`

`AAPS Advances in the Pharmaceutical Sciences Series
`
`The AAPS Advances in the Pharmaceutical Sciences Series, published in partnership
`with the American Association of Pharmaceutical Scientists, is designed to deliver
`well written volumes authored by opinion leaders and authoritarians from around
`the globe, addressing innovations in drug research and development, and best
`practice for scientists and industry professionals in the pharma and biotech industries.
`For more details and to see a list of titles in the Series please visit
`http://www.springer.com/series/8825
`
`Series Editors
`Daan J.A. Crommelin
`Robert A. Lipper
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`

`Editors
`Parag Kolhe
`Pharmaceutical R&D-BioTx
`Pharmaceutical Sciences
`Pfizer, Chesterfield, MO, USA
`
`Nitin Rathore
`Drug Product Technology
`Amgen, Thousand Oaks
`CA,USA
`
`Mrinal Shah
`LifeCell Corporation
`Bridgewater, NJ, USA
`
`ISSN 2210-7371
`ISBN 978-1-4614-7977-2
`DOI 10.1007/978-1-4614-7978-9
`Springer New York Heidelberg Dordrecht London
`
`ISSN 2210-738X (electronic)
`ISBN 978-1-4614-7978-9 (eBook)
`
`Library of Congress Control Number: 2013948456
`
`© American Association of Phannaceutical Scientists 2013
`This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
`the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
`broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
`storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
`now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection
`with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and
`executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this
`publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's
`location, in its current version, and permission for use must always be obtained from Springer.
`Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations
`are liable to prosecution under the respective Copyright Law.
`The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
`does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
`protective laws and regulations and therefore free for general use.
`While the advice and information in this book are believed to be true and accurate at the date of
`publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for
`any errors or omissions that may be made. The publisher makes no warranty, express or implied, with
`respect to the material contained herein.
`
`Printed on acid-free paper
`
`Springer is part of Springer Science+Business Media (www.springer.com)
`
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`Contents
`
`Part I Formulation Approaches for Sterile Products
`
`1 Basic Principles of Sterile Product Formulation Development ..........
`Martin A Joyce and Leonore C. Witchey-Lakshmanan
`
`3
`
`2 Molecule and Manufacturability Assessment Leading
`to Robust Commercial Formulation for Therapeutic Proteins...........
`Ranjini Ramachander and Nitin Rathore
`
`3 Polymer- and Lipid-Based Systems for Parenteral Drug Delivery.....
`David Chen and Sara Yazdi
`
`4 Formulation Approaches and Strategies
`for PEGylated Biotherapeutics..............................................................
`Roger H. Pak and Rory F. Finn
`
`5 Considerations for the Development of Nasal Dosage Forms.............
`Jason D. Ehrick, Samir A Shah, Charles Shaw, Vitthal S. Kulkarni,
`Intira Coowanitwong, Samiran De, and Julie D. Suman
`
`33
`
`47
`
`61
`
`99
`
`6 Formulation Approaches and Strategies
`for Vaccines and Adjuvants .................................................................... 145
`Kimberly J. Hassett, Pradyot Nandi, and Theodore W. Randolph
`
`Part II Process, Container Closure and Delivery Considerations
`
`7 Challenges in Freeze-Thaw Processing of Bulk Protein Solutions..... 167
`Hari R. Desu and Sunil T. Narishetty
`
`8 Best Practices for Technology Transfer of Sterile Products:
`Case Studies....................................................................... ...................... 205
`Leonore C. Witchey-Lakshmanan
`
`xiii
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`xiv
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`Contents
`
`9 Transfer Across Barrier Systems: A New Source of Simplification
`in Aseptic Fill and Finish Operations............ ......................... .. ............. 227
`Benoit Verjans
`
`10 Challenges and Innovation in Aseptic Filling:
`Case Study with the Closed Vial Technology................... ..................... 249
`Benoit Verjans
`
`11 Contemporary Approaches to Development and Manufacturing
