Journal of Applied Pharmaceutical Science 01 (07); 2011: 21-28
`
`ISSN: 2231-3354
`Received on: 27-08-2011
`Revised on: 03-09-2011
`Accepted on: 07-09-2011
`
`Advances in nasal trans-mucosal drug delivery
`
`Swatantra K.S. Kushwaha, Ravi Kumar Keshari and A.K. Rai
`
`ABSTRACT
`
`Transmucosal nasal delivery is a promising drug delivery option where common drug
`administrations, such as intravenous, intramuscular, or oral are inapplicable. Recently, it has been
`shown that many drugs have better bioavailability by nasal route than the oral route. This has
`been attributed to rich vasculature and a highly permeable structure of the nasal mucosa coupled
`with avoidance of hepatic first-pass elimination, gut wall metabolism and/or destruction in the
`gastrointestinal tract. The physiology of the nose presents obstacles, but offers a promising route
`for non-invasive systemic delivery of numerous therapies and debatably drug delivery route to the
`brain. Intranasal microemulsions, gels and microspheres have gained increased interest in recent
`years as a delivery system for protein and peptides through the nasal route. Thus this review
`focuses on nasal drug delivery, various aspects of nasal anatomy and physiology, nasal drug
`absorption mechanisms, various nasal drug delivery systems, and their applications in drug
`delivery.
`
`Key words: Nasal, Gel, Transmucosal, Delivery, in-situ.
`
`INTRODUCTION
`
`Nasal mucosa has been considered as a potential ad-ministration route to achieve faster
`and higher level of drug absorption because it is permeable to more com-pounds than the
`gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, neutral pH of the
`nasal mucus and less dilution by gastrointestinal contents (Krishnamoorthy and Ashim, 1998) In
`recent years many drugs have been shown to achieve better systemic bioavailability through nasal
`route than by oral administration. Nasal therapy, has been recognized form of treatment in the
`Ayurvedic systems of Indian medicine, it is also called “NASAYA KARMA”(Chein, 1989)Nasal
`drug delivery which has been practiced for thousands of years has been given a new lease of life. It
`is a useful delivery method for drugs that are active in low doses and show no minimal oral
`bioavailability such as proteins and peptides. One of the reasons for the low degree of absorption
`of peptides and proteins via the nasal route is rapid movement away from the absorption site in the
`nasal cavity due to the mucociliary clearance mechanism (Rathananand et al, 2007). The nasal
`route circumvents hepatic first pass elimination associated with the oral delivery: it is easily
`accessible and suitable for self-medication. During the past several decades, the feasibility of drug
`delivery via the nasal route has received increasing attention from pharmaceutical scientists and
`clinicians. Drug candidates ranging from small metal ions to large macromolecular proteins have
`been tested in various animal models. It has been documented that nasal administration of certain-
`hormones and steroids have resulted in a more complete absorption. This indicates the potential
`value of the nasal route for administration of systemic medications as well as utilizing this route
`
`Swatantra K.S. Kushwaha, Ravi
`Kumar Keshari and A.K. Rai
`Pranveer Singh Institute of
`Technology, Kanpur, India
`
`For Correspondence:
`Swatantra K.S. Kushwaha
`Assistant professor
`Pranveer Singh Institute of
`Technology,
`Kanpur, India-208020
`
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`Journal of Applied Pharmaceutical Science 01 (07); 2011: 21-28
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`for local effects (Hussain et al, 1990). For many years drugs have
`been administered nasally for both topical and systemic action.
`Topical administration includes the treatment of congestion,
`rhinitis, sinusitis and related allergic or chronic conditions, and has
`resulted in a variety of different medications including corticoids,
`antihistamines, anti-cholinergic and vasoconstrictors.
`In recent
`years, increasing investigations of the nasal route have focused
`especially on nasal application for systemic drug delivery (Kublik
`et al, 1998). Only a few nasal delivery systems used in
`experimental studies are currently on the market
`to deliver
`therapeutics into the nasal cavities, i.e. nasal drops as multiple or
`single-dose formulation, aqueous nasal sprays, a nasal gel pump,
`pressurized MDIs and dry powder inhalers. Intranasal delivery is
`currently being employed in treatments for migraine, smoking
`cessation, acute pain relief, osteoporosis, nocturnal enuresis and
`vitamin-B12 deficiency. Other examples of therapeutic areas under
`development or with potential for nasal delivery include cancer
`therapy, epilepsy, antiemetics, rheumatoid arthritis and insulin-
`dependent diabetes.
