ALTERNATIVE APPLICATIONS FOR DRUG DELIVERY:NASAL AND PULMONARY ROUTES
A. YEKTA OZERHacettepe University, Faculty of Pharmacy, Department of Radiopharmacy, Ankara 06531, TurkeyE-mail: [email protected]
For treatment of human diseases, nasal and pulmonary routes of drug delivery aregaining increasing importance. These routes provide promising alternatives to parenteraldrug delivery particularly for peptide and protein therapeutics. For this purpose, severaldrug delivery systems have been formulated and are being investigated for nasaland pulmonary delivery. These include liposomes, proliposomes, microspheres, gels,prodrugs, cyclodextrins and others. In this chapter, nasal and pulmonary drug deliverymechanisms and some of the relevant drug delivery formulations are evaluated
drug delivery systems, pulmonary drug delivery, nasal drug delivery, peptide delivery,protein delivery, liposomes, microspheres
Only few decades ago, pulmonary and nasal (intranasal) applications of drugs werenot as widespread as it is today. In the year 2000, there were 27 products on theU.S. market for intranasal use, with more than half of these having obtained FDAapproval between the years 1990 and 2000. With ever-increasing pharmaceuticaltechnology and numerous medicinal opportunities for intranasal administration, itspopularity will most likely continue .
Pulmonary and intranasal drugs may be administered for local treartment or
systemic action based on the therapeutic intention. Physicotropic drugs, hallu-cinogenes (cocain), snuffs, antibiotics, vasoconstrictors, antihystaminics and localanesthetics are the examples of nasal drugs administered locally in several dosageforms like nasal solutions, ointments and sprays. Recent observations of side effectsof intranasally administered antihistaminic and vasoconstrictor drugs have leadedto their systemic use . Intranasal drugs for systemic action include treatments formigraine headaches, calcium supplementation, Vitamin B12 deficiency and pain
M.R. Mozafari (ed.), Nanomaterials and Nanosystems for Biomedical Applications, 99–112. 2007 Springer.
relief as well as other therapeutic indications. In addition to either local or systemiceffects, drugs may be intended for acute or chronic treatments .
Additionally, delivery of drugs to or via the respiratory tract can offer several
advantages over alternative routes of administration. In general, pulmonary admin-istration of drugs is more satisfactory if the intention is to achieve local actionwithin the respiratory tract.
ADVANTAGES OF INTRANASAL DRUG ADMINISTRATION
With optimized formulations, intranasal administration presents many benefits whencompared to alternative delivery routes (1–3). These include:• Not only is the nasal cavity easily accessible, it is virtually non-invasive;
• In most cases, intranasal administration is well tolerated;
• Only slight irritation may occur due to the chemical nature of substance delivered;
• Hepatic first-pass metabolism is avoided with intranasal delivery;
• Destruction of drugs by gastric fluid is not a concern;
• Intranasal mucosae has a big number of microvilli, therefore has a high surface
• Subepithelial tissue has a high vascularization;
• It offers lower doses with more rapid attainment of therapeutic blood levels;
• Quicker onset of pharmacological activity;
• Porous endotheliel basement membrane;
• Drug is delivered directly to the brain along the alfactory nerves.
WHICH TYPES OF DRUGS ARE ADMINISTEREDINTRANASALLY?
Since many years, nasal route has been used for delivery of drugs and similar otherbioactive substances such as illicit drugs, psycotrops, snuffs, etc. Generally thefollowing material are being considered for intranasal delivery:• Drugs hardly absorbed by oral route;
• Drugs metabolized in the GI tract; and
• Drugs exposed to the first-pass effect of liver can be administered intranasally
Nasal cavity is circulated by cranium base at the bottom, hard palate at the top andnares and pharynx. The distance from the tip of the nose to the pharyngeal wall isabout 10–14 cm and has a 160 cm2 surface area. The nasal septum divides the noseinto two nasal cavities, each with a 2–4 mm wide slit opening and contains threedistinct functional regions: vestibular, respiratory and olfactory [1, 2, 4].
ALTERNATIVE APPLICATIONS FOR DRUG DELIVERY
The respiratory region contains the largest surface area and is located between
the vestibular and olfactory regions. The respiratory region is the most importantpart for drug delivery administered systemically. The vestibular region is locatedclosest to the nasal passage opening, contains long hairs and serves as a filter forincoming particles. The olfactory region is located in the uppermost portion of eachcavity and opposite the septum. This region is responsible for smelling .