`of Lyophilized Parenterals. ..... ...... ...... . .......... .. ..... ............. ........ .. ....... .... 27 5
`Edward H. Trappler
`
`12 Advances in Container Closure Integrity Testing................. ..... .......... 315
`Lei Li
`
`13 Pen and Autoinjector Drug Delivery Devices....................................... 331
`Ian Thompson and Jakob Lange
`
`Part III Regulatory and Quality Aspects
`
`14 Particulate Matter in Sterile Parenteral Products............................... 359
`Satish K. Singh
`
`15 Appearance Evaluation of Parenteral Pharmaceutical Products....... 411
`Erwin Freund
`
`16 Sterile Filtration: Principles, Best Practices
`and New Developments............................................................ ............... 431
`Herb Lutz, Randy Wilkins, and Christina Carbrello
`
`17
`
`Intravenous Admixture Compatibility for Sterile Products:
`Challenges and Regulatory Guidance................................................... 461
`Manoj Sharma, Jason K. Cheung, Anita Dabbara,
`and Jonathan Petersen
`
`18 Basics of Sterilization Methods.... ........................ .................................. 475
`Gregory W. Hunter
`
`19 Avoiding Common Errors During Viable Microbial
`Contamination Investigations................................................................ 501
`Kenneth H. Muhvich
`
`20 Validation of Rapid Microbiological Methods (RMMs)...................... 513
`Jeanne Moldenhauer
`
`21 Validation of Moist and Dry Heat Sterilization.................................... 535
`Jeanne Moldenhauer
`
`Index ........................................... ....................................................... ............... 575
`
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`Chapter 5
`Considerations for the Development
`of Nasal Dosage Forms
`
`Jason D. Ehrick, Samir A. Shah, Charles Shaw, Vitthal S. Kulkarni,
`Intira Coowanitwong, Samiran De, and Julie D. Suman
`
`Abstract The anatomy and physiology of the nasal cavity provide unique advantages
`for accessing targets for local, systemic, and potentially central nervous system drug
`delivery. This chapter discusses these advantages and the challenges that must be
`overcome to reach these targets. The chapter then comprehensively reviews nasal
`dosage forms, analytical testing, and regulatory requirements in the context of exist(cid:173)
`ing nasal spray products. Since nasal sprays are moving towards being preservative(cid:173)
`free, the chapter covers specialized methods of achieving a sterile product, namely,
`formulation strategies, manufacturing strategies, and the device landscape that sup(cid:173)
`port this upcoming platform. Finally, the chapter reviews various pathways for regu(cid:173)
`latory approval around the world, for brand and generic, with particular emphasis
`on the growing acceptance of in vitro data for locally acting nasal spray products.
`
`5.1 Introduction
`
`Preservative-free nasal spray drug products represent a small portion of the overall
`drug delivery market. However, the desire to remove preservatives from formula(cid:173)
`tions driven by concerns over potential damage from long-term use coupled with
`innovations in device technology has allowed Pharma companies to consider
`preservative-free nasal sprays as a viable option. In this chapter, an overview of nasal
`
`J.D. Ehrick (t:8J) • S.A. Shah
`Merck & Co., Inc., 556 Morris Avenue, S7-B2-MS 2210, Summit, NJ 07901, USA
`e-mail: jason.ehrick@merck.com
`
`C. Shaw • V.S. Kulkarni
`DPT Laboratories, Lakewood Township, NJ, USA
`
`I. Coowanitwong • S. De• J.D. Suman
`Next Breath, LLC, Baltimore, MD, USA
`
`P. Kolhe et al. (eds.), Sterile Product Development, AAPS Advances in the
`Pharmaceutical Sciences Series 6, DOI 10.1007/978-1-4614-7978-9_5,
`© American Association of Pharmaceutical Scientists 2013
`
`99
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`5 Considerations for the Development of Nasal Dosage Forms
`
`101
`
`The nasal mucosa is lined with stratified squamous, pseudostratified columnar,
`and transitional epithelia cells (Adams 1986). The stratified squamous and transi(cid:173)
`tional types are mainly found in the anterior third of each cavity. Cells in this region
`are neither ciliated nor well vascularized. The columnar type, also known as respira(cid:173)
`tory epithelium, is located in the posterior two thirds. The respiratory region contains
`ciliated cells, mucous secreting goblet cells, and basal cells (Petruson et al. 1984).
`The respiratory epithelium is also highly vascularized, innervated, and drained
`by an extensive lymphatic network (Pontiroli et al. 1989; Schipper et al. 199l).