`
`NASAL ANATOMY AND PHYSIOLOGY OF THE NOSE
`The human nasal cavity has a total volume of about 16 to
`19 ml, and a total surface area of about 180 cm2, and is divided into
`two nasal cavities by the septum. The volume of each cavity is
`approximately 7.5 ml, having a surface area approximately 75 cm2.
`Post drug administration into the nasal cavity, a solute can be
`deposited at one or more of anatomically distinct regions, the
`vestibular, respiratory and olfactory regions showing in figure-
`1(Pires et al, 2009).
`
`absorption for displaying systemic effects. Important candidates
`are the compounds, generally administered by injection and hardly
`absorbed after oral administration, due to their instability in the
`gastrointestinal tract, poor absorption properties, and their rapid
`and extensive biotransformation (Druce, 1986).
`
`MECHANISM OF NASAL ABSORPTION
`The absorbed drugs from the nasal cavity must pass
`through the mucus layer; it is the first step in absorption. Small,
`unchanged drugs easily pass through this layer but large, charged
`drugs are difficult to cross it. The principle protein of the mucus is
`mucin;
`it has the tendency to bind to the solutes, hindering
`diffusion. Additionally, structural changes in the mucus layer are
`possible as a result of environmental changes (i.e. pH, temperature,
`etc.) (Illum et al, 1999). So many absorption mechanisms were
`established earlier but only two mechanisms have been
`predominantly used, such as-
`
`(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 com-pounds.
`The molecular weight greater than 1000 Daltons having drugs
`shows poor bioavailability (Aurora, 2002).
`
`(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 which is showing in figure-
`2(Dodane et al, 1999).
`
`Fig 1: Nasal mucosa
`
`REASON FOR DEVELOPMENT OF NASAL DELIVERY
`Nasal drug delivery is a useful delivery method for drugs
`that are active in low doses and show minimal or no oral
`bioavailability. The nasal route circumvents hepatic first pass
`elimination associated with the oral delivery; it is easily accessible
`and suitable for self-medication. Currently, two classes of nasally
`delivered therapeutic agents are on the market. The first one
`comprises low molecular weight and hydrophobic drugs for the
`treatment of the nasal mucosa and sinus, including decongestants,
`topical steroids, antibiotics and other (OTC) products. The second
`class encompasses a few drugs, which have sufficient nasal
`
`Fig 2 (A1) Intercellular spaces, (A2) Tight junctions, (B1) Passive diffusion, (B2)
`Active transport, (C) Transcytosis
`
`from
`For examples: chitosan, a natural biopolymer
`shellfish, opens tight junctions between epithelial cells to facilitate
`drug transport (Remo et al 1998).
`
`BARRIERS TO NASAL ABSORPTION
`Nasal drug delivery system is considered has a profitable
`route for the formulation scientist because it has easy and simple
`formulation strategies. Intra-nasally administered drug products
`therapeutic efficacy and toxicities are influenced by number of
`factors (Striebel et al, 1993). Following factors are the barriers to
`the absorption of drugs through nasal cavity.
`i) Low bioavailability- Lipophilic drugs are generally well
`absorbed from the nasal cavity compared to polar drugs. The
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`pharmacokinetic profiles of lipophilic drugs are often identical to
`those obtained after an intravenous injection and bioavailability
`approaching 100%. A good examples of
`this is the nasal
`administration of Fentanyl where the Tmax for both intravenous and
`nasal administration have been shown to be very rapid (7 min or
`less) and the bioavailability for nasal anterior part of the nasal
`cavity can decrease clear administration was near 80%. The most
`important factor limiting the nasal absorption of polar drugs and
`especially large molecular weight polar drugs such as peptides and
`proteins is the low membrane permeability. Drugs can cross the
`epithelial cell membrane either by the transcellular route exploiting
`simple concentration gradients, by receptor mediated or vesicular
`transport mechanisms, or by the paracellular route through the tight
`junctions between the cells. Polar drugs with molecular weights
`below 1000 Da will generally pass the membrane using the latter
`route(McMartin et al, 1987). Larger peptides and proteins have
`been shown to be able to pass the nasal membrane using an
`endocytotic transport process but only in low amounts (Inagaki et
`al, 1985).
