Section II: Topical Treatment of Impaired Mucosal Membranes
`
`Surber C, Elsner P, Farage MA (eds): Topical Applications and the Mucosa.
`Curr Probl Dermatol. Basel, Karger, 2011, vol 40, pp 20–35
`
`Nasal Drug Delivery in Humans
`Christoph Bittera ⭈ Katja Suter- Zimmermanna ⭈ Christian Surbera,b
`
`aHospital Pharmacy and bDepartment of Dermatology, University of Basel Hospital, Basel, Switzerland
`
`Abstract
`Intranasal administration is an attractive option for local
`and systemic delivery of many therapeutic agents. The
`nasal mucosa is – compared to other mucosae – easily
`accessible. Intranasal drug administration is noninvasive,
`essentially painless and particularly suited for children.
`Application can be performed easily by patients or by
`physicians in emergency settings. Intranasal drug deliv-
`ery offers a rapid onset of therapeutic effects (local or
`systemic). Nasal application circumvents gastrointes-
`tinal degradation and hepatic first- pass metabolism
`of the drug. The drug, the vehicle and the application
`device form an undividable triad. Its selection is there-
`fore essential for the successful development of effec-
`tive nasal products. This paper discusses the feasibility
`and potential of intranasal administration. A series of
`questions regarding (a) the intended use (therapeu-
`tic considerations), (b) the drug, (c) the vehicle and (d)
`the application device (pharmaceutical considerations)
`are addressed with a view to their impact on the devel-
`opment of products for nasal application. Current and
`future trends and perspectives are discussed.
`Copyright © 2011 S. Karger AG, Basel
`
`Intranasal administration offers a variety of at-
`tractive options for local and systemic delivery of
`diverse therapeutic agents. The nature of the na-
`sal mucosa provides a series of unique attributes,
`all of which may help to maximize the patient’s
`safety, convenience and compliance.
`
`The nasal mucosa is – compared to other mu-
`cous membranes – easily accessible and provides a
`practical entrance portal for small and large mol-
`ecules. Intranasal administration offers a rapid
`onset of therapeutic effects, no first- pass effect,
`no gastrointestinal degradation or lung toxicity,
`noninvasiveness, essentially painless application,
`and easy and ready use by patients – particularly
`suited for children – or by physicians in emergen-
`cy settings. More recently a nasal influenza vac-
`cine spray (Flu Mist®) has been successfully intro-
`duced. The chances for direct nose- to- brain drug
`delivery are currently the subject of controversial
`debates [1, 2].
`Given these positive attributes, it is obvious
`to consider intranasal administration when im-
`proving the profile of existing drugs including life
`cycle management or when developing new ther-
`apeutics. A quick glance at the market and at cur-
`rent research activities confirms the attractiveness
`of intranasal drug administration. Table 1 shows
`selected drugs for intranasal administration with
`systemic effects.