`The olfactory epithelium, which contains cells that provide a sense of smell, is
`located near the superior turbinate and adjacent to the nasal septum (Schipper et al.
`1991). The main function of the nose is to warm and humidify inspired air and to
`filter inhaled, potentially toxic or infectious, particles from the airstream (Pontiroli
`et al. 1989). Thus, the nasal cavity primarily acts as a defense mechanism by pro(cid:173)
`tecting the lower respiratory tract (Andersen and Proctor 1983).
`Inhaled particles or droplets are thought to deposit in the nose by three mecha(cid:173)
`nisms: inertial impaction, gravitational sedimentation, and Brownian diffusion
`(Brain and Valberg 1979; Newman et al. 1982; Gonda and Gipps 1990). Of these,
`inertial impaction is the most predominant for two main reasons. First, the air pas(cid:173)
`sageway constricts sharply approximately 1.5 cm into the nose at the nasal ostium
`(Mygind 1985). This constriction accelerates the inhaled air and increases turbu(cid:173)
`lence (Yu et al. 1998). Secondly, the air stream must change direction at this con(cid:173)
`striction to enter the turbinate region. Particles that are large or moving at high
`velocity cannot follow the air stream as it changes direction due to their high
`momentum. Such particles continue in their original direction of travel and impact
`the airway walls, particularly at the leading edge of the turbinates. Because the
`drug-laden droplets for most aqueous nasal sprays are so large (30-60 µm) (Chien
`et al. 1989), a high percentage of the spray impacts in the anterior third of the nasal
`cavity (Hardy et al. 1985). However, droplets that are smaller than 10 µm may
`bypass the nasal cavity and deposit in the lower respiratory tract, which may be
`deemed as a risk by regulatory agencies.
`A particle that deposits on the nasal mucosa may exert a local effect and/or be
`absorbed into the blood stream. Absorption is facilitated by a highly vascularized,
`large surface area with relatively low enzymatic activity. Since blood leaving the
`nasal cavity bypasses the liver, first pass hepatic metabolism can be avoided, mak(cid:173)
`ing the nose a suitable target for drugs with low oral bioavailability. However, cyto(cid:173)
`chrome P-450-dependent monooxygenase has been reported to metabolize
`compounds in the nasal mucosa such as cocaine and progesterone (Dahl and Hadley
`1983; Brittebo 1982).
`Nasal absorption can be rapid. Concentration vs. time profiles similar to intrave(cid:173)
`nous administration have been reported for nicotine and butorphanol (Henningfield
`and Keenan 1993; Bristol Myers Squibb Company 1999). Absorption is thought to
`take place primarily in the respiratory zone (posterior, ciliated two thirds) of the
`nasal cavity. However, the absorption rate at specific deposition sites has not been
`clearly defined (Vidgren and Kublik 1998). Animal studies have shown that drugs
`can be absorbed through transcellular and paracellular passive absorption, carrier(cid:173)
`mediated transport, and by transcytosis (Bjork 1993; McMartin et al. 1987).
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`102
`
`J.D. Ehrick et al.
`
`Caution should be exercised when extrapolating results from animal models to
`man, according to some published literature (Illum 2000). Rats, rabbits, sheep,
`pigs, dogs, and monkeys have all been used as models for nasal drug absorption. In
`man, the surface area/body weight ratio is 2.5 cm2/kg (Illum 2000). The surface
`area/body weight ratios for the animals above range from 7. 7 to 46 cm2/kg except
`for sheep that have a ratio of 0.2 cm2/kg (Illum 2000). In addition, animal's nasal
`cavities are structurally different than man because they lack a third turbinate. To
`deliver nasal sprays into the nose of many of these animals, the animal needs to be
`anesthetized or sedated, which also can affect drug absorption. In short, animal
`models produce absorption results that fail to accurately predict the results in man
`(Illum 2000).
`The nose filters undesirable chemicals and bacterial and viral particles from the
`inhaled airstream. Particles depositing in the anterior regions are physically removed
`from the nose by wiping, blowing, or sneezing. Although these regions (nasal ves(cid:173)
`tibule and leading edge of the turbinates) are non-ciliated, some of the surfaces are
`covered with mucus. Here mucus flow is slow, 1-2 mm/h, and occurs mainly due to
`its connection to the mucus layer in the posterior nose (Hilding 1963).