Nasal mucosa has exopeptidases (like aminopeptidase, diaminopeptidase etc.) and
endopeptidases (like cerynproteinase, cysteinproteinase, metalloproteinase, etc.). These enzymes cause enzymatic degredation of peptides and proteins duringabsorption .
The primary function of the nose is olfaction – it heats and humidifies inspired
air and also filters airborne particles . Consequently, the nose functions as aprotective system against foreign material . The vestibular area serves as a buffersystem; it functions as a filter of airborne particles . The olfactory epithelium iscapable of metabolising drugs . The respiratory mucosa is the region where drugabsorption is optimal .
Intranasally administered drugs aimed to obtain systemic effect, pass to the circu-lation via nasal barrier (epithelium).
The epithelium of the respiratory region consists of four different cell types:
basal, mucus-containing goblet, ciliated columnar, and nonciliated columnar. Theciliated columnar cell is the most predominant. The cilia beat in a wave-like,coordinated manner to transport mucus and trapped particles to the pharynx area forsubsequent ingestion. Cells in the respiratory region are covered by approximately300 microvilli, which greatly increase the surface area of the nasal cavity. Therespiratory region also contains the inferior, middle and superior turbinates. Thelamina propria, below the epithelium houses blood vessels, nerves and both serousand mucus secretory glands . A drug may cross the nasal mucosa by three different mechanisms [1, 9]:
i. Transfer via transcellular or simple diffusion across the membrane;
ii. Paracellular transport: Movement through the spaces between cells and tight
iii. Transcytosis (particle internalization by vesicles).
Mast cells contain polymorphonuclear leucocytes and eosynophyls. Mucus consistsof salt 2.5–3%, musin 1–2% (sulphurated scyderoprotein) and water 95%. Lysozymes, enzymes and immunoglobulins, in addition to other proteins, may allbe found in the mucus. Proteins and carbohydrates are secreted from endoplasmicreticulum and golgi substance, respectively . Mucus is produced about 1–2 leveryday [2,10]. The mucus consists of an outer viscous layer of mucus and watery
layer located along the mucosal surface [1, 10]. The pH of secretions ranges from5.5 to 6.5 and from 5.0 to 6.7 in adults and children, respectively [1, 11]. Theepithelium is covered with new mucus layer approximately every 10 min .
Nasal mucosa is covered by cilia, which does not have the same temperature
and movement at every point. The optimum temperature is 18–37°C for mucociliarmovement and is blocked at 7–12°C .
Nose shows a barrier effect for the inspirated particles and viruses reaching
it externally. These particles are retained by the mucus covering the epithelium. The viscous layer of mucus, along with entrapped particles, is transported to thenasopharyngeal area for ingestion [2, 12]. The cilia beat at a frequency which isapproximately 10–13 Hz [1, 13].
Mucociliar clerance is affected by several factors such as viscoelasticity of mucus,
the thickness of mucus layer, gravity and air flux .
The physicochemical properties of the drug, nasal mucociliary clearance and nasalabsorption enhancers are the main factors that affect drug absorption through thenasal mucosa. One of the greatest limitations of nasal drug delivery is inadequatenasal absorption. Several promising drug candidates cannot be exploited via thenasal route because they are not absorbed well enough to produce therapeutic effects. This has led scientists to search for ways to improve drug absorption through thenasal route [3, 14]. The following parameters need to be considered in order tooptimize nasal drug delivery. a) Physicochemical Properties of the Drug: The rate and extent of drug absorption
may depend upon many physicochemical factors including the aqueaus-to-lipidpartititon coefficient of the drug, the pKa, the molecular weight of the drug,perfusion rate and perfusate volume, solution pH and drug concentration . It has been concluded that in vivo nasal absorption of compounds of molecularweight of less than 300, is not significantly influenced by the physicochemicalproperties of the drug . There is a direct correlation between the proportionof the nasally absorbed dose and the molecular weight .
b) Mucociliary Clearance: Particles entapped in the mucus layer are transported
with it and, thereby, effectively cleared from the nasal cavity. The combinedaction of mucus layer and cilia is called “mucociliary clearance”. This isan important, non-specific, physiological defence mechanism of the respiratorytract to protect the body against noxious inhaled materials [3, 12]. The normalmucociliary transit time in humans has been reported to be 12 to 15 min. The factors that affect mucociliary clearance include physiological factorssuch as age, sex, posture, sleep, exercise [19, 20]; common environmentalpollutants such as sulphur dioxide, sulphuric acid, nitrogen dioxide, ozone,hair spray and tobacco smoke ; diseases including asthma, bronchiectasis,chronic bronchitis, cystic fibrosis, acute respiratory tract infection, immotile ciliasyndrome, primary ciliary dyskinesia ; drugs ; and additives .