`
`ii) Low membrane transport -Another importance factor is low
`membrane transport
`is
`the general
`rapid clearance of
`the
`administered formulation from the nasal cavity due to the
`mucociliary clearance mechanism. This is especially the case for
`drugs that are not easily absorbed across the nasal membrane. It
`has been shown that for both liquid and powder formulations, that
`are not mucoadhesive, the half life of clearance is in the order of
`15–20 min (Soane et al 1999). It has further been suggested that
`the deposition of a formulation in the anterior part of the nasal
`cavity can decrease clearance and promote absorption as compared
`to deposition further back in the nasal cavity (Harris et al, 1986).
`
`iii) Enzymatic Degradation- Another contributing (but normally
`considered less important) factor to the low transport of especially
`peptides and proteins across the nasal membrane is the possibility
`of an enzymatic de-gradation of the molecule either within the
`lumen of the nasal cavity or during passage across the epithelial
`barrier. These sites both contain exo-peptidases such as mono- and
`di-aminopeptidases that can cleave pep-tides at their N and C
`termini and endopeptidases such as serine and cysteine, which can
`attack internal pep-tide bonds (Lee, 1988). The use of enzyme
`inhibitors and/or saturation of enzymes may be approaches to
`overcome this barrier (Morimoto, 1995).
`
`FACTORS AFFECTING THE CHARACTERISTICS OF
`NASAL DRUG DELIVERY:
`
`1-PHYSICOCHEMICAL PROPERTIES OF DRUGS
`
`i. Chemical form
`The chemical form of a drug is important in determining
`absorption. For example, conversion of the drug into a salt or ester
`form can also alter its absorption. Huang et al (1985) studied the
`effect of structural modification of drug on absorption.It was
`observed that in-situ nasal absorption of carboxylic acid esters of
`L-Tyrosine was significantly greater than that of L-Tyrosine.
`
`ii. Polymorphism
`Polymorphism is known to affect the dissolution rate and
`solubility of drugs and thus their absorption through biological
`membranes.
`
`iii. Molecular weight
`A linear inverse correlation has been reported between the
`absorption of drugs and molecular weight up to 300 Dalton.
`Absorption decreases significantly if the molecular weight
`is
`greater than 1000 Dalton except with the use of absorption
`enhancers. Shape is also important. Linear molecules have lower
`absorption than cyclic shaped molecules.
`
`iv. Particle size
`It has been reported that particle sizes greater than 10μm
`are deposited in the nasal cavity.
`
`v. Solubility & dissolution rate
`Drug solubility and dissolution rates are important factors
`in determining nasal absorption from powders and suspensions.
`The particles deposited in the nasal cavity need to be dissolved
`prior to absorption. If a drug remains as particles or is cleared
`away, no absorption occurs.
`
`•
`•
`
`FORMULATION FACTORS
`i.
`pH of the formulation
`Both the pH of the nasal cavity and pKa of a particular
`drug need to be considered to optimize systemic absorption. Nasal
`irritation is minimized when products are delivered with pH, in the
`range of 4.5 to 6.5. Also, volume and concentration are important
`to consider. The delivery volume is limited by the size of the nasal
`cavity. An upper limit of 25 mg/dose and a volume of 25 to 200
`μL/ nostril have been suggested:
`To avoid irritation of nasal mucosa,
`•
`To allow the drug to be available in unionized form for
`•
`absorption,
`To prevent growth of pathogenic bacteria in the nasal passage,
`To maintain functionality of excipients such as preservatives,
`and
`To sustain normal physiological ciliary movement.
`Lysozyme is
`found in nasal
`secretions, which is
`responsible for destroying certain bacteria at acidic pH. Under
`alkaline conditions, lysozyme is inactivated and the nasal tissue is
`susceptible to microbial infection. It is therefore advisable to keep
`the formulation at a pH of 4.5 to 6.5, keeping in mind the
`physicochemical properties of the drug as drugs are absorbed in the
`unionized form.