`Unabsorbable particles that adhere to the mucus layer that lines the respiratory
`epithelium are swept towards the nasopharynx by ciliated cells through a process
`called mucociliary clearance. They are ultimately swallowed.
`The mucus layer is predominately aqueous (90--95 % ). However, glycoproteins
`in mucus give it a gel-like structure. The velocity of mucus transport in ciliated
`regions is about 6 mm/min (Andersen and Proctor 1983). Particles that partition into
`mucus or deposit on its surface are typically removed from the nasal cavity in
`20 min (Andersen and Proctor 1983). Obviously, physical removal of particles
`either by wiping the nose or by mucociliary clearance is a major component of the
`nose's defense mechanism. For drug delivery, these processes can oppose local drug
`activity or absorption.
`The rate of mucociliary clearance can be altered by pathophysiology such as a
`common cold or cystic fibrosis, environmental conditions that affect the mucus con(cid:173)
`tent, by drug-induced side effects, or potentially by excipients found in nasal spray
`formulations. A controversial example of such an excipient is benzalkonium chlo(cid:173)
`ride (BAC) which is used to prevent microbial growth. A review of BAC (Marple
`et al. 2004) studies suggest that BAC may cause changes to ciliary beat frequency,
`ciliary morphology, mucociliary clearance or may potentially damage the epithelial
`lining. However, after assessing all the literature, the reviewers concluded that BAC
`is safe to use in nasal spray formulations. A more thorough discussion of use of
`BAC in formulations is presented later in this chapter (Sect. 5.4).
`When delivering drugs to the nose, one must consider the interplay between the
`formulation, device, and the patient. These three factors greatly affect where the
`drug-laden droplets or drug particles deposit within the nasal cavity. The site of
`deposition in the nose is recognized as one of the keys to success or failure of nasal
`drug therapy. Although this concept is widely recognized (Vidgren and Kublik
`1998), only one study actually relates deposition pattern to biologic response
`(Harris et al. 1986).
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`5 Considerations for the Development of Nasal Dosage Forms
`
`103
`
`Table 5.1 Initial site of deposition, clearance of radiolabel from the nose, and pharmacokinetics
`of intranasal desmopressin
`
`Initial deposition site
`Anterior
`Anterior
`Posterior and nasopharynx
`
`Device
`Spray (2x0.05 mL)
`Spray (2x0.l mL)
`Drops (Rhinyle
`catheter)
`244
`1,318
`14
`Posterior and nasopharynx
`Drops (Pipette)
`Results adapted from Harris (1986). Clearance of the radiolabel (99mTc-HSA) was determined by
`acquiring images with a gamma camera over an 8-h period
`
`50 % clearance
`(t112, min)
`240
`120
`20
`
`AUC
`(µgxh)
`3,675
`3,556
`1,599
`
`Cmox (pg/mL)
`675
`587
`316
`
`Pump B
`~
`-Upper
`
`~
`
`-Lower
`
`Pump A -!
`
`\
`
`Inner
`
`Outer
`
`Fig. 5.2 This figure shows gamma scintigraphs following use of Pump A and Pump B in the same
`volunteer. The nasal cavity was divided into a nine region grid. Deposition in the upper, lower,
`inner, and outer regions of the grid was calculated as described previously (Suman 1999). The
`outer region represents the anterior portion of the nasal cavity including the nostrils
`
`This detailed study related deposition pattern, clearance, absorption, and response
`for desmopressin admixed with radiolabeled HSA delivered by sprays and drops
`(Harris et al. 1986). The spray formulation deposited in the front of the nose (ante(cid:173)
`riorly) while the drops covered more surface area. Since the drops covered a larger
`surface area, it seems logical that the drops would have elicited a greater response.
`In fact, the opposite was true. The drops were cleared faster by mucociliary clear(cid:173)
`ance since they deposited in posterior regions of the nasal cavity (where cilia move
`the mucus layer faster). The spray was retained longer, allowing more time for
`absorption of desmopressin to occur (Table 5.1 ). The levels of factor VIII in the
`blood in response to delivery of desmopressin were significantly greater after
`administration with the spray compared to the drops.