ALTERNATIVE APPLICATIONS FOR DRUG DELIVERY
c) Nasal Absorption Enhancers: In order to solve the insufficient absorption of
drugs, absorption enhancers are employed. The absorption enhancement mecha-nisms can be grouped into two classes :
i. Physicochemical Effects: Some enhancers can alter the physicochemical
properties of a drug in the formulation. This can happen by alterning thedrug solubility, drug partition coefficient or by weak ionic interactions withthe drug; and
ii. Membrane Effects: Many enhancers show their effects by affecting the nasal
Surfactants, bioadhesive polymer materials, drug delivery systems, cyclodextrins,
bile salts, phosphatidylcholines and fusidic acid derivatives are known as absorptionenhancers [2, 3].
Nasal absorption of peptides and proteins through nasal mucosa is limited by their
high molecular weight. Nasal bioavailability of peptides and proteins is affectedby mucociliar clearance and enzyme activity in the nasal cavity. Therefore, nasalbioavailability enhancement can be achieved by different approaches such as modifi-cation of chemical structure, prodrug use, addition of absorption enhancers/enzymesand use of mucoadhesive dosage form .
DRUG DELIVERY SYSTEMS ADMINISTEREDINTRANASALLY
For the enhancement of nasal bioavailability, a drug delivery system should havethe following properties :• It should adhere to the nasal mucosa;
• It should cause the formation of viscous layer;
• It should keep the stability of the drug; and
• It should release the drug slowly. Some of the commonly used drug delivery systems for nasal administration areexplained in the following sections.
Liposomes have been used extensively for bioactive delivery by several routes. Alpar et al [25, 26] studied the potential adjuvant effect of liposomes on tetanustoxoid, when delivered via the nasal, oral and I.M. routes compared to delivery insimple solution in relation to the development of a non-parenteral immunizationprocedure, which stimulates a strong systemic immunity. They found that tetanustoxoid entrapped in DSPC liposomes is stable and is taken up intact in the gut[25, 26].
Intranasal administration of calcitonin-containing charged liposomes in rabbits
was investigated to evaluate the in vivo calcitonin absorption performance. Signif-icant level of accumulation of positively charged liposomes on the negativelycharged nasal mucosa surface was reported . Plasma calcitonin concentrationand pharmacokinetic parameters were calculated. Intranasal bioavailability demon-strated an order of calcitonin containing positively charged liposomes > calci-tonin containing negatively charged liposomes > calcitonin solution. The signif-icant enhancement of intranasal bioavailability of calcitonin for positively chargedliposomes may be due to charge interaction of positively charged liposomes with thenegatively charged mucosa. Marked accumulation of positively charged liposomeson the negatively charged nasal mucosa surface caused high retention of positivelycharged liposomes on the nasal mucosa which resulted in an increase in residencetime with high local concentration of calcitonin .
The major cause of mortality in patients with cystic fibrosis (CF) is a lung
malfunction. A DNA–liposome formulation was delivered to the nasal mucosa of CFpatients in repeated doses. It was reported that the DNA containing liposomes canbe succesfully re-administered without apparent loss of efficacy for CF treatment.
In a comparative permeability study, insulin liposomes have permeated more
effectively after pre-treatment by sodium glycocholate when compared to non-encapsulated insulin solution .
Goncharova et al  have mentioned the importance of nasal mucosa for the
immunisation against Tick-Borne encephalitis. To study intranasal immunizationagainst TBE virus, biodegredable micelles, cationic liposomes and live attenuatedbacterial/viral vectors were chosen. The results showed the expression of the gene intransfected cells, thereby demonstrating that the liposomal formulations are suitablefor mucosal immunization .
