Expert Opinion on Biological Therapy
`
`ISSN: 1471-2598 (Print) 1744-7682 (Online) Journal homepage: https://www.tandfonline.com/loi/iebt20
`
`Nasal Drug Delivery
`
`Julie D Suman
`
`To cite this article: Julie D Suman (2003) Nasal Drug Delivery, Expert Opinion on Biological
`Therapy, 3:3, 519-523, DOI: 10.1517/14712598.3.3.519
`To link to this article: https://doi.org/10.1517/14712598.3.3.519
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`Published online: 03 Mar 2005.
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`Meeting Highlights
`
`Delivery
`
`Nasal Drug Delivery
`24 – 25 March 2003, London, England
`
`Julie D Suman
`Next Breath, LLC, 1450 South Rolling Road, Baltimore, Maryland 21227, USA
`
`The Nasal Drug Delivery Conference was held at the Institute of Directors in
`London, England. The meeting was organised by the Management Forum Ltd
`and chaired by P Seeney (PA Consulting, UK) and Professor F Merkus (Leiden
`University, The Netherlands; Innoscience Technology, Belgium). The confer-
`ence covered a wide range of topics including aspects of nasal physiology,
`formulation, new nasal products, nasal vaccines, nose to brain transport and
`pain management via nasal sprays.
`
`Keywords: animal models, brain delivery, FDA guidance, in vitro tests, nasal drug delivery, nasal
`sprays, neuropeptide, olfactory region, preservative-free, toxicology, vaccine
`
`Expert Opin. Biol. Ther. (2003) 3(3):519-523
`
`1. Overview of nasal drug delivery
`
`1.1 Important considerations in nasal drug delivery
`Professor L Illum (IDentity, UK) presented a comprehensive overview using a case
`study approach to highlight developments and challenges for nasal administration.
`Lipophilic drugs such as the opioid fentanyl are well absorbed from the nasal cavity
`and can achieve bioavailabilities that approach 70 – 100%. Absorption of polar
`drugs, on the other hand, is more challenging because transport across the epithe-
`lium occurs more slowly, allowing the drug to be cleared from the nose by mucocili-
`ary clearance. Polar molecules, therefore, may require utilisation of absorption
`enhancers or bioadhesive agents to increase the rate and extent of absorption.
`In addition, peptides and proteins like insulin may necessitate use of absorption
`promoters. Historically, nasally administered insulin has been a challenge, due to
`low bioavailability. Formulations containing bile salts (INSERM, France) and chi-
`tosan (West Pharmaceutical Services) achieve plasma insulin levels that rival subcu-
`taneous injection. However, one should keep in mind that some absorption
`promoters can damage the nasal epithelium, leading to undesirable outcomes.
`Dr Illum also illustrated developments in nasal vaccines. Because the nasal passage
`contains nasal associated lymphoid tissue (NALT), the nose represents a low cost,
`non-invasive avenue for achieving mucosal and systemic immunity. The market
`potential for a nasal influenza vaccine alone is projected at US$1 billion (Med Ad
`News, January 2003).
`
`1.2 Nasal drug delivery: a surgeon’s view
`Dr T Woolford (Royal Hallamshire Hospital, University of Sheffield, UK) pro-
`vided the audience with images of nasal cavity using a nasendoscope. The pictures
`revealed the complexity and narrowness of the passageways. In addition, Dr Wool-
`ford presented feedback from patients with reasons why they did not use their nasal
`spray. Poor patient compliance could be attributed to an inconvenient dosing regi-
`men, a perception that the drug had a slow onset of action and an unpleasant taste.
`Other patients stated that they were unable to use their nasal spray during an upper
`respiratory infection. One reason for this ‘can’t use it’ statement, according to an
`image provided by Dr Woolford, was due to a physical blockage of the passage
`resulting from swelling and inflammation. Additional reasons for under-utilisation
`
`2003 © Ashley Publications Ltd ISSN 1471-2598
`
`519
`
`1. Overview of nasal drug delivery
`
`2. Nasal drug delivery challenges
`
`3. New therapies in nasal
`drug delivery
`
`4. New device concepts and
`in vitro spray characterisation
`
`5. Nose to brain transport – fact
`or fiction
`
`6. Expert opinion
`
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`
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`Nasal Drug Delivery
`
`of nasal medications were discomfort, rhinitis/crusting and
`minor nose bleeds.