`In order to estimate the feasibility and poten-
`tial of intranasal administration, a series of ques-
`tions regarding (a) the intended use (therapeutic
`considerations), (b) the drug, (c) the vehicle and
`
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`Table 1. Selection of compounds for transmucosal nasal drug delivery
`
`Compound
`
`Class
`
`Indication
`
`Investigation/product
`development/product and
`country (example)
`
`Reference
`
`Apomorphine
`
`dopamine agonist
`
`Parkinson’s disease
`(on- off symptoms)
`
`product development
`
`3, 4
`
`prostate cancer
`
`Profact, Germany
`
`migraine
`
`Stadol, USA
`
`osteoporosis
`
`Karil, Germany
`
`Nascobal, USA
`
`Minirin, Germany
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Buserelin
`
`Butorphanol
`
`Calcitonin
`
`Cobalamin
`(vitamin B12)
`
`peptide
`
`opioid
`
`protein
`
`vitamin
`
`Desmopressin
`
`protein
`
`Diazepam
`
`benzodiazepine
`
`Estradiol
`
`Fentanyl
`
`steroid
`
`opiate
`
`substitution of
`vitamin B12
`
`diabetes insipidus
`centralis, enuresis
`nocturna
`
`sedation, anxiolysis,
`status epilepticus
`
`substitution of
`estradiol
`
`analgesia,
`postoperative pain
`and agitation in
`children
`
`product development
`
`10
`
`Aerodiol, UK
`
`11, 12
`
`Instanyl, Germany
`
`13
`
`14
`
`Gonadorelin
`
`hormone
`
`peptide
`
`vaccine
`
`peptide
`
`Human growth
`hormone
`
`Influenza vaccine, live
`attentuated
`
`Insulin
`
`Ketamine
`
`L- Dopa
`
`undescended
`testicle
`
`growth hormone
`deficiency
`
`Kryptocur, Germany
`
`investigation
`
`flu prevention
`
`Flu Mist, USA
`
`diabetes mellitus
`
`investigation
`
`NMDA antagonist
`
`analgesia
`
`product development:
`Ereska
`
`nonproteinogenic
`amino acid
`
`Parkinson’s disease
`
`investigation
`
`Melatonin
`
`hormone
`
`jet lag
`
`Metoclopramide
`
`D2 receptor antagonist
`
`antiemesis
`
`Midazolam
`
`benzodiazepine
`
`sedation, anxiolysis,
`status epilepticus
`
`Morphine
`
`opiate
`
`analgesia
`
`investigation
`
`Pramidin, Italy
`
`investigation
`
`product development:
`Rylomine
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21, 22
`
`23, 24
`
`25
`
`Nasal Drug Delivery in Humans
`
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`Table 1. Continued
`
`Compound
`
`Class
`
`Indication
`
`Investigation/product
`development/product and
`country (example)
`
`Reference
`
`Nafarelin
`
`hormone
`
`central precocious
`puberty,
`endometriosis
`
`Synarel, USA
`
`Nicotine
`
`Oxytocin
`
`hormone
`
`addictive substance
`
`smoking cessation
`
`Nicotrol NS, USA
`
`lactation; treatment
`of social, cognitive
`and mood disorders
`
`Syntocinon spray,
`Switzerland
`
`infertility,
`amenorrhea
`
`investigation
`
`Progesterone
`
`hormone
`
`Sildenafil
`
`Sumatriptan
`
`PDE inhibitor
`
`erectile dysfunction
`
`investigation
`
`triptan
`
`migraines
`
`Testosterone
`
`hormone
`
`substitution of
`testosterone
`
`Imigran nasal spray,
`Switzerland
`
`investigation
`
`26
`
`27
`
`28
`
`12
`
`29
`
`30
`
`31
`
`Zolmitriptan
`
`triptan
`
`migraines
`
`Zomig, Switzerland
`
`32, 33
`
`NMDA = N- methyl- D- aspartate; PDE = phosphodiesterase.
`
`(d) the application device (pharmaceutical con-
`siderations) have to be addressed, e.g.:
`(a) Is the drug designated for local or systemic
`delivery, for single or repetitive administration, is
`the therapeutic target concentration known?
`(b) Are the physicochemical properties of the
`drug suitable for intranasal administration, can
`clinically relevant bioavailability be achieved?
`(c) Can the vehicle provide prolonged drug
`stability, ideal characteristics during (ejection)
`and after application (prolonged residence time
`on the mucosa) and support drug delivery to local
`target tissues or to the blood vessels for systemic
`delivery?
`(d) And finally, is the application device easily
`deployable and does it allow adequate drug/for-
`mulation deposition within the nose?
`
`These issues are addressed below with a view
`to their impact on the development of products
`for nasal application.
`
`The Nose – Anatomy and Function
`
`The nose is a complex multifunctional organ.
`The major functions of the nasal cavity comprise
`cleansing the inhaled air and olfaction. Moreover,
`it exerts important protective and supportive ac-
`tivities; it filters, heats and humidifies the inhaled
`air before it reaches the lower parts of the airways.