In another study using nicotine proliposomes, it has been reported that nicotine
delivery was prolonged in rats when administered intranasally .
Microspheres of different ingredients have been evaluated as nasal drug deliverysystems. Microspheres of starch, albumin, chitosan, and DEAE-dextran have beeninvestigated. Chemical class of the polymer, binding ability, penetration, polymerconcentration, pH, and hydration level are among the factors affecting intranasaldelivery .
Degredable Starch Microspheres (DSM) is the most frequently used microsphere
system for nasal drug delivery and has been shown to improve the absorption ofinsulin in particular and other bioactive compounds in general. Insulin administeredin DSM to rats resulted in a rapid dose-dependent decrease in blood glucose [32,33]. In another study in rabbits, apomorphine release from DSM microspheres wascompared with CMC and lactose applied intranasally and the fastest absorption wasobtained with lactose .
ALTERNATIVE APPLICATIONS FOR DRUG DELIVERY
Illum et al  introduced well-characterized bioadhesive microspheres for
prolonging the residence time in the nasal cavity of human volunteers. The slowestclearance was detected for DEAE-dextran, where 60% of the delivered dose wasstill present at the deposition site after 3h. On the contrary, these microspheres werenot successful in promoting insulin absorption in rats .
Human growth hormone (hGH)-loaded microparticles prepared by polycarbophil-
cysteine (PCP-Cys) in combination with glutathione (GSH) represented a promisingtool for the delivery of hGH for nasal bioavalability .
In another study, microspheres intended as a sustained release carrier for oral or
nasal administration were prepared by polyacrylic acid molecules . A modeldrug oxyprenolol HCl was chosen and it was found that some of the formulationvariables can influence the release characteristics. The internal structure (by X-raydiffraction, thermal analysis and optical microscopy) and release mechanism wereinvestigated. The work revealed the potential of this pharmaceutical system as analternative controlled-release dosage form for the intranasal administration .
Chitosan and chitin have been suggested for use as vehicles for the sustainedrelease of drugs. A sustained drug release based on chitosan salts for vancomycinhydrochloride delivery has been investigated by using different chitosan saltslike aspartate, chitosan glutamate and chitosan hydrochloride. Vancomycinhydrochloride was used as the peptidic drug, the nasal sustained release of whichshould avoid first-pass metabolism in the liver. This in vitro study evaluated theinfluence of chitosan salts on the release behaviour of vancomycin hydrochlorideand it has been reported that in vitro release of vancomycin was retarded mostlyby chitosan hydrochloride . Similar results were obtained by Tengamuayet al .
Vila et al  have prepared chitosan nanoparticles by an ionics cross-linking
technique and used tetanus oxoid as model antigen. These nanoparticles wereadministered intranasally to mice in order to study their feasibility as vaccinecarriers. In vitro release studies showed an initial burst followed by an extendedrelease of active toxoid. Following intranasal administration, tetatanus toxoid-loaded chitosan nanoparticles elicited an increasing and long-lasting immunogenityas compared to the fluid vaccine. Interestingly, the ability of these nanopar-ticles to provide improved access to the associated antigen to the immunesystem was not significantly affected by the chitosan molecular weight. Highand long lasting responses could be obtained with low molecular weight chitosanmolecules.
Additionally, the response has not been influenced by the chitosan dose. This
group concluded that nanoparticles made of low molecular weight chitosan arepromising carriers for nasal vaccine delivery .
It was observed that the chitosan delivery (microspheres) of a drug had signifi-
cantly reduced rates of clearance from the nasal cavity as compared to the control
(solution). Chitosan delivery systems have the ability to increase the residance timeof drug in the nasal cavity thereby providing the potential for improved systemicmedication .
Insulin loaded chitosan nanoparticles have been prepared with trehalose as
cryoprotectant by freeze-drying method. The in vivo evaluation of chitosan nanopar-ticles in rabbits revealed that these nanoparticles are able to reduce glucose levelsto a greater extent than insulin-chitosan solution when applied intranasally [43, 44].
Nasal absorption of nifedipine from gel preparations, PEG 400, aqueous carbopol
gel and carbopol-PEG has been studied in rats. Nasal administration of nifedipinein PEG resulted in rapid absorption and high c
nifedipine from plasma was very rapid. The plasma concentration of nifedipine inaqueous carbopol gel formulation was very low when administered intranasally. Theuse of PEG 400 in high concentrations in humans should be considered carefully. This is because PEG 400 is known to cause nasal irritation in concentrations higerthan 10% .