`
`anaesthetised animals to eliminate confounding results due to
`stress associated with dosing.
`
`1.3 Toxicology in relation to studies for nasal products
`Dr R Forster (CIT, France) covered issues surrounding safety
`evaluations using animal models. Commonly used species in
`nasal toxicology include rats, rabbits, beagle dogs and
`cynomolgus monkeys. Of these, monkeys appear to be most
`similar to humans in terms of turbinate structure, scarcity of
`olfactory epithelium and the cellular components of respira-
`tory epithelium. In terms of volume, dogs (20 ml) were most
`similar to humans (30 ml).
`A typical regulatory study, according to Dr Forster, would
`include clinical observations of factors such as body weight,
`food consumption and physiological measurements. In
`addition, laboratory investigations, such as haematology and
`immune system toxicity, and post mortem examinations on
`a wide range of tissues should be conducted. In evaluating
`the results, one should consider the study design, including
`how the device was used and reliability of dosing, the
`number of sprays per session and the number of sessions per
`day. Investigators should also consider functional changes in
`mucociliary clearance and other specific tissues, such as the
`olfactory bulb. Histological exams should involve assessment
`of serial sections of the turbinates and evaluation of the
`squamous, transitional, respiratory and olfactory epithelia
`within the nasal cavity.
`
`2. Nasal drug delivery challenges
`
`2.1 Nose models in animals – is there an animal model
`we can trust?
`Dr S Gizurarson (University of Iceland and Lyfjathróun
`Biopharmaceuticals, Iceland) addressed the use of animal
`models in terms of selection of the right species, based on
`anatomical and physiological factors complimentary to the
`study objectives. For example, small rodents such as rats are
`amenable to histological examination of the NALT because
`inspired air passes over the area of interest in both rats and
`man. Since cats and sheep contain a large amount of fluid
`in the nose, drugs can precipitate in the nasal cavity and
`interfere with measuring irritation. Pharmacokinetics with
`frequent sampling may be easier in larger animals such as
`rabbits, dogs and sheep. On the other hand, rats and
`guinea-pigs are suitable for determining flux across the
`nasal mucosa. For evaluating new devices, Dr Gizurarson
`suggests using dogs, minipigs, sheep and primates. How-
`ever, primates are best for assessing regional distribution of
`the spray, as the flow of air and mucus is most similar (due
`to anatomical and cellular structure).
`Toxicology involving the nasal mucosa should include both
`short-term and long-term studies, as the surface can regener-
`ate in some species. Dr Gizurarson also suggested that some
`species are capable of building resistance to nasal irritants. In
`addition, Dr Gizurarson’s presented an irritation model using
`
`2.2 The challenges of bringing an established
`European product to the US market
`Dr H Nilsson (AstraZeneca R&D, Sweden) shared the lessons
`learned from bringing Rhinocort Aqua (budesonide) into
`the US Market. Three guidances were highlighted in Dr Nils-
`son’s presentation: Q1A Stability Testing of New Drug Sub-
`stances and Products, ICH August 2001; Container Closure
`Systems and Packaging of Human Drugs and Biologics
`July 1999; and Nasal Spray and Inhalation Solution, Suspen-
`sion and Spray Drug Products Chemistry, Manufacturing and
`Controls July 2002.
`Based on his interactions with the FDA, Dr Nilsson rec-
`ommended a pre-New Drug Application (NDA) meeting
`with the Agency. In defining the product, one should allow
`for batch variability to create space for setting of specifica-
`tions. In addition, the specification limits should be reasona-
`ble and data-driven. The methods used to characterise the
`product should, if possible, be standard and known to the
`FDA. One should be prepared to work closely with suppliers
`and utilise all consulting opportunities during development
`and/or before NDA submission. Finally, Dr Nilsson sug-
`gested that the product should not change after Phase II
`clinical trials.
`
`2.3 Difficulties in the development of an intranasal
`flu vaccine
`Dr R Glück (Berna Biotech Ltd, Switzerland) presented clini-
`cal experiences with a heat-labile enterotoxin (LT)-adjuvanted
`intranasal vaccine. Nasalflu® (Berna Biotech Ltd) is an inacti-
`vated influenza vaccine, composed of influenza antigens in a
`virosomal formulation with Escherichia coli-derived LT adju-
`vant. Vaccination required two doses separated by 1 week.