`Nasal hairs and mainly the nasal mucosa with its
`sticky mucus blanket help to prevent xenobiotics
`like allergens, pathogens or foreign particles from
`reaching the lungs. It represents a most efficient
`
`22
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`Olfactory area
`
`Vestibular area
`
`Superior turbinate
`Middle turbinate
`Inferior turbinate
`
`Respiratory area
`
`Nasopharynx
`
`Fig. 1. Sagittal section of the nasal cavity.
`
`first line of defense for the body’s airway as it
`copes with more than 500 liters of air that are fil-
`tered hourly into the lung. During this time it is
`thought that more than 25 million particles are
`processed by this epithelium [34, 35]. Mucociliary
`activity removing mucus towards the nasophar-
`ynx, immunological activities involving a vari-
`ety of immunocompetent cells and metabolism
`of endogenous substances are further essential
`functions of the nasal structures. The nasal cav-
`ity connected to other cavities such as the frontal
`and maxillary sinus and the ear also serves as a
`resonant body.
`There are 3 distinct functional areas (fig. 1)
`in the nasal cavity, the vestibular, olfactory and
`respiratory zones. The vestibular area (approx.
`0.6 cm2) serves as a first barrier against airborne
`particles with low vascularization comprised of
`stratified squamous and keratinized epithelial
`
`cells with nasal hairs. The olfactory area (ap-
`prox. 15 cm2) enables olfactory perception and
`is highly vascularized. The respiratory area (ap-
`prox. 130 cm2) serves with its mucus layer pro-
`duced by highly specialized cells as an efficient
`air- cleansing system [36]. The surface of this zone
`is enlarged by the division of the cavity by lateral
`walls into 3 nasal conchae or turbinates and by
`the magnification of the mucosa by microvilli and
`cilia. The magnification in terms of square centi-
`meters is unknown. The zone is highly vascular-
`ized. The posterior region of the nasal cavity is
`the nasopharynx. Its upper part consists of cili-
`ated cells, the lower part contains squamous epi-
`thelium. The area is also part of the mucosal im-
`mune system.
`Due to the rich vascularization, the olfactory
`and in particular the respiratory zone may serve
`as an efficient absorption surface for topically
`
`Nasal Drug Delivery in Humans
`
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`Gel layer
`
`Sol layer
`
`Mucous layer
`
`Nonciliated cell with microvilli
`
`Ciliated cell
`
`Goblet cell
`
`Basal cell
`
`Basement membrane
`
`Fig. 2. Cell types of the nasal epithelium with covering mucous layer.
`
`applied drugs. The olfactory region with its vicin-
`ity to the cerebrospinal fluid and direct nervous
`interface to the brain has attracted research inter-
`est for possible nose- to- brain delivery.
`The respiratory epithelium as well as other
`parts of the nasal cavity and airways are lined by
`superficial epithelium (fig. 2) consisting primar-
`ily of 2 types of cells: mucus- producing goblet
`cells (20%) and ciliated cells (80%). The various
`cell types of the epithelium are joined together
`by tight junctions. Mucus continuously produced
`by goblet cells traps inhaled particulate and in-
`fectious debris while the propulsive force (about
`1,000 strokes/min) generated by ciliated cells
`transports the mucus towards the nasopharynx
`and the gastrointestinal tract for elimination. This
`effective cleansing mechanism is called mucocili-
`ary clearance (MCC) [37]. The MCC time is ap-
`proximately 20 min but is subject to great inter-
`subject variability. The MCC is dependent on the
`function of the cilia and the characteristics of the
`covering mucus, which can be influenced by acute
`or chronic illnesses like common cold or allergic
`rhinitis. Many substances can influence the MCC
`of the airways, either by stimulation or inhibition.
`A stimulatory effect of drugs on the MCC is of
`
`clinical importance, because these substances can
`possibly be used to improve pathological condi-
`tions of the MCC. Components (drug, ingredient)
`of nasally administered formulations with a too
`pronounced MCC- impairing activity may limit
`their use.
`
`Nasal Delivery
`
`The intranasal administration represents a viable
`option for local and systemic delivery of many
`therapeutic agents. Therapeutic and pharmaceu-
`tical considerations direct the development of na-
`sal products [38].