`Today's generations of nasal devices typically deposit droplets in the anterior
`portions of the nasal cavity due to inertial impaction and the size and/or velocity of
`the droplets. For example, the deposition patterns from two commonly used nasal
`spray pumps (Suman et al. 2002) were compared in human volunteers. A radiola(cid:173)
`beled nasal nicotine solution was administered in a crossover study. Deposition pat(cid:173)
`tern was determined by gamma scintigraphy. The mean droplet sizes for each of the
`pumps were 47 and 53 µm for Pump A and Pump B, respectively. The results,
`Fig. 5.2, indicated that both pumps produced similar deposition patterns and that the
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`104
`
`J.D. Ehrick et al.
`
`droplets were deposited primarily in the anterior regions of the nose and along the
`floor of the nasal cavity. In this case, the size of the droplets determined the primary
`site of deposition.
`While nasal nebulizers have been shown to cover more surface area in the nasal
`cavity by decreasing droplet size (Suman et al. 1999), a simple reduction in droplet
`size alone does not guarantee an increase in the deposition pattern beyond the ante(cid:173)
`rior nose. Nasal aerosols (Newman et al. 1987b) that utilize propellants to generate
`the spray have been shown to have smaller droplets compared to conventional nasal
`sprays. However, the deposition pattern is even more localized because of the exit
`velocity of the plume. The droplets cannot make the bend in the nasal airway and
`deposit in the front of the nose. This also leads to slower clearance from the nasal
`cavity for the pressurized formulation as the droplets deposit on non-ciliated regions
`of the nose.
`Despite the challenges of delivery and maintaining contact with the nasal epithe(cid:173)
`lium, the nose is a very attractive site for administration for both locally and sys(cid:173)
`temically acting drugs.
`
`5.3 Local vs. Systemic Action
`
`The easy access to the middle meatus and turbinates gives nasal drug delivery a
`unique advantage for local pharmacological action, systemic delivery, and potential
`for nose to brain delivery. The turbinates are richly vascularized and have a large
`surface area, which makes them an ideal target for systemic drug delivery. In addi(cid:173)
`tion, both the olfactory nerve and trigeminal nerve innervate the nasal cavity, which
`makes them a potential target for nose to brain delivery (Dhuria et al. 2009). Drugs
`reaching these targets can be rapidly absorbed across the thin membranes and can
`achieve potentially faster onset of action at lower doses while avoiding the disad(cid:173)
`vantages of oral dosage forms, namely, first pass metabolism and side effects from
`drug interactions with other organs (Dhuria et al. 2009; Laube 2007).
`By delivering directly to sites of action, nasal drug delivery offers greater conve(cid:173)
`nience and safety. It is a noninvasive and a painless method of drug administration,
`encouraging greater compliance compared to other routes of administration.
`Another advantage of nasal drug delivery for patients taking multiple drugs is that a
`nasally delivered drug may act as an adjunct to another drug given orally or intrave(cid:173)
`nously (Behl et al. 1998a; Costantino et al. 2007).
`
`5.3.1 Local Targets for Allergies
`
`For the treatment of allergies, nasal drug delivery can place therapeutic agents
`within close proximity of the middle meatus and turbinates, the sites of inflamma(cid:173)
`tion. Thus sufficiently high levels of potent corticosteroids, antihistamines, or
`decongestants (Newman et al. 2004) can reach receptor sites at the target tissue,
`while systemic blood levels of these drugs are minimized.
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`5 Considerations for the Development of Nasal Dosage Forms
`
`105
`
`Reducing this systemic exposure minimizes well documented side effects
`(Trangsrud et al. 2002; van Drunen et al. 2005). For example, antihistamines are
`known to sedate and interfere with psychomotor abilities. Delivered intranasally,
`these symptoms are absent (Costantino et al. 2007) because the drug does not reach
`the blood. Locally acting drugs have minimal or low bioavailability, and any blood
`levels that are detected have no correlation to efficacy because the drugs act locally.
`Table 5.2 summarizes commercially available prescription treatments for locally
`acting drugs approved in the United States and EU.
`
`5.3.2 Systemic Delivery
`
`In addition to topical treatments, the vascular-rich turbinates lend themselves to
`systemic drug delivery. Absorption in the nose can be rapid, and allows some mol(cid:173)
`ecules to achieve a greater bioavailability compared to oral administration. The tur(cid:173)
`binates have a large surface area and thin membranes. When drug contacts these
`membranes, rapid absorption into the blood occurs (Laube 2007; Newman et al. 2004).