`Clinical evaluation determined that Nasalflu generated
`immunogenicity. Safety evaluations indicated that Nasalflu
`was locally well-tolerated and had systemic side effects that
`were comparable to the licensed intramuscular vaccines.
`Uncommon adverse reactions associated with the nasal vac-
`cine included a temporal association with Bell’s palsy. Bell’s
`palsy is a one-sided paralysis of facial muscles of sudden and
`unknown cause.
`The vaccine was registered in Europe in 2000/2001 and
`~ 100,000 doses were administered. Between October 2000
`and March 2001, 56 transient cases of Bell’s palsy were
`reported in patients vaccinated with Nasalflu. The pathogene-
`sis of Bell’s palsy is not well-defined and may be associated
`with viral infection, trauma, metabolic disorders and toxins.
`Retrospective case-controlled studies indicated that the inci-
`dence of the adverse reaction were in line with the normal rate
`of incidence as reported in the literature. Nevertheless, Berna
`and the Swiss Medic Agency decided to withdraw Nasalflu
`from the market. Additional prospective studies are ongoing
`to compare Nasalflu with a parenteral vaccine.
`
`520
`
`Expert Opin. Biol. Ther. (2003) 3(3)
`
`Opiant Exhibit 2094
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 3
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`

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`3. New therapies in nasal drug delivery
`
`3.1 PT-141: a melonacortin agonist for the treatment
`of male and female dysfunction
`Dr A Shadiack (Palatin Technologies, US) presented an
`overview of the development of PT-141 from animal studies
`through Phase II clinical studies. Melanocortins are associ-
`ated with a variety of functions including grooming, yawn-
`ing, inflammation, feeding and sexual function. PT-141,
`which binds to receptors in the hypothalamus, is a seven
`amino acid analogue of the peptide α-melanocyte-stimulat-
`ing hormone (α-MSH). Biological activity studies indicated
`that PT-141 induces penile erection in male rats and mon-
`keys and increases proceptive sexual behaviour in female
`rats. Phase I safety studies revealed that the intranasal dose is
`proportional to onset and duration of action. No serious
`adverse effects were found during dose escalation studies.
`The nasal bioavailability of PT-141 is ~ 14%. Phase II stud-
`ies demonstrated an increase in erectile function in men
`compared with placebo (> 60%), and an increase in vaginal
`blood flow to women compared with the placebo (> 63%).
`No increases in systemic blood pressure were found. Clinical
`trials are ongoing.
`
`3.2 Nasal drug delivery opportunities in pain
`management therapeutics
`Dr D Wermeling (Intranasal Technology, Inc., USA) provided
`a comprehensive overview of opiate analgesics for intranasal
`administration. Agents to treat acute pain should be potent
`and possess good aqueous solubility, especially at higher con-
`centrations. The pH of the formulation should be between
`4 and 6. In addition, opiates used for acute pain should be
`lipophilic to rapidly cross the nasal mucosa and achieve an
`onset of action within 5 – 20 min.
`The devices used to deliver the dose should be appropriate
`for the clinical setting. For example, a hospital pharmacy is
`more likely to administer unit dose medications. On the other
`hand, an ambulatory patient is likely to require a multi-dose
`device. Potent analgesics, such as fentanyl, necessitate accurate
`and precise dosing to prevent adverse drug reactions. Formu-
`lations should be sterile to guard against infection in immu-
`nocompromised individuals such as cancer patients. Finally,
`the device should prevent diversion and limit abuse potential.
`
`3.3 Pain management – migraine
`Dr B Charlesworth (AstraZeneca, UK) presented results
`from studies that investigated the pharmacokinetic and bio-
`logical response to zolmitriptan (Zomig®, AstraZeneca)
`nasal spray. A positron emission tomography study was con-
`ducted in six human subjects to study the distribution of
`zolmitriptan in the nasopharynx, gut, lung and brain follow-
`ing nasal administration. Plasma levels of zolmitriptan and
`its active metabolite were also measured. Nearly 100% of
`the dose deposited within the nasal cavity. At 5 min post-
`dose, zolmitriptan appeared in the plasma due to rapid
`
`Suman
`
`absorption from the nose. No drug was present in the gut
`at 5 min.
`Because zolmitriptan is absorbed orally, a four-way cross
`over study (tablet, tablet + charcoal block, nasal spray and
`nasal spray + charcoal block) was conducted to determine
`the percentage of the dose absorbed from the nasal cavity.