`
`Therapeutic Considerations
`Answers to key questions whether the drug is
`intended for (a) local or systemic delivery or for
`(b) single or repetitive administration and (c)
`patient- related issues (e.g. adults, children) de-
`fine the development strategy for the nasal prod-
`uct. An idea of the clinically effective drug con-
`centration in the target site should exist in order
`to estimate the feasibility of the nasal application
`route.
`
`24
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`Local Delivery
`Prominent examples for locally acting intranasal-
`ly administered drugs are decongestants for nasal
`cold symptom relief, antihistamines and corticos-
`teroids for allergic rhinitis. Due to the fact that rel-
`atively low doses are effective when administered
`topically, the intranasal administration of antihis-
`tamines and corticosteroids has a weak potential
`for systemic adverse effects as opposed to system-
`ic therapy. Intranasal administration is therefore a
`logical delivery choice for the topical (local) treat-
`ment of nasal symptoms.
`
`Systemic Delivery
`The nasal mucosa provides a practical en-
`trance portal for systemically acting molecules.
`Intranasal administration offers a rapid onset of
`therapeutic effects, avoids the first- pass effect or
`gastrointestinal degradation of drugs, is noninva-
`sive, essentially painless and finally easily admin-
`istered by patients or by physicians in emergency
`settings. The intranasal administration provides a
`true alternative route for systemic drugs presently
`delivered more conventionally by oral or paren-
`teral routes.
`
`Single versus Repetitive Administration
`The disease, the therapeutic goal and the thera-
`peutic agent predefine the dosing regimen. Dosing
`frequencies of currently marketed intranasally ad-
`ministered products range from weekly dosing to
`multiple times daily. To avoid multiple parenteral
`applications, repetitive intranasal administration
`may be practical for the situation of chronic appli-
`cation with orally insufficient drug bioavailability.
`The delivery target (local, systemic) as well as
`the intended dosing schedule govern the devel-
`opment strategy and therefore predefine the drug
`form (dissolved, ionized etc.), the vehicle form
`(solid, semisolid, liquid) including the specific
`ingredients to form the vehicle system (powder,
`gels, microspheres, solution etc.) and the applica-
`tion device, which determines the drug deposition
`within the nose.
`
`Patient- Related Issues
`The nasal physiology and anatomy have a po-
`tential
`impact on
`intranasal administration.
`Temperature, humidity, airflow and the nasal cy-
`cle – an alternating congestion and decongestion
`of the nasal mucosa – may change the absorption
`area. Any impairment of the physiological and an-
`atomical situation – whether natural (nasal cycle)
`or pathological (inflammation, nosebleed, altera-
`tions as a result from smoking, snuffing, decon-
`gestant addiction or nasal drug abuse) – may have
`a potential impact on intranasal absorption. The
`extent of this impact is unknown.
`Even though the epithelial tissue within the na-
`sal cavity provides an ideal absorption area, the nat-
`ural permeation barrier and the efficient cleansing
`mechanism confine the total amount of drug that
`can be absorbed. Therefore the clinically effective
`drug concentration at the target site requires a
`therapeutic agent with sufficient potency.
`
`Pharmaceutical Considerations
`Once the therapeutic goal and the therapeutic
`agent have been defined, the formulation scien-
`tist is challenged to incorporate the drug into a
`vehicle system that provides prolonged drug sta-
`bility, ideal dispensing characteristics from a
`tailor- made delivery device during (ejection) and
`after application (prolonged residence time on the
`mucosa) which supports drug delivery to a local
`target site (penetration; e.g. antihistamines such
`as levocabastine) or to the blood vessels for sys-
`temic delivery (permeation; e.g. benzodiazepines
`such as midazolam).
`Thoughtful consideration of all elements in
`a formulation triad – comprising drug, vehicle
`form/system and delivery device – is the basis
`of a successful formulation development (fig. 3).
