Expert Opinion on Therapeutic Patents

Martini, Muggetti & Warchol

Nasal and pulmonary drug delivery systems
Monthly Focus: Biologicals, Immunologicals & Drug Delivery

Nasal and pulmonary drug delivery

systems
Alessandro Martini, Lorena Muggetti & Mark P Warchol
http://www.ashley-pub.com Pharmacia & Upjohn, New Drug Delivery Systems, Pharmaceutical
Development, Viale Pasteur 10, 20014 Nerviano, Italy
Review
The respiratory route of administration has long been the medically desired
1. Nasal drug delivery drug delivery portal for the administration of topical anti-inflammatory drugs.
These drugs are administered either to the lung, i.e., the lower respiratory
1.1 Introduction
system to treat asthma, or to the nasal cavity, i.e., the upper respiratory system
1.2 Technology platform to treat allergic rhinitis. This therapeutic focus dominates the drug delivery
applications for the respiratory system. More recently, the respiratory system
1.3 Therapeutic patents has provided a non-invasive method for the administra- tion of
2. Pulmonary drug delivery biotherapeutics. And finally, formulation and device advancements have led
to the consideration of the respiratory route for a number of other therapeutic
2.1 Introduction applications where systemic delivery is desirable. All of these factors have
2.2 Technology platforms resulted in the therapeutic patents that are discussed in this review.

2.3 Therapeutic patents Keywords: aerosol, allergic rhinitis, asthma, biotherapeutics, dry powder,
nasal, nebulizer, pulmonary, spray
3. Expert opinion
Bibliography Exp. Opin. Ther. Patents (2000) 10(3):315-323
Patents
1. Nasal drug delivery
1.1 Introduction
In recent years, the nasal route of administration has received a great deal of
attention as a convenient and reliable method not only for local but also for
systemic administration of drugs, especially those that are orally ineffective
and must be administered by injection [1].
Published work carried out in many laboratories has shown that drugs with a
wide variety of chemical structures are well absorbed through the nasal
membranes of animals and man. Based on the above observations, it would
appear that the nasal route could be considered promising mainly for low
dose, chronically used drugs that are ineffective orally and need rapid entry to
the general circulation. The rate of absorption for compounds through a
physiological membrane can be significantly influenced by physico- chemical
properties such as the state of ionisation and the lipophilicity of the
compound, as well as the size of the molecule and possibly the ability of the
compound to hydrogen bond with the components of the membrane.
Many drugs such as peptides, narcotic antagonists, male and female hormones
are ineffective orally due to their metabolism in the gastrointes- tinal tract or
the first-pass effects in the liver. These drugs may be absorbed nasally and
some of them are already marketed as prescription nasal products [2]. The
penetration of bioactive molecules through the nasal
315
2000 © Ashley Publications Ltd. ISSN 1354-3776
316 Nasal and pulmonary drug delivery systems