`Unlike oral dosing, this absorption into the blood happens without first undergoing
`enzymatic degradation in the gastrointestinal (GI) tract nor first pass metabolism in
`the liver (other than the small amount that may be swallowed). Bypassing these
`metabolic pathways for poorly absorbed drugs allows comparable or greater blood
`levels, faster onset, and at a lower dose. These advantages (e.g., improved bioavail(cid:173)
`ability, faster onset of action, lower dose) are particularly beneficial for drugs with
`potential toxic effects on the liver. When delivered through the nasal cavity, only a
`fraction of dose that may be swallowed could potentially reach the liver, instead of
`the entire dose when orally administered. When given orally, all drugs that clear the
`gastrointestinal tract are then available for the liver. Systemically acting drugs could
`therefore be more effective and safer when delivered intranasally directly to the
`blood supply within the turbinates.
`Several marketed products use the intranasal route of administration to systemi(cid:173)
`cally deliver drugs for conditions such as pain and osteoporosis. Medlmmue's
`FluMist®, approved in 2003, delivers an annual influenza vaccine intranasally (see
`Product Profile) while Novartis' Miacalcin® and Unigne Laboratories' Fortical® are
`indicated for osteoporosis. Other systemically acting nasal products include pain
`medications for migraines: Imitrex® (sumtriptan nasal spray) marketed by
`GlaxoSmithKline, Migranal® (marketed by Valeant), and Zomig® (marketed
`AstraZeneca) and examples for pain management indications include Sprix® (mar(cid:173)
`keted by Daiichi Sankyo) and lnstanyl® (marketed by Takeda). Refer to Table 5.3
`for a summary of the current commercial prescription landscape for systemically
`delivered nasal products in the United States and EU. Several areas of research and
`development are ongoing for nasal delivery routes of administration including the
`delivery of insulin for treatment of Type 1 diabetes (including Nasulin® under
`development by Cpex Pharmaceuticals) and the treatment of infectious diseases
`(including hepatitis C, HRV/SARS).
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`106
`
`J.D. Ehrick et al.
`
`TableS.2 Commercially available locally acting nasal prescription products in the United States
`and EU as of December 2011 (courtesy of Lauren Seabrooks, Merck and Co., Inc.)
`
`Commercially available Rx locally acting nasal products
`Product
`API
`Delivery Company
`Veramyst
`Fluticasone
`Spray
`GlaxoSmithKline
`Avamys
`Furoate
`Flonase
`Flixonase
`Flunase
`Fluxonal
`Patanase
`
`Spray
`
`GlaxoSmithKline
`
`Fluticasone
`Propionate
`
`Olopatadine
`
`Spray
`
`Alcon
`
`Otrivin
`
`X ylometazoline
`
`Spray
`
`Novartis
`
`Flunisolide
`
`Spray
`
`Hoffmann-La Roche
`
`Triamcinolone
`acetonide
`Azelastine HCl
`
`Aerosol
`
`Sanofi
`
`Spray
`
`Meda
`
`Indication
`Allergic
`Rhinitis
`Allergic
`Rhinitis
`Polyp, nasal
`
`Allergic
`Rhinitis
`Allergic
`Rhinitis
`Allergic
`Rhinitis
`
`Allergic
`Rhinitis
`Allergic
`Rhinitis
`
`Syntaris
`Synaclyn
`Bronalide
`Lunis
`Bronalide
`Rhinalar
`Nasacort HFA
`
`Astepro Azeptin
`Astelin
`Afluon
`Allergodil
`Omnaris AQ
`
`NasacortAQ
`TriN asal Allemaze
`Rhinocort Aqua
`Rhinicortol
`Topinasal
`Pulmicort Nasal
`Budecort Nasal
`Budecort Aqua
`Nasonex
`NasonexAQ
`Nasalcrom
`
`Ciclesonide
`
`Spray
`
`Rhinaaxia
`
`Spaglumic acid
`
`Spray
`
`Triamcinolone
`acetonide
`Budesonide
`
`Spray
`
`Spray
`
`Allergic
`Sunovion
`Pharmaceuticals, Inc. Rhinitis
`Novartis
`Allergic
`Rhinitis
`Allergic
`Rhinitis
`Allergic
`Rhinitis
`Polyp, nasal
`
`AstraZeneca
`
`AstraZeneca
`
`Mometasone furoate Spray
`
`Merck
`
`Cromolyn sodium
`
`Spray
`
`Prestige Brands Inc.
