujarat, India.
*Corresponding Author E-mail: email@example.com
Many therapeutic drugs are difficult to reach the central nervous system (CNS) from the systemic blood circulation because the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier which prevents most molecules from passing through it. There is the unique relationship between nasal cavity and cranial cavity tissues makes intranasal delivery to the brain feasible. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. The nasal mucosa is nearby the brain, cerebrospinal fluid (CSF) and the drug concentrations can exceed plasma concentrations. Intranasal delivery provides a noninvasive method of bypassing the BBB to rapidly deliver therapeutic agents to the brain, spinal cord, lymphatics and to the vessel walls of the cerebrovasculature for treating CNS disorders.
As drug delivery system is expanding its central role to assist physicians to deliver therapeutic active substances to their target sites, it is not surprising that a large number of research studies based on this domain were reported in various pharmaceutical journals. However, even with the fast pace in drug delivery design, targeting of drugs to the central nervous system (CNS) is still a challenging task. A great number of drugs are candidates for treatment of CNS diseases, but the drug delivery is still the major problem for brain targeting, especially for biotechnology products.The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) that encircle the brain form a very effective barrier to regulate brain homeostasis.1 Brain targeting of drug substances by nasal route can be seen in Fig 1.
However, 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. The sagittal section of human nasal cavity can be seen in Fig 2. A number of advantages are particularly attractive such as non-invasive rapid systemic absorption, fast onset of action, avoidance of first-pass metabolism, increasing drug bioavailability, and less systemic side effects.
Nasal mucosa has been considered as a route of administration to achieve faster and higher level of drug absorption.2 The richly supplied vascular nature of the nasal mucosa coupled with its high drug permeation makes the nasal route of administration attractive for many drugs, including proteins and peptides.3 In addition, absorption of drug at the olfactory region of the nose provides a potential for a pharmaceutical compound to be available to the central nervous system.4
Fig 1: Brain targeting by nasal route
Fig 2: Schematic of a sagittal section of human nasal cavity showing the nasal vestibule (A); atrium (B); respiratory region -- inferior turbinate (C1), middle turbinate (C2), and the superior turbinate (C3); the olfactory region (D); and nasopharynx (E).5
Mechanism of drug uptake into the brain
The feasibility of using olfactory neurons to serve as a direct drug transport route to the CSF and brain has been investigated extensively during the last decades. Now we understand that the mechanisms of drug uptake into the brain from the nasal cavity mainly through two different pathways (Fig 3). One is the systemic pathway by which some of the drug is absorbed into the systemic circulation by the rich vasculature of the respiratory epithelium and subsequently reaches the brain by crossing the BBB. The other is the olfactory pathway by which the drug is directly delivered to brain tissue, bypassing the BBB. Drugs across olfactory epithelial cells may simply move slowly through tight interstitial space of cells, or across the cell membrane by endocytosis, or transported by vesicle carriers and neurons.6, 7
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.8
The 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 exracellular 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.
Advantages of nose to brain drug 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 effects.
· Rapid onset of action.
· No destruction by stomach acid.
· No first pass metabolism.
Most of the current brain research studies are focused on the enhancement of drug delivery to the brain.
The novel approaches used to improve the uptake of the drugs include:
(1) Mucoadhesive 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.
Fig 3: The transportation of intranasal delivery of drugs.
Using mucoadhesive polymers various formulations can be made like mucoadhesive powder, nasal gel, micro emulsion, nanoemulsion 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)
Various mucoadhesive formulations can be made for delivery of drugs through nasal route like mucoadhesive powder, gel, microemulsion, nanoemulsion, microspheres etc.
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.9
Therefore, administration of nasal powders may increase patient compliance, especially if the smell and taste of the delivered drug is unacceptable. After getting in contact with the nasal mucosa, polymer-based powders are believed to form a viscous gel following absorbing water from the nasal mucus . Then, the free polymer chains penetrating into the tissue crevices can hold back the ciliary movement, which will increase the retention time of the drugs in the nasal cavity.