`ii. Buffer capacity
`Nasal formulations are generally administered in small
`volumes ranging from 25 to 200μL. Hence, nasal secretions may
`alter
`the pH of
`the administered dose. This can affect
`the
`concentration of unionized drug available
`for
`absorption.
`Therefore, an adequate formulation buffer capacity may be
`required to maintain the pH in-situ.
`
`•
`
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`Journal of Applied Pharmaceutical Science 01 (07); 2011: 21-28
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`iii. Osmolarity
`affected by tonicity of
`Drug absorption can be
`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.
`
`iv. Gelling / Viscosity building agents or gel-forming carriers
`Pennington et al (1988) demonstrated that increase in
`solution viscosity may provide a means of prolonging the
`therapeutic effect of nasal preparations. Suzuki et al (1999) showed
`that a drug carrier such as hydroxypropyl cellulose was effective in
`improving the absorption of low molecular weight drugs but did
`not produce the same effect for high molecular weight peptides.
`
`v. Solubilizers
`Aqueous solubility of drug is always a limitation for nasal
`drug delivery in solution. Conventional solvents or co-solvents
`such as glycols, small quantities of alcohol, Transcutol (diethylene
`glycol monoethyl ether), medium chain glycerides and Labrasol
`can be used to enhance the solubility of drugs. Other options
`include the use of surfactants or cyclodextrins such as HP-β-
`cyclodextrin that serve as a biocompatible solubilizer and stabilizer
`in combination with lipophilic absorption enhancers.
`
`vi. Preservatives
`Most nasal formulations are aqueous based and need
`preservatives to prevent microbial growth. Parabens, benzalkonium
`chloride, phenyl ethyl alcohol, EDTA and benzoyl alcohol are
`some of the commonly used preservatives in nasal formulations.
`Van De Donk et al (1980) showed that mercury containing
`preservatives have a fast and irreversible effect on ciliary
`movement and should not be used in nasal systems.
`
`vii. Antioxidants
`Usually, antioxidants do not affect drug absorption or
`cause nasal irritation. Commonly used antioxidants are sodium
`metabisulfite, sodium bisulfite, butylated hydroxyl
`toluene and
`tocopherol.
`
`viii. Humectants
`Many allergic and chronic diseases are often connected
`with crusts
`and drying of mucous membrane. Therefore
`humectants can be added especially in gel-based nasal products.
`Humectants avoid nasal irritation and are not likely to affect drug
`absorption. Common examples include glycerin, sorbitol and
`mannitol.
`
`ix. Drug concentration, dose & dose volume
`Drug concentration, dose and volume of administration
`are three interrelated parameters that impact the performance of the
`nasal delivery performance. Nasal absorption of L-Tyrosine was
`shown to increase with drug concentration in nasal perfusion
`experiments.
`
`x. Role of absorption enhancers
`Absorption enhancers may be required when a drug
`
`exhibits poor membrane permeability, large molecular size, lack of
`lipophilicity and enzymatic degradation by amino peptidases.
`Osmolarity and pH may accelerate
`the
`enhancing effect.
`Absorption enhancers improve absorption through many different
`mechanisms, such as increasing membrane fluidity,
`increasing
`nasal blood flow, decreasing mucus viscosity, and enzyme
`inhibition.
`
`PHYSIOLOGICAL FACTORS
`i. Effect of deposition on absorption
`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 posterior
`portion of the nose is where the drug permeability is generally
`higher, and provides shorter residence time.
`
`ii. Nasal blood flow
`Nasal mucosal membrane is very rich in vasculature and
`plays a vital role in the thermal regulation and humidification of
`the inhaled air. The blood flow and therefore the drug absorption
`will depend upon the vasoconstriction and vasodilatation of the
`blood vessels.
`
`iii. Effect of enzymatic activity
`Several enzymes that are present in the nasal mucosa
`might affect
`the stability of drugs. For example, proteins and
`peptides are subjected to degradation by proteases and amino-
`peptidase at the mucosal membrane. The level of amino-peptidase
`present
`is much lower than that
`in the gastrointestinal
`tract.
`Peptides may also form complexes with immunoglobulin (Igs) in
`the nasal cavity leading to an increase in the molecular weight and
`a reduction of permeability.