mucosa has been shown to achieve good bioavail- drug absorption through the mucosa [6]. As far as the
ability and nasal formulations offer great convenience increase in contact time is concerned, bioadhesive or
to patients. Two parts mainly compose the dosage microsphere based formulations are matters of
forms suitable for nasal delivery: the formulation and relevant scientific research. Bioadhesive excipients
the device that allows the reproducible delivery of the work by their ability to adhere to a biological tissue for
formulation itself. Even if the device field [3] is beyond an extended period of time, thus limiting the
the scope of this review, it is important to note that few clearance of the formulation [7]. Microsphere-based
patents have been filed in recent years on these formulations, which transport the drug by physical
subjects. A great deal of effort, on the other hand, has entrapment, when in contact with nasal mucosa
been dedicated to formulation optimisation and to absorb water to form a gel that adheres tightly and for
explore this route of administration for new actives and a prolonged time to the surface allowing a longer
new therapeutic indications. release in situ of the active from the formulation [8].
On the other hand, as far as penetration enhancers are
1.2 Technology platform concerned, most of these systems are based on surfac-
The most suitable dosage form and delivery system tants and the improvements in absorption are often
have to be identified in order to gain the desired coupled with tissue damages [9].
absorption drug profile after intranasal administra- tion.
Hence, a key goal in formulation development for
The choice of dosage form generally depends on the
nasal products is the capacity to provide high bioavail-
drug, clinical indication, patient population and, last but
ability with minimum or no tissue side effects. This
not least, marketing aspects.
can be achieved by using certain phospholipid
Several different nasal dosage forms have been compounds, and more particularly cationic polymers
developed: drops, solution and suspension sprays, such as chitosans [10].
powders, gels, emulsions and ointments, as well as
sp ecialised systems such as lip osomes a nd 1.3 Therapeutic patents
microspheres. Liquid preparations are the most
widely used, they are mainly composed of aqueous 1.3.1Management of seasonal or perennial
formulations that are administered to patients by allergic rhinitis
means of proper devices (e.g., metered dose nasal More than half of the brand products on the market as
actuator systems). Although liquid preparations are nasal prescription drugs are for the treatment of
considered the easiest formulation approach, this seasonal or perennial allergic rhinitis. Active drug
perspective is simplistic, since several variables such substances used for this local therapy are mainly
as the active drug physicochemical stability in steroids, such as beclomethasone dipropionate,
solution, microbiological stability of the dosage form budesonide and triamcinolone acetonide. Interest in
and the impact of the formulation of the physiological this pathology is still active in the patent literature,
clearance mechanisms from the nasal mucosa have to both through the improvement of the current formula-
be carefully taken into consideration [4]. tions and the proposal of alternative therapies to
solve /alleviate the pathology. As example, Rhône-
Moreover, particularly when a systemic pharmacol-
Poulenc Rorer has recently claimed a reformulation of
ogical effect is desired, these formulations could have
triamcinolone acetonide in a thixotropic solution
limited value due to the fact that simple solutions are
com p osed mainly of q uater nary ammonium
readily cleared from the administration site through the
compounds and cellulose derivatives [101]. This
combined action of mucus secretion and the beating
formulation displays a sustained retention in the nasal
movements of cilia [5]. This means that even if the
cavity, with enhanced therapeutic efficacy. Also Astra
absorption of the active is rapid, its extent is limited by
AB proposes a novel metered dose formulation of
the short residence time in situ .
budesonide that allows the delivery of a 10-fold lower
In order to overcome this problem two alternatives dose than conventional MDI formulations, without
are feasible: to increase the contact time of the drug reduction in the efficacy of the treatment of rhinitis
with the nasal mucosa by the use of appropriate [102]. The formulation can be delivered simply as
excipients, or to modify the formulation by adding a nasal drops or as nasal aerosol according case by case
chemical substance capable of acting as a penetration on the formulation, dose and device characteristics.
enhancer, thus increasing the rate and the quantity of McNeill PPC [103,104] has claimed a different
© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)
 Martini, Muggetti & Warchol 317