Nasal absorption of Calcitonin and Insulin from polyacrilic acid gel has been
investigated in rats. It has been reported that nasal absorption of insulin is greaterfrom 0.15% (w/v) polyacrylic acid gel than from 1% (w/v) gel. There seem to bean optimum concentratiton and possibly an optimum viscosity for the polyacrilicacid gel base .
Ugwoke et al  have prepared apomorphine mucoadhesive preparations incor-
porating Tc-99m labelled colloidal albumin. Drug residence time in rabbit nasalcavity was evaluated by gamma scintigraphy using different agents like Carbopol971P, CMC and lactose (control), each with or without apomorphine. The useof mucoadhesives such as Carbopol 971P or CMC in nasal gels increases theirresidence time within the nasal cavity and provides opportunity for sustained nasaldrug delivery .
Phosphatidylcholines are surface-active amphiphilic compounds present inbiological membranes and liposomes. Several reports have appeared in the literatureshowing that these phospholipids can be used for enhancing the systemic nasal drugdelivery .
Another intensive study has been put on fusidic acid derivatives and among
these Sodium Tauro-24, 25-dihydrofusidic acid (STDHF) is the most extensivelystudied derivative of fusidic acid. STDHF was reported as a good candidate for thetransnasal delivery of drugs like insulin, octreotide, and human growth hormone[49–52].
Radioimmunoactive bioavailability of intranasal salmon calcitonin was deter-
mined in healthy human volunteers. The nasal absorption of calcitonin was improvedby STDHF and it caused a limited transient irritation of the nasal mucosa in somesubjects .
ALTERNATIVE APPLICATIONS FOR DRUG DELIVERY
Didecanoyl-L-phosphatidylcholine (DDPC) has been used as enhancer for
intranasal insulin administration in human volunteers. It was observed that intranasalinsulin administration was absorbed in a dose dependent manner with slight or nonasal irritation . Another study revealed that Glycyrrhetinic acid derivativesenhance insulin uptake without nasal irritaition or insulin degredation .
Several compounds have been investigated for their nasal absorption enhancement. Cyclodextrins are observed as the best-studied group of enhancers. The most-studiedof them are: -cyclodextrin, -cyclodextrin, -cyclodextrin, methylcyclodextrin andhydroxypropyl -cyclodextrin. Among these, -cyclodextrin is being considered forpossessing a GRAS (Generally Recognised As Safe) status [56, 57].
Cyclodextrins have been used successfully to increase the absorption of many
substances including salmon calcitonin [58, 59], insulin  and human growthhormone .
The utility of nasal route for the systemic delivery of 17-beta-estradiol was studiedusing water-soluble prodrugs of 17-beta-estradiol. This method was examined todetermine if it would result in preferential way to the brain. In vivo nasal exper-iments were carried out on rats. Absorption was fast following nasal delivery ofprodrugs with high bioavailability. These products were found to be capable ofproducing high levels of estradiol in the cerebral spinal fluid and as a result mayhave a significant value in the treatment of Alzheimer’s disease .
Studies on the delivery of drugs to or via the respiratory tract have been carriedout in the recent 25 years. This route can offer considerable advantages over otherdrug dministration ways as listed below [63, 64]:• Provides local action within the respiratory tract;
• Allows for a reduction in systemic side-effects;
• Reduces extracellular enzyme levels compared to GI tract due to the large alveolar
• Reduces evasion of first pass hepatic metabolism by absorbed drug; and
• Offers the potential for pulmonary administration of systemically active materials.
On the other hand, it has some disadvantages as well [63, 64], which include:• The duration of activity is often short-lived due to the rapid removal of drug
from the lungs or due to drug metabolism; and
Which Types of Drugs are Administered via Pulmonary Route?
Drugs are absorbed from the lungs mainly by the following two mechanims:i) Passive diffusion; andii) Active endocytosis . Drugs for asthma, allergy and chronic obstructive pulmonary diseases are usedvia pulmonary route. Beta agonists, anticholinergic drugs, mucolytics and corticos-teroids are some examples for these drugs .