`
`iv. Effect of mucociliary clearance
`The absorption of drugs is influenced by the residence
`(contact) time between the drug and the epithelial tissue. The
`mucociliary clearance is inversely related to the residence time and
`therefore inversely proportional
`to the absorption of drugs
`administered showing in figure- 3.
`
`v. Effect of pathological condition
`Intranasal pathologies may affect the nasal mucociliary
`transport process and/or capacity for nasal absorption.
`
`Fig 3 Effect of mucociliary clearance on nasal drug absorption.
`
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`
`CHALLENGES AND OPPORTUNITIES FOR NASAL
`DELIVERY SYSTEMS
`Existing nasal delivery devices such as spray pumps and
`pipettes cannot fully exploit the described potential advantages of
`nasal delivery. A large fraction of the dose is deposited on the
`anterior segment lined by skin, which is not the target for either
`topical drugs or systemic drugs. Drugs transported along the floor
`of the nose may cause bad taste and irritation and reduce patient
`acceptance. Finally,
`inadequate and variable deposition in the
`remote region housing the openings to the sinuses and middle ears,
`as well as the olfactory region, represents a real challenge for
`extended use of nasal administration of drugs and vaccines. This
`applies in particular to the new advanced and expensive drugs
`requiring demanding combination of reliable dosing, high patient
`compliance and reproducible bio-availability to ensure their
`efficacy and safety. Regarding actual formulation, most nasal
`products are currently formulated as liquids and delivered by
`metered spray pumps.
`
`Problem
`Poor physiochemical properties of drug
`Low permeability of nasal membrane
`Enzymatic degradation
`Mucociliary clearence
`
`Challenges
`Improve physiochemical properties of drug & formulation
`Increase drug permeability & dissolution
`Modify nasal membrane
`Enhance drug residence time
`Reduce drug affinity to nasal enzymes
`Inhibit nasal enzymes
`Protect drug from nasal enzymes
`Reduced the rapid mucociliary clearance
`
`Solution
`Prodrugs, Cosolvents, Cyclodextrins novel drug formulation
`Absorption enhancers
`Mocoadhesive systems
`Enzymatic inhibitors
`Deposit the formulation in anterior part of nasal cavity
`
`CURRENT APPROACHES FOR NASAL PERMEATION
`ENHANCEMENT
`is
`drugs
`administered
`nasally
`of
`Bioavailability
`particularly restricted by low drug solubility, rapid enzymatic
`degradation in nasal cavity, poor membrane penetration and rapid
`MCC. Thus several approaches have been suggested to overcome
`these limitations.
`
`1. Prodrugs
`Intranasal drugs are commonly administered as solutions
`or as powder formulations which need to undergo a dissolution
`process before absorption. Lipophilic drugs easily pass through
`biomembranes, however they are poorly water soluble. In this way,
`they should be administered as a prodrug with higher hydrophilic
`character in order to make possible the production of an aqueous
`nasal formulation with a suitable concentration. Once in the blood
`
`stream, the prodrug must be quickly converted to the parent drug.
`Kao et al. produced various prodrugs of L-Dopa and observed that
`their solubility enhanced significantly in comparison with the
`parent drug, allowing, hence, the development of adequate nasal
`formulations (Kao et al, 2000).
`Similar results were obtained for testosterone which is
`also poorly water-soluble (Wang et al, 2005). In contrast, very
`hydrophilic polar drugs may not have the ability to cross
`biomembranes. Therefore, if they are administered as prodrugs
`with higher
`lipophilic character,
`the penetration through the
`membrane may increase. Some researchers have also used the
`prodrug approach for improving enzymatic stability of drugs. For
`example, Yang et al stated that L-aspartate- β-ester prodrug of
`acyclovir was more permeable and less labile to enzymatic
`hydrolysis than its parent drug (Yang et al, 2001). In addition, the
`potential use of prodrugs to protect peptide drugs from nasal
`enzymatic degradation has been discussed and suggested as a
`powerful strategy to increase the bioavailability of peptides when
`administered intranasally(Costantino et al, 2007).
`
`2. Co-Solvents
`An alternative approach to the use of prodrugs in order to
`increase drug solubility is the use of co-solvents. Co-solvents most
`used in intranasal formulations include glycerol, ethanol,
`propyleneglycol, and polyethylene glycol and may be of the most
`important, since they are nontoxic, pharmaceutically acceptable,
`and nonirritant to nasal mucosa.