`The results indicated that the area under the curve (AUC)
`for the nasal spray + charcoal was 29% of that for the nasal
`spray alone.
`A randomised, double-dummy study involving ~ 1500
`patients indicated that the biological response in terms of pain
`relief postdose may be attributed to rapid absorption of zol-
`mitriptan from the nasal cavity. In addition, the headache
`response over time may be attributed to delayed plasma con-
`centrations of the active metabolite from the nasal spray com-
`pared with the oral tablet.
`
`3.4 Nasal penetration of particles and their use for
`delivery of drugs
`Professor O Alpar (University of London, UK) presented
`strategies for improving nasal delivery of peptides, proteins
`and vaccines through the use of particles such as bioadhesive
`starch microspheres, poly(lactide-co-gycolide) microparticles
`and liposomes. Particle uptake was investigated by radiola-
`belled microspheres, confocal laser scanning microscopy,
`modified Ussing chamber and cell culture.
`
`4. New device concepts and in vitro
`spray characterisation
`
`4.1 An update on bidirectional nasal delivery: flow
`modelling and clinical results
`Dr P Djupesland (OptiNose AS, Norway) described a new
`concept for targeting the nasal cavity. The device (OptiMist)
`contains two nozzles, one that is inserted into the mouth and
`one nozzle that is inserted into a nostril. As a patient exhales
`through the device, the soft palate closes and seals off the nasal
`cavity. Exhaled air mixes with the formulation in the device
`and exits through the nosepiece into the nasal cavity. Because
`the nasal cavity is closed, inhaled air flows along one side of
`the nasal cavity and exits through the opposing nasal passage.
`This mechanism allows OptiNose to minimise lung deposi-
`tion (< 1% of the total dose deposited in the lungs after bidi-
`rectional delivery compared to a nasal nebuliser which
`deposited 23% of the total dose in the lungs) and maximise
`distribution of aerosolised droplets in the nose.
`Clinical results were shown from a nasal vaccination trial
`in humans that compared serum titres in volunteers that
`received a) diphtheria antigen (Ag) from a nasal spray pump,
`b) diphtheria Ag plus adjuvant from a nasal spray pump, or
`c) diphtheria Ag plus adjuvant using OptiNose’s technology.
`Preliminary results indicated that the bidirectional device
`significantly increased serum titre levels compared to the
`spray pump (diphtheria Ag alone). Additional clinical studies
`are ongoing.
`
`Expert Opin. Biol. Ther. (2003) 3(3)
`
`521
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
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`Nasal Drug Delivery
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`4.2 Preservative-free nasal sprays: what technology
`should be selected and how should it be evaluated?
`Guillaume Brouet (Valois Pharm, France) highlighted the
`challenges associated with formulating a preservative-free,
`multi-dose, nasal spray suspension. Eliminating preservatives
`can reduce nasal irritation and allergies, and reduce any poten-
`tial effects on mucociliary clearance. In Germany, the use of
`benzalkonium chloride (BKC) was banned in nasal products.
`BKC is the most commonly used preservative, especially in the
`US market. While this may make formulation development
`easier, removing preservatives may make registration of Euro-
`pean products into the US much more challenging.
`Delivery system technology for unit dose nasal sprays is
`readily available. However, multi-dose, preservative-free sys-
`tems are still being evaluated. The attributes of a preservative-
`free system include protection of the product during storage,
`no need to protect the nosepiece between uses and avoiding
`contamination through air uptake into the device. Strategies
`for designing a preservative-free aqueous spray pump include
`use of mechanical seals (obturation), bacteriostatic agents
`such as silver ions, filtering systems within the device to
`extract contaminants, and negative pressure within the con-
`tainer. Mr Brouet presented the results from an assessment of
`a Valois multi-dose spray with a self sealing nozzle (obtura-
`tion) controlled by hydraulic pressure. The device contained a
`preservative-free beclomethasone suspension stored at room
`temperature. Elimination of BKC had a negative influence on
`suspension stability. However, the self sealing actuator main-
`tained sterility after microbial challenge tests.
`
`4.3 In vitro tests on nasal delivery systems – a
`practical guide
`Dr J Suman (Next Breath, LLC, USA) presented an overview
`of the FDA Guidance: Nasal Spray and Inhalation Solution,
`Suspension and Spray Drug Products Chemistry, Manufac-
`turing and Controls July 2002. The talk focused on practical
`applications for measuring in vitro spray characteristics such
`as spray pattern, plume geometry, droplet sizing by laser dif-
`fraction and cascade impaction and pump delivery.