From the trachea, the airways divide dichotomously to form bronchi, respiratoryand terminal bronchioles and ultimately alveoli. The role of the airways graduallychanges from one of conduction by the large airways to one of gaseous exchangefor the peripheral lung (respiratory bronchioles and alveoli) .
Nearly 95% of the alveolar cells are Type I cells which are 5 µm in size. Type II
cells are 10–15 µm in size and secrete surfactants which are important for the functionof the lungs. Phosphatidylcholine and phosphatidylglycerol are the main phospho-lipids of lung surfactants . Lung surfactants deposit a monomolecular film on thealveoli and prevent pulmonary oedema and provide protection against infections .
The size of inhaled particles is the main factor affecting pulmonary delivery. Theimportant size property for deposition in the lungs is called aerodynamic diameter. It is determined by the actual size of the particle, its shape and its density. Theparticles in the aerodynamic size range of about 3.5–6.0µm can penetrate, to someextent, at slow inspiratory flow rates beyond the central airways into the peripheralregion of the lungs. On the other hand, particles less than 3.5µm and greater thanabout 0.5µm will mostly bypass the bronchial airways during inhalation and penetratealmost entirely to the deep lung. Larger particles are dominated by their inertialmass and will impact in upper airways due to their inertia. Smaller particles (withaerodynamic diameters less than 0.5µm) are dominated by thermal interactions withthe air molecules and will diffuse to the respiratory tract surfaces during inhalation .
Diseases of the respiratory tract and hygroscopicity of the powders are the other
factors affecting pulmonary delivery .
There are three types of conventional methods of inhalation delivery for thetreatment of respiratory diseases :
i. Pressurized Metered-Dose Inhalers (MDIs or pMDIs);
ALTERNATIVE APPLICATIONS FOR DRUG DELIVERY
The conventional inhalation systems are designed primarily to generate particles ofsuitable size for topical delivery to the airways.
The lung presents a very attractive route for the invasive delivery of systemically
Among the modified-release carrier systems, liposomes are the most frequently
used ones. The main advantage of the use of liposomes as drug carriers in the lungis that they can be prepared from phospholipid molecules endogenous to the lung ascomponents of lung surfactant . Secondly, liposomes help to develop controlledrelease systems for local and systemic delivery. Thirdly, improved pulmonarytherapy and lower side-effects can be obtained by liposomal drugs.
Anticancer drugs (ARA-C, 5-fluorouracil), antimicrobials (pentamidin, amikasin,
enviroksim), peptides (insulin, calcitonin), enzymes (superoxide dismutase), antial-lergic and antihistaminic compounds (salbutamol, metaproterenol), immunosu-pressive (siklosporin) and antiviral (ribavirin) drugs are some examples of the activecompounds used in the pulmonary delivery research (e.g. see Ref. 5). Atropine,benzylpenicillin, carboxyfluorescein, cytarabine, enviroxime, glutathione, glyceryl-trinitrite, orciprenaline, oxytocine and pentamidine are other examples of severaldrugs delivered to the lungs of the animals .
Another group of researchers have been studying the delivery of the genetic drugs
via the lungs [69, 70] while progress and improvements in the field are ongoing.
Nasal and pulmonary routes of drug delivery are increasingly gaining impor-tance in drug therapy. Particularly, these routes are considered as alternative waysto parenteral route for peptide and protein therapeutics. It has been shown thatintranasal and intratracheal administration to the mucosae are important routesand were found effective for the immunospecific reaction response. It has beenreported that various therapeutic and vaccine formulations can be administeredsuccessfully by thes nasal and pulmonary routes. However, because of the manyhurdles in administration, pulmonary delivery is not usually preferred as yet. Inconclusion, nasal and pulmonary drug delivery systems, described in this chapter,seem particularly appropriate techniques for drug delivery with great futuristicpotential applications.
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Spett. Associazione Agenti Marittimi La Spezia c/o Assindustria Via Don Minzoni, 2 La Spett. Associazione Spedizionieri La Spezia Spett. Associazione Doganalisti La Spezia c/o Assindustria Via Don Minzoni , 2 La Spezia 19100 Spett. Associazione Terminalisti La Spezia c/o Assindustria Via Don Minzoni, 2 La Spezia 19100 e, p.c. All’Ufficio Acquisizione Area G.T. All’Ufficio Procedure Dom
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