approach, where the proposed formulations are one is the delivery of the macromolecule to the target
combinations of topical steroids or topical antihista- organ in terms of reaching an effective contact
minics with topical mast cell stabilisers as useful tools between the formulation and the mucosal surface and
for the prevention or treatment of seasonal and passage of the active inside the appropriate cells so as
perennial allergic rhinitis. In fact, the chronic to have a therapeutic effect. Recent patent literature
symptoms of perennial allergic rhinitis are most reports many attempts made to solve this issue. An
frequently caused by reaction to perennial allergens. enhanced immune response is reported when
When allergens are present, they bind to the immuno- vaccines are administered together with chitosan
globulin on the surface of mast cells and trigger the glutamate [105] or with deacylated chitin [106] in an
breakdown, or degranulation, of the cell [11]. intranasal formulation. Microspheres and nanoparti-
cles composed of macromolecules such as nucleic
Upon degranulation, mast cell components, including acid and chitosan are described in a patent as a
mediators for symptoms associated with allergic rhinitis valuable intranasal formulation due to the effective
such as histamine and proteases, are released. The adhesive properties of the chitosan leading to
topical mast cell stabilisers herein function by improved mucosal absorption [107]. Different
preventing degranulation of mast cells in response to antigens and different mucosal absorption sites can be
allergens. The topical mast cell stabilisers are selected combined to induce a more effective immune
from cromolyn sodium, nedocromil or lodoxamide. The response. In this case, intranasal delivery is consid-
topical nasal steroids available are corticosteroids that ered as a first choice so that the vaccine is targeted to
inhibit the release of mediators for the symptoms the nasal immune inductive sites [108-110]. Gene
associated with allergic rhinitis from mast cells and delivery is also potentially feasible through nasal
basophils, thus reducing inflammation [12,13]. administration for the treatment of genetic disease,
tumours and viral infections as claimed in a Chiron
1.3.2 Delivery of macromolecules Viagene patent [111].
The challenge to deliver macromolecules, such as
peptides and proteins, through an administration 1.3.3 Absorption promotion
route other than parenteral, continues to be one of the Effective therapeutic delivery of many active
major research areas in drug delivery development. molecules by the intranasal route has not been
The nasal delivery route has shown most promise, as achieved simply because the required level of absorp-
highlighted by the presence on the market of at least tion of the drug is often not reached because the cell
four different formulations containing peptides: membranes present a selectively p ermeable
salmon-calcitonin, for treating postmenopausal barrier [17].
osteoporosis; oxitocin, to promote milk ejection in
breast feeding mothers; nafarelin acetate, for treating To improve nasal absorption there is active research
central precocious puberty and endometriosis; and into the identification of substances acting as absorp-
desmopressin acetate, for preventing and control of tion promoters. The ideal absorption promoter should
polydipsia, polyurea and dehydration in patients with enhance the passage of the drug through membrane
diabetes insipidus. The need for a convenient barriers without damaging either the active molecule
macromolecule administration route, such as nasal, is or its metabolites or the structural integrity and
also highlighted by the fact that two out of three biological functions of the membrane [18]. New
investigational drug products for the nasal route are molecules are under evaluation as absorption
peptides or proteins [2]. The patent literature also enhancers and are described in some patents as novel
follows this trend with particular attention to the excipients that facilitate intracellular delivery of
mucosal delivery of vaccines and/ or agents able to biologically active molecules. In a patent owned by
induce a mucosal immune response [14,15]. Influenza Genzyme cationic amphiphilic molecules are
vaccines that elicit both local secretory responses at reported to promote the absorption of biologically
the respiratory tract mucosa level and a systemic active molecules into tissues and organs when
antigen response should provide superior immunity administered by different routes including the
to current injected vaccines [16]. transmucosal [112]. Due to their amphiphilic nature,
these materials can advantageously be used to
Different problems have to be faced when dealing with produce particular drug delivery systems such as
this route of administration. The most relevant liposomes that are vesicles formed by more or less
© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)
318 Nasal and pulmonary drug delivery systems

spherical bilayer of the amphiphile entrapping the 2. Pulmonary drug delivery

biologically active molecules. The amphiphilic nature
of these materials permits their intimate association 2.1 Introduction
with the lipids of the cell membrane allowing for
The inhalation route of drug delivery offers an
effective absorption of the drug through the cell
effective means of delivering drug therapies to the
membrane. A different approach has been filed by the lung for the treatment of respiratory diseases [20,21]
University of Maryland, Baltimore [113] where the use and, more recently, of delivering drug therapies
of a substantially pure mammalian protein, i.e., through the lung for the treatment of a wide range of
zonulin, which is a physiological modulator of other disorders [22,23]. Lung anatomy and lung
mammalian tight junctions is claimed. This protein has physiology provides a number of advantageous
been shown to be capable of reversibly opening tight features, which makes the pulmonary route a good
junctions in the mucosa thus enhancing mucosal target for these drug delivery therapies. Among those
absorption of a co-administered therapeutic agent features, the following are the most noteworthy:
[19]. A more recent patent from the same source [114]
• a large surface area of about 150 m 2
claims the use of attenuated Vibrio cholerae toxin in
nasal formulations to mimic the effects of zonulin. • an extremely well vascularised and thin epithelial
lining surface
Another effective way of promoting the absorption of
These advantageous features result in the following
actives through the nasal mucosa is to incorporate
benefits for pulmonary drug delivery:
them onto bioadhesive materials that, due to their
physical interactions with the mucus layers, are able • a non-invasive method of drug delivery providing
to prolong the residence time at the administration the patient with an alternative to injection therapies
site. In the recent patent literature two publications
• a direct access to systemic circulation providing for
are to be highlighted. A patent from Pharmacia SpA
a more rapid onset of action where such a response
[115] claims waxy bioadhesive starches, prepared by a
is important especially for acute treatments
low cost technology, for nasal absorption enhance-
ment. A second patent from Warner-Lambert discloses • an avoidance of first-pass metabolism and of
ionic polysaccharides in conjunction with cross- linking gastrointestinal degradation resulting in lower
agents that enable the formulation to adhere to mucosae doses of medication and concomitantly producing
[116]. fewer unwanted side effects
• a more convenient means of drug administration,
i.e., a non-clinical setting
1.3.4 Other therapeutic areas
In order to utilise this route of drug administration a
Nasal administration of drugs is also proposed for number of technology platforms have been
other therapeutic indications such as smoking developed over the last half-century. The current
cessation, diabetes, pain and migraine. pulmonary drug delivery platforms include:

For example, Procter and Gamble claims suitable • pressurised metered dose inhalers (pMDIs)
compositions for nasal administration of nicotine and • dry powder inhalers (DPIs)
caffeine for the treatment of nicotine craving or
smoking withdrawal symptoms [117,118]. A patent • classical nebulizers and, more recently, aqueous
from Ferring AB covers the use of nasal sprays of mist inhalers (AMIs)
desmopressin for the treatment of diabetes insipidus Effective drug delivery to the lung involves an
with improved absorption properties versus the understanding of the drug formulation, the inhaler
already marketed formulations from Rhône-Poulenc device and the patient. This review will briefly
Rorer through the use of osmotic pressure controlling explore the aforementioned aspects of their effects
agents [119]. Pherin Corporation proposes the nasal upon the various technology platforms before
route as a valid way of administering 19-norcholane proceeding onto an examination of the therapeutic
steroids, in order to treat anxiety [120]. patents in the pulmonary drug delivery area.
© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)
 Martini, Muggetti & Warchol 319

2.2 Technology platforms Table 1: Advantages and disadvantages of pMDIs.

2.2.1 Pressurised metered dose inhalers Advantages Disadvantages

Convenient Requires patient training
pMDIs represent the most widely used of the inhala-
Portable Oropharyngeal deposition
tion devices in the respiratory care drug delivery area likely
[24]. Also, this technology platform is almost Inexpensive
Cold sensation
exclusively associated with the treatment of asthma
and, as such, these devices commonly contain
-agonists or corticosteroids. First introduced by Riker
Table 2: Advantages and disadvantages of DPIs.
Laboratories (a subsidiary of 3M Pharmaceuticals) in
1956, these devices utilise a number of chlorofluoro- Advantages Disadvantages
carbon propellants (CFCs), commonly called freons, Convenient Requires high inspiratory
to aerosolise and deliver micronised drug suspension Portable flow rate
formulations. When actuated, these pMDIs deliver the Breath actuated requiring Oropharyngeal deposition
aerosolised drug particles at very high velocities little patient training possible
approaching 30 m/ sec [25]. Unless the device Capable of delivering Difficult to deliver high doses
actuation is co-ordinated with the breathing process, a biotherapeutics Irritation of airways due to
large amount of the drug impacts at the back of the dry powder
throat and is swallowed. Therefore, the major factor
effecting the delivery of drugs by this administration
route is inhaler technique. A comparison of the co-ordination than pMDIs. Again, a comparison of the
advantages and the disadvantages of this drug advantages and the disadvantages of this drug
delivery technology platform can be made ( Table 1). delivery technology platform can be made ( Table 2).

To mitigate the effects of the disadvantages of conven- Improved powder processing and the use of impellers
tional pMDIs a number of device enhancements have (Dura Pharmaceuticals’ Spiros®) to assist the patient
been developed. Breath actuated devices (for example, with aerosolisation represent attempts at addressing
the Autohaler® and Easi-Breathe ®) have proven to be some of the disadvantages of DPIs.
effective in improving the co-ordination problems often
associated with these devices. Likewise, integrated 2.2.3 Nebulizers and aqueous mist inhalers
(Azmacort ®) and add-on (Spacehaler®) spacers have
proven to be beneficial in reducing oropharyngeal Patients such as infants or geriatric patients, often
deposition. cannot use either of the aforementioned pulmonary
drug delivery technology platforms. Compressed air
2.2.2 Dry powder inhalers (jet) or ultrasonic nebulizers provide alternatives. In
these devices, aqueous or ethanol based solutions are
In order to further address some of the disadvantages nebulized to the appropriate droplet size required for
of the pMDI, the DPI was developed in the late 1960s inhalation (typically 2 to 5 microns). While therapy
and the early 1970s to provide the patient with an takes longer with nebulizers, treatments lasting 15 to
alternative to the pMDI. More recently, however, the 20 min are common, drug delivery is technique
‘Montreal Protocol’ of 1987 calling for a phase-out of independent and it occurs during normal tidal breathing.
CFCs and other environmentally harmful chemicals, The main drawback with conventional nebulizers is
and the desire to deliver biotherapeutics via the their size and their lack of portability. However, it
inhalation route, has spurred a rapid development of should be noted that that these devices can deliver
devices in this area. In these devices the patient virtually any drug, including biotherapeu- tics, in
inhales micronised drug particles with or without a virtually any dose.
drug carrier (usually lactose). Whereas early DPIs
were single dose capsule-based devices (Fisons’ In order to retain the advantages of nebulizers and
Spinhaler ® and GlaxoWellcome’s Rotohaler ® ), remove the disadvantages ( Table 3), AMIs have
improved multiple dose devices (GlaxoWellcome’s evolved. These compact devices deliver liquid aerosol
Diskhaler ® and Diskus® as well as Astra Draco’s sprays of approximately 50 l in a metered fashion. As
Turbuhaler ®) are now available. As these devices such, they marry the advantages of the pMDIs with
dispense only during inhalation, they require less those of nebulizers to create an improved drug
© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)
320 Nasal and pulmonary drug delivery systems