`Based on the properties of the drug molecule, the
`vehicle form/system (solid; powder, semisolid;
`gel, emulsion or liquid; solution) is determined
`first; second, the device is chosen, and third the
`ingredients are chosen to create an optimal ve-
`hicle. Skillful selection of vehicle form/system
`
`Nasal Drug Delivery in Humans
`
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`Predetermined
`
`Anatomy
`Physiology
`Pathophysiology
`
`Nasal mucosa as
`absorption barrier
`
`Triad of
`nasal drug
`delivery
`
`Drug
`
`Vehicle
`
`Device
`
`Influenceable parameters
`to be determined
`
`Nasal
`application
`
`Systemic
`bioavailability
`
`Fig. 3. Consideration of all elements in a formulation triad – comprising drug, vehicle form/sys-
`tem and delivery device – is the basis of a successful formulation development. Skillful selection
`of vehicle form/system and ingredients bypasses natural attributes of the mucus blanket and the
`MCC.
`
`and ingredients bypasses natural attributes of the
`mucus blanket as a protective layer (i.e. increase
`drug absorption) and of the MCC as an effective
`cleansing mechanism (i.e. increase resident time
`of formulation on the mucous layer).
`
`Drug Characteristics
`The influence of physicochemical characteristics
`[38– 40] of drug molecules on the rate and extent
`
`of absorption through biological membranes is
`generally well explored. In numerous predomi-
`nately animal studies, the influence of the drug
`characteristics in nasal absorption was studied.
`Lipophilic drugs are in general well absorbed
`from the nasal cavity, presenting pharmacoki-
`netic profiles often similar to those obtained af-
`ter intravenous administration. Lipophilic mol-
`ecules with molecular weights less than 1 kDa
`
`26
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`

`are rapidly and efficiently transcellularly ab-
`sorbed across the nasal membrane. The extent of
`absorption for lipophilic molecules larger than
`1 kDa is significantly lower. Absorption of hy-
`drophilic drugs is generally low and highly de-
`pendent on the molecular weight. Absorption
`through membranes is not only affected by lipo-
`philicity/hydrophilicity or molecular weight, but
`also by the amount of drug existing as uncharged
`species. This depends on the drug pKa and the
`pH at and in the absorption site – the nonion-
`ized fraction of the drug is more permeable than
`the ionized one. The pH of the nasal epithelium
`is 5.5– 6.5. A pH lower than 5.5 or higher than
`6.5 combined with a buffer capacity higher than
`that of the nasal epithelium may cause local ad-
`verse effects and may therefore affect drug per-
`meation. Only the molecularly disperse form of
`a drug at the absorption site may cross the nasal
`epithelium. Therefore sufficient drug solubility
`is a prerequisite for any drug absorption. Due to
`the limited amount of vehicle that can be lasting-
`ly applied to the nasal cavity without losing drug
`through vehicle runoffs via the nasopharynx in-
`cluding subsequent ingestion or via the vestib-
`ular area of the nose, the solubility of the drug
`must guarantee sufficient bioavailable molecules
`to achieve a clinical effect. Some characteristics
`are important when choosing a drug candidate
`for transmucosal nasal drug delivery in an aque-
`ous formulation (table 2).
`Against this background it becomes obvious
`that selecting drug candidates for transmucosal
`nasal application may become challenging. The
`biopharmaceutical drug classification system [41]
`reveals that drug candidates that fit into class I
`(high permeability, high solubility) have the high-
`est potential for nasal delivery. To further refine
`the selection criteria for small molecules in aque-
`ous solution, one may – in the style of the Rule of
`Five defined by Lipinski et al. [42] – establish the
`following rule of thumb:
`• drug characteristics: molecular weight <500
`Da, logP <5;
`
`• dose per spray puff (left and right nostril):
`potency <5 mg/dose;
`• volume maximally 100 μl/spray puff: solubility
`>50 mg/ml;
`• drug in solution: pH approximately 5.5,
`osmolality <500 mosm/kg.