`
`3. Enzymatic inhibitors
`Nasal mucus layer and nasal mucosa act as enzymatic
`barriers during nasal drug delivery, because they have a wide
`variety of enzymes. Various approaches have been used to avoid
`enzymatic degradation,
`including the use of proteases and
`peptidases
`inhibitors. For example, bestatine and comostate
`amylase are used as aminoptidases inhibitors and leupeptine and
`aprotinin as
`trypsine
`inhibitors probably involved in the
`degradation of calcitonin. Furthermore, bacitracin, amastatin,
`boroleucin and puromycin(Bernkop 1998) have been used to avoid
`enzymatic degradation of drugs such as leucine enkephalin(Hoang,
`2002) and human growth hormone(O(cid:783)Hagan, 1990). Finally,
`enzymatic inhibition can also be achieved using certain absorption
`enhancers (bile salts and fusidic acid). It
`is demonstrated that
`disodium EDTA, an absorption enhancer,
`reduces enzymatic
`degradation of beta sheet breaker peptide used for the treatment of
`Alzheimers disease (Greimel et al, 2007).
`
`4. Permeation enhancers
`Small and large hydrophilic drugs may be poorly
`permeable across nasal epithelium and may show insufficient
`bioavailability. Their
`permeation
`can
`improve
`by
`being
`administered in combination with absorption enhancers which
`induce reversible modifications on the structure of epithelial
`barrier. (Table -1)
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`Table 1: Mucosal penetration enhancers and mechanisms of action.
`
`Classification
`Surfactants
`
`Bile salts
`
`Cyclodextrins
`
`Fatty acids
`
`Cationic
`compounds
`
`Chelators
`
`+ve charged
`polymers
`
`Bioadhesive
`Materials
`
`Examples
`Anionic: Sodium lauryl
`sulphate
`Cationic:Cetylpyridiniu
`m Chloride
`Nonionic:Poloxamer,Spa
`n,Tween
`Sodium
`glycodeoxycholate,
`Sodium glycocholate,
`Sodium
`taurodeoxycholate
`α,β,γ
`Cyclodextrin,
`Methylated
`β–Cyclodextrins
`Oleic acid, Methyloleate,
`Lauric
`acid, Caprylic
`acid,
`Phosphotidylcholine
`Poly-L-arginine,
`lysine
`
`L-
`
`Citric Acid,
`EDTA,
`Sodium citrate, Sodium
`Salicylate
`Chitosan,Trimethyl
`chitosan
`
`Mechanism
`Perturbation of intercellular lipids,
`Protein domain integrity, Distrusts
`membrane
`
`Distrusts membrane, Open tight
`junctions, Mucolytic activity
`
`membrane
`of
`Inclusion
`Compounds, Open Tight junctions
`
`Increase fluidity of phospholipid
`domains, Distrusts membrane
`
`Ionic interaction with negative
`charge on the mucosal surface
`
`Interfere with Ca Polyacrylates
`
`Ionic interaction with negative
`charge on the mucosal surface
`
`Carbopol,
`Chitosan
`
`Starch,
`
`Reduce nasal clearance,
`Open tight junctions
`
`FOR
`
`DELIVERY SYSTEM BASED APPROACHES
`INTRANASAL DRUG DELIVERY
`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 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.
`
`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 the 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 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.
`
`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
`stability of
`the absence of preservative and superior
`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. Liposomes
`Liposomes are phospholipids vesicles composed by 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 (Alsarra et al, 2008). In fact, 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 (Kato et al, 1993). Protection of the entrapped peptides
`from enzymatic degradation and mucosal membrane disruption.
`The results demonstrated that this formulation was effective and
`that its mucoadhesive property is a viable option for a sustained
`release of insulin. Moreover, liposomal drug delivery systems were
`also reported as useful for influenza vaccine and non-peptide drugs
`such as nifedipine(Vyas et al, 1995 ).
`
`6. Nanoparticles
`Nanoparticles may offer several advantages due to their
`small size, but only the smallest nanoparticles penetrate the
`mucosal membrane by 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 (Simon et al, 2005).