Table 3: Advantages and disadvantages of nebulizers. 2.3.3 Other pulmonary diseases

Advantages Disadvantages The treatment of chronic obstructive pulmonary
Do not require patient Limited portability disease (COPD) is also an area in which inhalation
training drug delivery plays an important role. In this area, the
Long treatment regimens
Capable of high dose administration of a novel surfactant, -tocopheryl-
Excessive drug consumption,
administration wasteful
-phosphocholine, to the lung airways to improve the
Capable of delivering a wide clearance of mucus is claimed [130]. Also, the delivery
variety of drugs of a microparticulate pharmaceutical dispersed in a
Capable of delivering perfluorocarbon liquid into the lung is claimed to be
biotherapeutics applicable in the treatment of a wide variety of lung
diseases [131]. Finally, the use of a uridine 5 -dipho-
sphate derivative in hydrating lung mucus secretions
delivery system. Aradigm’s AERx® and Boehringer’s
for treating cystic fibrosis has been reported [132].
Respimat® represent the leading device entries into this
field.
2.3.4 Other therapeutic areas
Administration of anticancer cytolytic bradykinin
2.3 Therapeutic patents antagonists by Cortech [133] and of anticancer cytotoxic
drugs by Battelle Memorial Institute [134] represent
2.3.1 Asthma novel uses for pulmonary drug delivery. Additionally,
the aerosol administration of drugs for the treatment of
The treatment of asthma constitutes a major focus for
respiratory viral infections represents another potential
inhalation drug delivery. Corticosteroids offer a broad
application for pulmonary drug delivery [135].
range of pathway interactions to inhibit lung eosino-
philia [26]. However, recent activities of the Glaxo
Group using peptides and peptidomimetics to bind to 3. Expert opinion
the IL-5 receptor and thereby inhibit lung eosinophilia
are claimed to offer alternatives to the traditional
therapy [121,122]. In a similar vein, Genentec employs The development of nasal product is still facing many
anti-IgE antibody antagonists to bind to basophils, challenges. A better understanding of how the proper-
again interfering with the inflammatory pathways, ties of drug molecules, formulation compositions, the
resulting in a possible maintenance therapy for the nasal mucosa itself and the drug delivery system affect
treatment of asthma [123]. drug absorption through the nasal route, is invaluable.
Even if the main attention in the field is still maintained
2.3.2 Delivery of macromolecules on local therapies, macromolecular delivery is truly
The administration of biotherapeutics to the lungs has perceived as a breakthrough and a convenient way of
been enabled by the improvements in the DPI and AMI drug administration.
technology platforms. The delivery of insulin via
The possibility of gaining a rapid onset of action has
Aradigm’s AERx® device [124] and the production of recently been demonstrated by the introduction of
zinc-free insulin crystals suitable for pulmonary butorphanol tartrate in a nasal spray as an alternative to
delivery by Novo Nordisk AS [125] represents the the injectable form for the relief of pain and migraine
progress of the Aradigm/Novo Nordisk collaboration headaches. This is further supported by the line
in this area. Also, gene delivery efforts have been extension of sumatriptan as a nasal spray for migraine.
realised through the formulation efforts of Chiron Rapid onset of action offers true and therapeutically
Viagene [126] using polycationic gene delivery effective marketing possibilities in the field of pain
vehicles to assist in uptake by the host cells. Genetic management.
Therapy [127] has used lipids containing surfactants
for the introduction of an expression vehicle into lung The major focus for inhalation drug delivery has been
cells. Furthermore, the use of antisense treatments for and will continue to be directed toward the treatment of
pulmonary diseases through the delivery of oligonu- asthma. Novel therapeutic entities will continue to be
cleotidies has been reported by the University of developed but corticosteroids will still comprise the
Sheffield [128] and by East Carolina University [129]. major class of drugs. The reformulation of pMDIs
© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)
 Martini, Muggetti & Warchol 321