Nasal gels are high-viscosity thickened solutions or suspensions. The advantages of a nasal gel includes 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.10
Thermoreversible mucoadhesive gel has been developed to deliver the sumatriptan drug using pluronic F 127(thermoreversible polymer) and carbopol 934 P( mucoadhesive polymer).it is as such in solution form and after administration converts into gel form at nasal cavity temperature.11
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.12
Nanoemulsion 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 980.13
Intranasal delivery of risperidone concluded that significant quantity of risperidone was quickly and effectively delivered to the brain by intranasal administration of mucoadhesive nanoemulsion of risperidone.14
Liposomes are spherical microscopic vesicles composed of one (unilamellar) 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.15
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 Pgp 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 characterised biophysical properties and mechanism(s) of transit into the CNS.16 Research showed that surface modified nanoparticles enhanced transnasal delivery and gene therapy to target cancer cells.17
(4) Nasal spray
The nasal spray deposits anteriorly in the nasal atrium provide greater residence time, while the drops are dispersed throughout the length of the nasal cavity. Nasal sprays deposit more anteriorly, having more potential for brain delivery. The permeability of the posterior nasal passage is generally higher than the anterior passage. Intranasal delivery of diazepam with nasal spray results in rapid onset and this approach may be helpful during emergency treatment of status epilepticus.
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 200 μm. The particle size and morphology (for suspensions) of the drug and viscosity of the formulation determine the choice of pump and actuator assembly.18
These are similar to liposomes in morphology but with different compositions; they are formed from the self-assembly of non-ionic amphiphilic in combination with other lipidic surfactants in aqueous medium . Niosomes or non-ionic surfactant vesicles are microscopic lamellar structures formed from admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media resulting in closed bilayer structures like liposomes, aqueous dispersions of niosomes may exhibit fusion, aggregation, leaking, or hydrolysis of encapsulated drugs, therefore limiting the shelf life of the dispersion.
Niosomes are widely studied as an inexpensive alternative of non-biological origin to liposomes. Niosomal surfactants are biodegradable, biocompatible, and non-immunogenic. It has greater accessibility, superior chemical stability, and relatively low cost of niosomes compared with liposomes, resulting in easier storage leading to the exploitation niosomes as alternatives to phospholipids. Theoretically, niosomal formulation requires presence of a particular class of amphiphile and an aqueous system.19,20
Applications of nose to brain drug delivery
1. Delivery of drugs in Epilepsy and Schizophrenia
Various type of researches have been done to provide drug delivery through nose in these diseases. Shende et al. developed microemulsion of lomotrigone from nose to brain delivery. Intranasal administration allows transport of the drug to the brain circumventing the BBB, thus providing the better option to target drug to the brain with quick onset of action in case of emergency in epilepsy.21
Mucoadhesive microemulsion for the antiepileptic drug clonazepam has been formulated.12 The aim was to provide rapid delivery to the rat brain. Brain/blood ratio at all sampling points up to 8 hours following intranasal administration of clonazepam mucoadhesive microemulsion compared to i.v. was found to be 2-fold higher, indicating larger extent of distribution of the drug in the brain.
Microemulsion containing valproic acid resulted in fractional diffusion efficiency and better brain bioavailability efficiency.22 Hence microemulsions are the promising approach for delivery of valproic acid for treatement of epilepsy.
Clobazam microemulsion formulations were also assessed for the average onset of seizures in pentylene tetrazole treated mice. This study showed high brain targeting efficiency of prepared clobazam microemulsion and delayed onset of seizures induced by pentylene tetrazole in mice after intranasal administration of developed formulation.23
Further clinical evaluation of the developed formulation may result in a product suitable for the treatment of acute seizures due to status epileptics and patients suffering from drug tolerance and hepatic impairment on chronic use in the treatment of epileptics, schizophrenia and anxiety.
2. Delivery of antidepressant
Microemulsion of eucalyptus oil has been formulated for intranasal delivery to the brain.24It was demonstrated that the microemulsion of eucalyptus oil provides the rapid onset in soothing stimulant and antidepressant action. It was also cost effective.
3. Treatment of amnesia and alzhiemer’s disease
Microemulsion and mucoadhesive microemulsion of tacrine, assessed its pharmacokinetic-pharmacodynamic performances for brain targeting and for improvement of memory in scopolamine-induced amnesic mice.25The results demonstrated rapid and larger extent of transport of tacrine into the mice brain and faster regain of memory loss in scopolamine-induced amnesic mice after intranasal microemulsion administration.