`
`Vehicle System
`The assignment of a pharmaceutical vehicle is
`to provide prolonged drug stability, ideal char-
`acteristics during (e.g. ejection) and after ap-
`plication (e.g. prolonged residence time on the
`mucosa) and to support drug delivery to local
`target tissues or to the blood vessels for systemic
`delivery.
`It is obvious that drug stability is a basic prereq-
`uisite for a marketable product. Referring strate-
`gies and modalities are discussed elsewhere.
`To support drug absorption through the nasal
`mucosa, 2 natural protective functions have to be
`bypassed – the MCC and the barrier properties
`of the tissue.
`The MCC mechanism efficiently removes
`product from the application site, by reducing
`product contact (time and adhesion) in the po-
`tential absorption area. Skillfully chosen ingredi-
`ents that form the vehicle are able to temporarily
`modulate the MCC and may therefore eventually
`increase drug absorption. Mucoadhesive ingredi-
`ents enable the vehicle encasing the drug an inti-
`mate and prolonged contact with the mucosa [43].
`Adhesion provided by polymers such as carbom-
`ers, chitosans, cellulose or starch derivates results
`from van der Waals, hydrogen, hydrophobic and
`electrostatic forces (wanted) and chemical bonds
`(unwanted). Concurrently they increase viscos-
`ity of the formulation and prevent loss of product
`towards the nasal vestibule or the nasopharynx.
`However, very high product viscosities will stim-
`ulate the cleansing mechanism. The relevance of
`viscosity for bioavailability of nasal drug products
`is still unknown.
`It is possible to significantly improve the
`absorption of molecules if they are applied in
`
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`Table 2. Characteristics to consider when choosing a small- molecular- weight drug candidate for transmucosal nasal
`drug delivery in an aqueous formulation
`
`Sequence of
`importance
`
`Character of drug
`candidate
`
`Envisaged target range
`
`Comments/suggestions for improvement
`
`+++
`
`+++
`
`+++
`
`+++
`
`potency
`
`max. 20 mg/dose
`
`local mucosal toxicity
`
`no toxicity and tissue
`damage
`
`solubility
`
`>100 mg/ml (for a
`potency of 20 mg/dose)
`
`solubility and spray
`volume
`
`maximal 100- 200 μl
`(1 or 2 puffs with 100 μl)
`
`+++
`
`stability in solution
`
`≥2 years
`
`+++
`
`molecular weight
`
`<1,000 Da
`
`++
`
`++
`
`++
`
`+
`
`compatibility with
`adjuvants
`
`prerequisite
`
`logP
`
`1–5
`
`pH of solution
`
`(3.5) 4–7.5
`
`osmolality of solution
`
`290–500 mosm/kg
`
`nasal bioavailability of drug has to be
`considered to reach the therapeutic
`target dose/none
`
`minor damage tolerable for emergency
`or single- application use, no toxicity or
`damage for chronic use/none
`
`none/solubility can be improved by
`means of prodrugs, solubility enhancers,
`other salt forms, polymorphic forms
`
`spray volumes may be increased by
`means of mucoadhesive formulations up
`to 150 μl for a puff without runoff
`problems/none
`
`prerequisite for reasonable shelf life/
`stability of solution can be improved by
`solubility enhancers, stabilizers and
`prodrugs
`
`smaller size is an advantage/permeability
`enhancers like chitosan can boost the
`paracellular absorption
`
`choose appropriate excipients, the triad
`of nasal drug delivery (drug, vehicle and
`device) has to be in balance, slight
`changes may alter clinical effects/none
`
`none/permeability enhancers like
`chitosan can boost the paracellular
`absorption of hydrophilic drugs, very
`lipophilic drugs need special vehicle
`systems
`
`slightly acid is recommended,
`impairment of ciliary function possible at
`very low and very high pH, avoid buffers/
`none
`
`higher values tolerable for emergency or
`single- application use, isotonic
`conditions for chronic use, hypotonic
`solutions should be avoided/if solution is
`hypertonic, revise formulation
`
`+ = Moderate; ++ = high; +++ = very high. The character of each drug candidate is ranked according to its
`importance. An envisaged target range and concomitant comments and suggestions for formulation improvements
`are presented (see also the section on pharmaceutical trends and perspectives).