from traditional CFCs to ‘ozone friendly’ HFAs 5. ILLUM L: Drug delivery systems for nasal application.
STP Pharma. (1987) 3:594-598
(hydrofluoroalkanes) has been largely accomplished
• General description of the delivery systems suitable for
with pMDIs delivering a ‘softer puff’ [24] to the user in intranasal administration of drugs.
these reformulated products. Finally, device improve-
6. BEHL CR, PIMPLASKAR HK, SILENO AP et al.: Optimiza-
ments, and enhancements, will also continue to be tion of systemic nasal drug delivery with pharmaceu-
introduced in order to address some of the previously tical excipients. Adv. Drug Deliv. Rev. (1998) 29:117-133.
noted pMDI shortcomings. Some fundamental •• This review discusses the most widely used formulation
approaches to improve drug absorption through the nasal
medical questions remain unanswered, most notably
administration route.
the specific target for these drugs, and more research
work directed toward answering these questions 7. DUCHENE D, TOUCHARD F, PEPPAS NA:Pharmaceutical
and medical aspects of bioadhesive systems for drug
remains to be done. administration. Drug Devel. Indust. Pharm. (1988)
14:283-318.
A rapidly emerging area for inhalation drug delivery • This paper deeply investigates bioadhesion mechanisms,
will be the use of the lung as a portal for systemic drug factors influencing bioadhesion phenomema, bioadhesive
delivery for both small molecular entities as well as for polymers and dosage forms.
biotherapeutics. The Inhale Therapeutics/ Pfizer 8. PERESWETOFF-MORATH L: Microspheres as nasal drug
insulin collaboration has provided significant ground delivery systems. Adv. Drug Deliv. Rev. (1998) 29:185-194.
• Review on different types of microspheres that can be used
breaking work in this area [27]. Many other develop- to improve nasal absorption of drugs. Microspheres made of
ment programs are in progress (for example, different materials are compared for their in vivo behavior as
Aradigm/Novo Nordisk for insulin and Dura Pharma- drug delivery also considering toxicological aspects.
ceuticals /Lilly for insulin). Additionally, the 9. DE PONTI R, LARDINI E: Use of chemical enhancers for
pulmonary delivery of genetic material will continue n a s al d e liv ery . Drug Dev. I n d . Phar m . ( 1991 )
to be an area of investigation. However, numerous 17(11):1419-1436.
• This paper gives a general and widespread overview on
drug delivery questions remain to be examined [28]. chemical enhancers considered for nasal drug delivery.
10. KOTZÉ AF, LUESSEN HL, DE BOER AG, VERHOEF JC,
JUNGINGER HE: Chitosan for enhanced intestinal
permeability: prospects for derivatives soluble in
Bibliography neutral and basic environments. Eur. J. Pharm. Sci.
(1998) 7:145-151.
Papers of special note have been highlighted as: • This reference offers a deep experimental evaluation of
• of interest chitosan as a mucoadhesive polymer suitable to be used to
•• of considerable interest enhance trough transmucosal drug absorption.
1. DAVIS SS: Delivery of peptide and non-peptide drugs 11. MEGGS WJ: Mechanis m of allergy and ch e mical
through the respiratory tract. Pharm. Sci. Technol. sensitivity. Toxicol. Ind. Health (1999) 15(3-4):331-338.
Today (1999) 2:450-456. • This paper describes allergy and chemical sensitivity
• Review on recent advances in the delivery of both peptide mechanism.
and non-peptide drugs to the respiratory tract. A
comparison between nasal and pulmonary delivery is made. 12. SUONPAA J: Treatment of allergic rhinitis. Ann. Med.
(1996) 28(1):17-22.
2. BEHL CR, PIMPLASKAR HK, SILENO AP, DEMEIRELES J, • The reference describes therapeutic strategies to treat
ROMEO VD: Effects of physicochemical properties and allergic rhinitis.
other factors on systemic nasal drug delivery. Adv.
13. KRAUSE HF: Pharmacoth erapy of pere nnial and
Drug Deliv. Rev. (1998) 29:89-116.
seasonal allergic rhinitis. Clin. Immunother. (1995)
•• Review on the feasibility evaluation of drug nasal delivery
3(4):308-324.
from anatomical considerations to preformulation studies
• The reference describes therapeutic strategies to treat
leading to the development of a final formulation.
allergic rhinitis by the use of anti-histamines, corticosteroids,
3. BOMMER R: Adva n c es i n n a s al drug d e liv ery decongestants, mast cell stabilisers and other agents, such as
technology. Pharm. Technol. Eur. (1999):26-33. mucolytics and anticholinergics.
• Review on some of the latest devices for liquid and dry 14. LAVELLE E: Targeted mucosal delivery of drugs and
powder formulations including preservative-free systems. vaccines. Exp. Opin. Ther. Patents (2000) 10(2):179-190.
• This review examines the potential for targeted mucosal
4. BATTS AH, MARRIOTT C, MARTIN GP, BOND SW: The
drug and vaccine delivery.
effect of some preservatives used in nasal prepara-
tions on mucociliary clearance . J. Pharm. Pharmacol.
(1989) 41:156-159.
• This reference describes the effects of some preservatives
used in multi-dose nasal preparations on mucociliary
transport rate.