The liposomes of Rivastigmine for Alzheimer disease have been formulated. Rivastigmine is an acetyl cholinesterase which can be rapidly absorbed after oral administration but extensively metabolized by cholinesterase-mediated hydrolysis. Liposomes my provide carrier system for this drug through nasal route to CNS. In a comparative study intranasal liposome was compared with the oral free drug and it was recorded that liposomal formulation can provide ten times higher Cmax, higher systemic AUC, and higher concentration in the brain compared to oral administration. The liposomal formulation provided better absorption into the brain following intranasal administration compared to the free drug. This might also be due to direct transfer of the drug from nasal mucosa to the brain via the olfactory route.26
4. Treatment of migraine
Migraine treatment has evolved in the scientific arena, and opinions differ on whether migraine is primarily a vascular or a neurological dysfunction.27 Sumatriptan is rapidly but incompletely absorbed following oral administration and undergoes first-pass metabolism, resulting in a low absolute bioavailability of 14% in humans . The transport of Sumatriptan across the blood-brain barrier (BBB) is very poor.28 Studies have demonstrated that intranasal administration offers a practical, noninvasive, alternative route of administration for drug delivery to the brain.
5. Treatment of angina pectoris and neurological deficit
Microemulsion has been prepared to improve the solubility and enhance the brain uptake of nimodipine , which was suitable for intranasal delivery. The uptake of nimodipine in the olfactory bulb from the nasal route was three folds, compared with intravenous (i.v.) injection. The ratios of AUC in brain tissues and cerebrospinal fluid to that in plasma obtained after nasal administration were significantly higher than those after i.v. administration. These results suggest that the microemulsion system is a promising approach for intranasal delivery of Nimodipine for the treatment and prevention of neurodegenerative diseases.29
6. Delivery of genes
A major clinical challenge for delivery of genes to the CNS results from the limitations of the currently available vectors. Most of the viral vectors are too big, and have to be injected directly into brain tissues. Therefore, nasal administration for delivery of plasmid DNA encoding therapeutic or antigenic genes is gaining attention in recent years as an alternative method due to its non-invasive administration.
One study investigated the intranasal delivery of Calcitonin gene-related peptide (CGRP), a potent vasodilator, to the brain. The data suggested that intranasal CGRP significantly relieved vasospasm, improved cerebral blood flow, and reduced cortical and endothelial cell death. Intranasal route was shown to be an effective way to deliver CGRP for brain targeting.30
The beta-galactosidase protein encoded by the recombinant plasmids was significantly expressed in brain tissues following intranasal administration. Over 1 hour after dosing, the brain targeting efficiencies were shown consistently higher for plasmid DNA administered intranasally than that administered intravenously. The authors concluded that intranasally applied plasmid DNA may reach the brain through a direct route, possibly via the olfactory bulb, and that the nasal route might be an alternative method to deliver plasmid DNA to the brain.31
The advantage of the vectors based on herpes simplex virus is that they are neurotropic. However, previous study has reported that vectors based on the type 1 herpes simplex virus (HSV-1) induced apoptosis in CNS neurons, causing severe and often fatal encephalitis in immunocompetent humans.32 However, vectors based on herpes simplex type 2 virus, ΔRR, is less virulent in the CNS than HSV-1, and it does not trigger apoptosis in CNS neurons.33A study showed that ΔRR delivered by intranasal route protected rats and mice from seizures and neuronal loss, granting it as a promising therapeutic platform for the treatment of chronic neurodegenerative diseases.34.
7. Delivery of proteins and peptides
Oral administration of peptides is impossible because of gastrointestinal enzymatic degradation and hepatic first-pass effects. Increasing evidence suggests that the intranasal route of administration may be an attractive and convenient option for the delivery of certain compounds to the brain. In fact, several peptides, including luteinizing-hormone-releasing hormone, oxytocin, calcitonin, and vasopressin, are routinely administered intranasally in clinical practice, and other peptides, including insulin, glucagon, growth hormone, growth hormone-releasing hormone, and somatostatin, are currently under investigation.1,35
Nose to brain drug delivery has the potential to treat both acute and chronic diseases. It reduces systemic exposure and hence side effects. It acts as an alternative to parenteral therapy and provides better therapeutic efficacy compared to oral route of drug administration. The identification of ways to increase the bioavailability of drugs in the brain opens possibilities for the causal treatment of diseases associated with a deficiency in neurosteroids and neurotransmitters in the brain. Despite several limitations, intranasal delivery seems to be the most promising application to improve CNS disorders, including brain injuries, by medicine. The feasibility of intranasal brain targeting was encouraging although most of the results were based on animal models. Whatever the on-going debate on the validity of data interpreted, olfactory pathway is standing strong on the clinical ground in its position as a potential route to deliver drugs directly into the human brain.
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Received on 06.02.2013 Modified on 28.02.2013
Accepted on 10.03.2013 © RJPT All right reserved