`
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`combination with absorption- enhancing ingre-
`dients. They reversibly modify the barrier prop-
`erties of the nasal epithelium. In intranasal drug
`delivery, surfactants, bile salts, fatty acids and
`polymeric enhancers have been proposed for
`absorption enhancement [44]. However, their
`local tolerance is often awkward and has there-
`fore to be carefully evaluated. Local or systemic
`intolerance after ingestion or inhalation or im-
`pairment of the MCC has to be avoided by all
`means. The addition of dexpanthenol as excipi-
`ent proved to be an option to avoid cytotoxic-
`ity [45]. The knowledge of the mechanism of ac-
`tion of absorption enhancers is still incomplete
`but they change the permeability of the epithe-
`lial cell layer by increasing the fluidity of the bi-
`layers (increasing transcellular transport) or by
`weakening the cellular junctions (increasing par-
`acellular transport). Unfortunately a correlation
`between enhancing bioavailability and damag-
`ing the membrane does exist for many enhancer
`molecules. This is particularly important to re-
`member when designing products for chronic
`use.
`Chitosan – a linear polysaccharide biopoly-
`mer – has emerged as an optimal molecule that
`reveals mucoadhesive properties and opens tran-
`siently the tight junctions increasing paracellular
`transport of polar drugs [46].
`Osmolality and pH of the vehicle affect local
`tolerance and the current state of the drug (ion-
`ized, nonionized). Osmolality and pH should
`whenever possible be adapted to the physiologi-
`cal situation.
`
`Application Device
`The intended use and the pharmaceutical form
`of a nasal product (lavages, drops, squirt sys-
`tems, sprays) predetermine the character of the
`application device. The dose (volume per puff
`normally only 100 μl), the dosing options (single
`vs. multiple), the users (consumer, patient, chil-
`dren, elderly individuals, any involved health-
`care professionals) and a patient’s state of health
`
`predetermine the character of the application
`device.
`Material and design of application devices for
`lavages, drops and squirt systems are straightfor-
`ward whereas in recent years for sprays (liquid,
`powder) dedicated material and ingenious designs
`have been chosen to attain optimal and specific
`clinical effects (see the section on pharmaceutical
`trends and perspectives). Earlier it was revealed
`that the application mode as a consequence of the
`pharmaceutical form and the application device
`influence product deposition within the nose [47,
`48]. Furthermore the suitability of an application
`device frequently depends on a patient’s position
`(supine vs. upright).
`Today the range of devices one can choose
`from is huge. Due to the ubiquitous reports on
`preservative- mediated intolerance, the goal of
`any evaluation should be to find a device that al-
`lows the use of a preservative- free formulation.
`Preservative- free single- and bi-dose devices
`filled under sterile conditions are directly dis-
`posed of after use. But even modern multidose
`device systems prevent formulation contamina-
`tion under multiple- use conditions. This allows
`also for multidose device systems to be filled with
`preservative- free formulations. In addition to a
`better tolerance, the formulation development
`becomes simplified.
`With single- or bi-dose device systems (2 puffs
`for each nostril, e.g. with Bidose Liquid from
`Aptar; http://www.pfeiffer- group.com), the pa-
`tient’s position is less essential (supine vs. up-
`right) whereas with multidose device systems the
`upright position is essential for correct dosing.
`Single or bi-dose device systems allow drug and
`dose accountability which make them suitable for
`narcotic drugs.
`Requirements concerning device performance
`such as plum geometry or droplet size are strictly
`regulated. The clinical relevance of some of these
`parameters remains unknown; however, for the
`development and registration of generic drug
`products it is apparently a prerequisite.
`
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`
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`Trends and Perspectives
`
`Therapeutic Trends and Perspectives
`Nose- to- Brain Delivery
`The olfactory region located in the upper remote
`parts of the nasal passages offers the potential
`for certain compounds to circumvent the blood-
` brain barrier and enter the brain. Although the
`clinical potential of this delivery route is the sub-
`ject of controversial debates, there is considerable
`interest [49] in exploring the route for the treat-
`ment of common intracerebral diseases such as
`Alzheimer’s [50] or obesity [51].