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)
322 Nasal and pulmonary drug delivery systems
15. JENKINS PG: Mucosal vaccine delivery. Exp. Opin. Ther. 24. ROSS DL, GABRIO BJ: Advances in metered dose inhaler
Patents (1999) 9(3):255-262. t e c hno l o g y w i t h t h e d e v e l o pm e n t o f a
• This reference offers a description of the recent advances on chlorofluorocarbon-free drug carrier system. J. Aerosol
drug delivery strategies for mucosal administration of Med. (1999) 12(3):151-160.
vaccines. Strengths and weaknesses of different approaches • Article presents formulation implications observed in
are discussed. CFC-free pMDIs.
16. McCLUSKIE MJ, DAVIS HL: Novel strategies using DNA 25. KELLER M: Developments and trends in pulmonary
for the induction of mucosal immunity. Crit. Rev. drug delivery. Chimica Oggi (1998) 16:(11/12):16-24.
Immunol. (1999) 19(4):303-329. • Review of inhalation drug delivery and of the importance of
• This paper describes the recent advances in vaccination its understanding for effectively dealing with pulmonary
strategies using DNA delivered to mucosal surfaces. functions and diseases.
17. CORNAZ AL, BURI P: Nasal mucosa as an absorption 26. MOBLEY JL, CHIN JE, RICHARDS IM: Glucocorticoster-
barrier. Eur. J. Pharm. Biopharm. (1994) 40(5):261-270. oids, old and new: biological function and use in the
• This paper provides a detailed description of the nasal treatment of asthma. Exp. Opin. Invest. Drugs (1996)
mucosal barrier: a good comprehension of the factors 5(7):871-884.
limiting drug permeation trough nasal mucosa can lead to • Expert opinion on old and new glucocorticosteroids used in
the identification of effective strategies to improve intranasal the treatment of asthma.
absorption of drugs.
27. PATTON JS, BUKAR J, NAGARAJAN S: Inhaled insulin.
18. MERKUS FWHM, VERHOEF JC, MARTTIN E et al.: Adv. Drug Deliv. Rev. (1999) 35(2,3):235-247.
Cyclodextrins in nasal drug delivery. Adv. Drug Deliv. • A review of clinical observations from inhaled insulin
Rev. (1999) 36:41-57. studies.
• In the review the use of cyclodextrins in nasal drug formula-
tion both as solubilising agents and absorption enhancers is 28. WU-PONG S, BYRON PR: Airway-to-biophase transfer of
discussed. It is an example of a new class of safe enhancers. inhaled oligonucleotides. Adv. Drug Delivery Rev. (1996)
A special focus is given to intranasal protein and peptide 19(1):47-71.
intranasal formulation. • A review of oligonucleotide delivery to and uptake by the
lung. While systemic delivery remains problematical, topical
19. MARINARO M, DI TOMASO A, UZZAU S, FASANO A, DE delivery appears reasonable.
MAGISTRIS MT: Zonula occludens toxin is a powerful
mucosal adjuvant for intranasally delivered antigens.
Infect. Immun . (1999) 67(3):1287-1291.
• This reference focuses on the possibility the use Zonula Patents
occludens toxin (ZOT) as an adjuvant to deliver soluble
antigens through the nasal mucosa. 101. RHÔNE-POULENC RORER, INC.: WO9800178 (1998).