`
`5. Nose to brain transport – fact or fiction
`
`Conventional drug uptake into the brain and cerebrospinal
`fluid (CSF) occurs via transport from the systemic circulation
`across the blood–brain barrier (BBB). A few recent publica-
`tions [1-5] have introduced and debated the concept that direct
`transport into the CSF may occur via the olfactory region
`located in the superior regions of the nasal cavity. Transport
`can occur either along the olfactory neuron (intraneuronal) or
`between junctions in the olfactory epithelium (extraneuro-
`nal). This topic, bypassing the BBB through the nose, sparked
`a rather heated debate at the Nasal Drug Delivery Confer-
`ence. The following sections summarise the research that was
`presented during this session. A summary of the discussion, as
`well as the opinion of the author, appears in section 6.
`
`5.1 Sniffing neuropeptides: a transnasal approach to
`the human brain
`Dr W Kern (Medical University of Luebeck, Germany)
`described three studies that were performed in human sub-
`jects that indicate, in his opinion, drug transport is occur-
`ring directly from the nose into CSF. In those studies,
`volunteers were dosed using a traditional nasal spray pump.
`Plasma and CSF samples were drawn during each study
`visit. The nasal spray was administered while the volunteers
`were sitting upright.
`Three neuropeptides were administered: melanocortin, insu-
`lin and vasopressin, which effect learning, memory and body
`weight regulation through receptor interactions in the brain.
`Of interest, are the profiles for intranasal insulin. Within
`10 min after dosing, insulin concentrations increase from base-
`line levels in the CSF to an average value of ~ 22 pmol/l,
`whereas insulin blood levels are no different from the placebo
`and do not increase after intranasal delivery. Vasopressin levels
`also rapidly increased in both the CSF and serum after intrana-
`sal administration. A 10 mg dose of melanocortin
`(α-MSH 4-10) produced an AUC of 515 ng.min/ml in the
`CSF compared to an AUC of 11 ng.min/ml in serum [1]. Like
`insulin, MSH levels rapidly increased in the CSF within
`10 min, while serum levels remain near baseline.
`
`5.2 Transport of non-peptide drugs from the
`nose to CSF
`Dr P Merkus (Academic Hospital of Vrije University, Neth-
`erlands) presented the results from a patient study where
`patients received intranasal and intravenous administration
`of hydroxocobalamin or melatonin. The study population
`consisted of postoperative patients with no history of ana-
`tomical disorders in the nose. The formulations were admin-
`istered to supine patients using traditional spray pumps.
`CSF and plasma levels were measured on each study day.
`The results for hydroxocobalamin, a hydrophilic drug,
`indicated a similar increase in AUC in the plasma and CSF
`following both modes of administration (nasal and intrave-
`nous). The difference in AUC was ~ 2-fold at 180 min post-
`dose. For melatonin, which is a lipophilic drug, both the
`AUC in the CSF for the two routes of administration were
`nearly superimposable. Dr Merkus indicated that the results
`from these studies provided no evidence for a nose to brain
`pathway in humans.
`
`5.3 Nose to brain transport – fact or fiction
`Dr F Merkus (Leiden University, The Netherlands and
`Innoscience Technology, Belgium) provided a historical
`perspective regarding the potential nose to brain pathway.
`Among the studies presented, Dr Merkus discussed a study
`by Tenk et al. [6] in which patients inhaled nasal mida-
`zolam. There was an attempt to correlate time to maximum
`concentration (tmax) with sleep onset. The tmax for the 5 mg
`dose was 8 ± 1 min, whereas the tmax for the 10 mg dose was
`10 ± 5 min. At 8 min, two of five patients had fallen asleep
`
`522
`
`Expert Opin. Biol. Ther. (2003) 3(3)
`
`Opiant Exhibit 2094
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
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`Suman
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`with the low dose, while only one patient had fallen asleep
`with the 10 mg spray. At 10 min, a larger per cent of
`patients (four of five) fell asleep with the 10 mg spray.
`Dr Merkus indicated that this was, in his opinion, due to
`systemic concentrations of midazolam and not due to a
`pathway into the brain.