`
`Vasoconstriction/Vasodilatation
`Vasoconstrictors have been used to reduce nasal
`congestions by reducing blood vessel diameter,
`blood flow and by increasing blood pressure. In
`combination – in ophthalmology or anesthesiol-
`ogy – with other drugs to prevent adverse system-
`ic effects by reducing systemic absorption or to
`prolong the duration of action by reducing clear-
`ance from the delivery site. Vasodilators have also
`been used to enhance the systemic bioavailability
`of drugs. Documented only recently in animal ex-
`periments, the vasoconstrictor phenylephedrine
`in a nasal formulation enhanced intranasal tar-
`geting of neuropeptide therapeutics to the central
`nervous system (CNS) [52]. Nasal formulations
`with vasoconstrictors may have particular rele-
`vance for CNS therapeutics with adverse side ef-
`fects where it would be advantageous to limit sys-
`temic exposure. However, any pharmacological
`exertion of influence holds – particularly in the
`olfactory region – many dangers, e.g. infections.
`
`Efflux Transport Proteins
`It is known from oral absorption investiga-
`tion that gastrointestinal drug absorption can
`be diminished due to efflux transporters, e.g. P-
`glycoproteins [53]. There are relatively few re-
`ports regarding the importance of transporter
`systems for drug transport across the nasal epi-
`thelium. Newer papers have focused on the role of
`
`P- glycoproteins in the olfactory epithelium [54].
`Uptake into the brain was enhanced when drugs
`were administered in combination with the P-
`glycoprotein efflux inhibitor rifampicin. Deeper
`understanding of the role of these systems in
`achieving therapeutically relevant concentrations
`of drug in the CNS may have an important impact
`on future development of nose- to- brain delivery.
`
`Nasal Vaccination
`The vast majority of disease- causing bacteria, vi-
`ruses and parasites reach the body through the
`mucosal surfaces. It is obvious, therefore, that
`most of the immune system is either located in,
`or in direct contact with, mucosal membranes,
`thus providing a ‘first line of defense’ system
`against harmful microorganisms. Among other
`mucosal sites, nasal delivery is especially attrac-
`tive for immunization, as the nasal epithelium
`is characterized by reasonable permeability, low
`enzymatic activity and by the presence of an im-
`portant number of immunocompetent cells [16].
`Despite these encouraging characteristics, free
`antigens alone are usually unable to elicit protec-
`tive responses following their intranasal adminis-
`tration. The physical properties of a vaccine can
`greatly influence its performance. Nasal vaccines
`must be specifically formulated and optimized to
`achieve a good immune response and at the same
`time prevent local irritation and other potential
`adverse effects. In order to enhance the potency
`of the nasal vaccines, adjuvants (i.e. immunos-
`timulatory molecules) such as Toll- like receptor
`ligands, toxin- based adjuvants or cytokines [55]
`need to be included in the formulation [56]. Based
`on current insights, encapsulation of antigens into
`bioadhesive (nano)particles is a further approach
`towards improved nasal vaccine delivery. These
`antigen- loaded particles – some of which are in
`clinical investigation – can be tailor made by sup-
`plying them with targeting ligands, adjuvants or
`endosomal escape mediators to form the desired
`vaccine that provides long- lasting protective im-
`munity [57].
`
`30
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`Currently only very few nasal vaccine prod-
`ucts are approved for human use, indicating
`that advances towards new effective vaccines
`are still slow. Opportunities in nasal vaccina-
`tion are not in a single research field but require
`the integration of many research fields includ-
`ing immunology, biotechnology, microbiology
`and pharmaceutical sciences. A concerted ap-
`proach, combining various targeting techniques
`including the use of particulate antigen carriers
`furnished with distinct functionalities such as
`mucoadhesive polymers, cell- specific targeting
`ligands, adjuvants an