20. NEWMAN SP: Optimizing delivery of drugs to the lungs. 102. ASTRA AB: WO9824450 (1998).
Clin. Asthma Rev. (1998) 2:123-128. 103. MCNEILL PPC, INC.: WO9701341 (1997).
• Review of current trends of optimising delivery devices for
the effective treatment of asthma. 104. MCNEILL PPC, INC.: WO9701340 (1997).
21. Inhalation Aerosols. Hickey AJ (Ed.), Marcel Dekker, Inc., 105. MEDEVA HOLDINGS BV: WO9610421 (1996).
New York, USA (1996).
106. MEDEVA EUROPE LTD.: WO9927960 (1999).
•• This reference combines the physical chemistry of formula-
tion with the physics of aerosol generation and aerodynamic 107. DANBIOSYST UK LTD.: WO9801160 (1998).
behavior in order to better understand their therapeutic
implications for inhalation aerosols. 108. PASTEUR MERIEUX SERUMS ET VACCINS SA: WO9631234
(1996).
22. YU J, CHIEN YW: Pulmonary drug delivery: physiologic
and mechanistic aspects. Crit. Rev. Ther. Drug Carrier 109. GBF GMBH: WO9848026 (1998).
Syst. (1997) 14(4):395-453. 110. EMORY UNIV.: WO9848626 (1998).
• Presentation of numerous case studies for the pulmonary
delivery of proteins and peptides. 111. CHIRON VIAGENE, INC.: WO9620732 (1996).
23. Inhalation Delivery of Therapeutic Proteins and Peptides . 112. GENZYME CORPORATION: WO9813026 (1998).
Adjei LA, Gupta PK (Eds.), Marcel Dekker, Inc., New York,
113. UNIV. OF MARYLAND BALTIMORE: WO9852415 (1998).
USA (1997).
•• This reference offers a comprehensive analysis of protein 114. UNIV. OF MARYLAND BALTIMORE, CHIRON SPA:
and peptide delivery through the lung including a detailed US5908825 (1999).
description of the human respiratory tract and its impact on
both local and systemic delivery of biotherapeutic and 115. PHARMACIA SPA: WO9534582 (1995).
macromolecular drug systems. 116. WARNER-LAMBERT CO.: WO9731621 (1997).
117. PROCTER & GAMBLE CO.: WO9600071 (1996).
118. PROCTER & GAMBLE CO.: WO9600069 (1996).
119. FERRING AB: US5498598 (1995).

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)
 Martini, Muggetti & Warchol 323
120. PHERING CORP.: WO9746574 (1997). 130. GENETIC THERAPY, INC.: WO9630051 (1996).
121. GLAXO GROUP LTD.: WO9857979 (1998). 131. UNIV. OF SHEFFIELD: WO9911778 (1999).
122. GLAXO GROUP LTD.: WO9857980 (1998). 132. EAST CAROLINA UNIV.: WO9913886 (1999).
123. GENENTECH, INC.: WO9704807 (1997). 133. CORTECH, INC.: WO9709347 (1997).
124. CLARION PHARM., INC.: US5883084 (1998). 134. BATTELLE MEMORIAL INST.: WO9829110 (1998).
125. ALLIANCE PHARM. CORP.: WO9614056 (1996). 135. SCHINAZI RF et al.: WO9614838 (1996).
126. INSPIRE PHARM., UNIV. OF NORTH CAROLINA:
WO9909998 (1999). Alessandro Martini1†, Lorena Muggetti1, Mark P Warchol2
†Author of correspondence
127. ARADIGM CORPORATION: WO9613161 (1996). 1Pharmacia & Upjohn, New Drug Delivery Systems, Pharmaceutical

128. NOVO NORDISK AS: WO9842749 (1998). Development, Viale Pasteur 10, 20014 Nerviano, Italy
2 Pharmacia & Upjohn, Licensing & Technology, Pharmaceutical

129. CHIRON VIAGENE, INC.: WO9620732 (1996). Development, 7000 Portage Road, Kalamazoo, MI 49001, USA

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (2000) 10(3)