`
`7. Intranasal microemulsion
`Intranasal microemulsion is one of the focused delivery
`options for noninvasive drug delivery to systemic circulation.
`Vyas(2006) has reported that 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. In other studies, Vyas et al
`reported rapid and larger extent of drug transport into rat brain
`following
`intranasal
`administration
`of
`mucoadhesive
`microemulsions of zolmitriptan and sumatriptan. Mukesh et al
`(2008) studied the intranasal delivery of risperidone and concluded
`that significant quantity of risperidone was quickly and effectively
`delivered to the brain by intranasal administration of mucoadhesive
`nanoemulsion of risperidone. Elshafeey(2009) showed that
`the
`intranasal delivery of microemulsion of sildenafil citrate showed
`shorter Tmax and higher AUC compared to the oral tablets in rabbits
`and higher relative bioavailability of sildenafil citrate.
`
`8. Intranasal microspheres
`Microsphere technology has been widely applied in
`designing formulations for nasal drug delivery. Microspheres are
`usually based on mucoadhesive polymers (chitosan, alginate),
`which
`present
`advantages
`for
`intranasal
`drug
`delivery.
`Furthermore, microspheres may also protect
`the drug from
`
`26
`
`Nalox1013
`Nalox-1 Pharmaceuticals, LLC
`Page 6 of 8
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`Journal of Applied Pharmaceutical Science 01 (07); 2011: 21-28
`
`enzymatic metabolism and sustain drug release, prolonging its
`effect. Wang et
`al., have
`investigated laminated gelatin
`microspheres as a nasal drug delivery system for insulin. They
`have
`observed
`a
`significant
`hypoglycemic
`effect when
`administered intranasally in dry powder form to rats, but no
`significant effect was achieved when given in a suspension. Gavine
`et al have analyzed nasal mucosa after its exposure to microspheres
`of alginate/chitosan containing metoclopramide(Gavini et al 2006).
`They observed open tight junctions in the epithelium and also
`stated that
`these spray-dried microspheres have promising
`properties as mucoadhesive nasal carriers.
`
`APPLICATION OF NASAL DELIVERY
`Intranasal administration confers a simple, economic,
`convenient and noninvasive route for rapid drug delivery to
`systemic circulation.(table-2)
`
`1. Treatment of epilepsy and schizophrenia:
`2. Treatment of migraine
`3. As an antidepressant
`4. Treatment of angina pectoris and neurological deficit
`5. Treatment of amnesia
`6. Intranasal delivery of peptides
`7. Intranasal delivery of vaccine
`8. Intranasal delivery of analgesics
`
`CONCLUSION
`The nasal mucosa offers several advantages for controlled
`drug delivery. The mucosa is well supplied with both vascular and
`lymphatic drainage; first-pass metabolism in the liver and pre-
`systemic elimination in the GI tract is avoided. The area is well
`suited for a retentive device and appears to be acceptable to
`patients. With the proper formulation and dosage form design, the
`permeability and the local environment of the mucosa can be
`controlled and manipulated to accommodate drug permeation.
`Nasal drug delivery is a promising area for systemic delivery of
`orally inefficient drugs as well as an attractive alternative for non-
`invasive delivery of potent peptide and perhaps protein drug
`molecules. The intranasal route is an accessible alternative to
`parenteral routes. The need for safe and effective nasal permeation
`and absorption enhancers is a crucial component for a promising
`future in the area of nasal drug delivery.
`Table 2: Advantages and challenges in intranasal vaccination.
`Advantages
`Challenges
`
`Easily accessible mucosal organ
`
`Narrow nasal entrance
`
`Highly vascularised mucosa
`
`Complex geometry with narrow passages
`
`surface
`Large
`absorption
`
`Both mucosal
`immune responses
`
`available
`
`for
`
`Variable dosing with traditional delivery
`method
`
`and
`
`systemic
`
`Mucociliary clearance and nasal cycle
`
`Protection at distant mucosal sites
`
`Reformulation of vaccines required
`
`Suitable for mass vaccination
`
`Needle free vaccination
`
`required for good immune
`
`Adjuvant
`response
`Influences of nasal
`obstruction
`
`inflammation and
`
`27
`
`REFERENCES
`
`Alsarra IA, Ham