`
`6. Expert opinion
`
`The Nasal Drug Delivery Conference covered topics ranging
`from selection of animal models during preclinical develop-
`ment to providing strategies and tips for interacting with the
`FDA. By far the most interesting and controversial topic was
`the possibility of direct brain transport via the nose. The opin-
`ions of the audience were varied, but nonetheless very strong.
`There were those who believed that transport along or around
`an olfactory neuron is absolutely not possible, while others
`acknowledged that direct transport into the CSF is possible.
`The three presentations by Dr W Kern, Dr P Merkus and
`Dr F Merkus were difficult to compare because of the model
`compounds that were selected. Selection of an appropriate
`compound is the key to determining whether a neuronal
`pathway exists. Ideally, the drug should not cross the BBB, in
`order to avoid confounding results. Admittedly, properties
`that facilitate absorption via the olfactory region increase the
`probability that the drug does cross the BBB. If the drug is
`absorbed into the brain via the bloodstream either from the
`nose or gut (due to clearance from the nasal cavity), study
`arms should be included to determine the contribution from
`bloodstream. For example, a charcoal block could be used to
`rule out absorption from the gastrointestinal tract.
`
`Of the data that was presented, the most promising evi-
`dence indicating that an olfactory pathway exists is the study
`performed with insulin. Insulin is poorly absorbed from the
`nasal cavity and not absorbed in the gut. The fact that insulin
`was measured in the CSF within 10 min after nasal adminis-
`tration, in the author’s opinion, demonstrates that absorption
`occurred via an extraneuronal pathway. While insulin does
`cross the BBB, the rate at which this occurs is likely to be
`slower than direct uptake into the brain. However, this does
`not mean that the levels achieved in the CSF are within a
`therapeutic range.
`While a pathway to the brain may exist, there are several
`important issues that should be addressed in future studies.
`Bioavailability through olfactory transport has been reported
`to be around 0.01% – 0.1% in humans [3]. If one can achieve
`a therapeutic response at those levels, then the product is via-
`ble (provided it makes financial and clinical sense to waste
`> 99% of the drug). Secondly, the studies discussed in
`section 5 used traditional spray pumps, which likely deposited
`very little, if any, drug in the olfactory region. One must ask
`the question, could transport increase by targeting the supe-
`rior regions of the nasal cavity, and is it worth developing a
`device to achieve deposition in the olfactory region? (It should
`be noted that smaller particles have a greater chance of reach-
`ing the olfactory region; however, the percentage of particles
`that bypass the nose and deposit in the lung could increase as
`particle size decreases [7]).
`It goes without saying that more information needs to be
`produced to demonstrate the feasibility of direct nose to brain
`transport. Nevertheless, the studies presented at this meeting
`sparked the interest of all those in attendance.
`
`Bibliography
`BORN J, LANGE T, KERN W,
`1.
`MCGREGOR G, BICKEL U, FEHM H:
`Sniffing neuropeptides: a transnasal
`approach to the human brain. Nat. Neurosci.
`(2002) 5(6):514-516.
`
`2.
`
`FREY W: Bypassing the blood brain barrier
`to deliver therapeutic agents to the brain and
`spinal cord. Drug Del. Tech. (2003)
`2(5):46-49.
`
`3.
`
`ILLUM I: Transport of drugs from the nasal
`cavity to the central nervous system. Eur. J.
`Pharm. Sci. (2000) 11:1-18.
`
`7.
`
`4. MERKUS P et al. Neurology (2003).
`
`5. MATHISON S, NAGILLA R,
`KOMPELLA U: Nasal route for direct
`delivery of solutes to the central nervous
`system–fact or fiction? J. Drug Target. (1998)
`5:415-441.
`
`6.
`
`TENK et al.: Pharmaceutisch Weekblad
`(2003) 138:99-103.
`
`SUMAN JD, LAUBE BL, DALBY R:
`Comparison of nasal deposition and
`clearance of aerosol generated by a nebulizer
`and aqueous spray pump. Pharm. Res.
`(1999) 16:1648-1652.
`
`Affiliation
`Julie D Suman RPh, PhD
`Next Breath, LLC, 1450 South Rolling Road,
`Baltimore, Maryland 21227, USA
`Tel: +1 410 455 5904; Fax: +1 410 455 5966;
`E-mail: julie.suman@nextbreath.net
`
`Expert Opin. Biol. Ther. (2003) 3(3)
`
`523
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`Opiant Exhibit 2094
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 6
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