`
`Allergic
`Rhinitis
`Allergic
`Rhinitis
`Rhinorrhea
`
`Atrovent
`
`Ipratropium bromide Spray
`
`Boehringer Ingelheim
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`5 Considerations for the Development of Nasal Dosage Forms
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`Table 5.3 Commercially available systemically acting nasal prescription products in the United
`States and EU as of December 2011 (courtesy of Lauren Seabrooks, Merck and Co., Inc.)
`
`Dihydroergotamine
`Zolmitriptan
`
`Spray
`Spray
`
`Company
`GSK
`
`Indication
`Migraine
`
`Novartis
`AstraZeneca
`
`Migraine
`Migraine
`
`Daiichi Sankyo
`Archimedes
`
`Pain management
`Pain management
`
`Takeda
`AstraZeneca
`
`Pain management
`Vaccine
`
`Commercially available Rx systemic acting nasal products
`Product
`API
`Delivery
`Imigran
`Sumatriptan
`Spray
`succinate
`Imitrex
`Suminant
`Migranal
`AscoTop
`Zomig
`Sprix
`PecFent
`Lazanda
`lnstanyl
`FluMist
`
`Spray
`Spray
`
`Spray
`Spray
`
`Ketorolac
`Fentanyl
`
`Fentanyl
`Cold-adapted
`trivalent influenza
`vaccine (CAIV-T)
`Calcitonin
`Salmon Calcitonin
`Elcatonin
`Calcitonin
`Desmopressin
`
`Calsynar
`Miacalcin
`Fosatur
`Salcatonin
`DDAVP
`Minirin
`Defirin
`Desmoressin
`Adiuretin
`
`Spray
`Spray
`Spray
`Spray
`Spray solution
`(Defirin)
`
`Sanofi
`Novartis
`Therapicon
`Therapicon
`Perring
`
`Osteoporosis
`Osteoporosis
`Osteoporosis
`Osteoporosis
`Diabetes
`insipidus
`
`5.3.2.1 Product Profile: Medlmmune's FluMist® (Influenza Vaccine
`Live, Intranasal)
`
`FluMist® is an annual influenza vaccine that is delivered intranasally (see Fig. 5.3).
`It is a live attenuated influenza vaccination (LAIV, trivalent, types A and B) that is
`preservative-free and contains three live attenuated influenza virus reassortants rec(cid:173)
`ommended by the US Centers for Disease Control and Prevention (CDC) (identified
`for the Northern Hemisphere 2011-2012 flu season as an A/Califomia/7/2009
`(H1Nl)-likevirus;anA/Perth/16/2009(H3N2)-likevirus;andaB/Brisbane/60/2008-
`like virus) (Fiore et al. 2010; Medlmmune, online 2003), the same three CDC(cid:173)
`recommended influenza strains in the traditional flu shot (a needle injection which
`builds up the body's immunity to the flu through antibody production carried in the
`bloodstream-using inactivated (dead) virus (TIV)).
`Once dosed intranasally (one 0.1 mL spray per nostril), the formulation stimu(cid:173)
`lates an immune response by producing antibodies in the lining of the nose where
`the flu virus typically enters the body. FluMist is termed cold-adapted since the virus
`is engineered to replicate efficiently at temperatures below that of the body (25 °C)
`as is the case in the nasal passages (2003). Protective immunity is built up in the
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`5 Considerations for the Development of Nasal Dosage Forms
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`shedding and immune response, along with providing additional revaccination data)
`and one nonclinical commitment (to complete additional reproductive toxicology
`studies) (U.S. Food and Drug Administration, online). FluMist 2011 revenue totaled
`$161 MM and $174 MM for full year 2010 (Astrazeneca, online).
`
`5.3.3 Nose to Brain
`
`Nasal delivery also offers the opportunity to bypass the blood-brain barrier and
`deliver drugs directly to the central nervous system. This barrier prevents systemi(cid:173)
`cally delivered drugs, whether delivered orally, intravenously, or by other routes,
`from reaching significant concentrations in the brain. Two cranial nerves, the olfac(cid:173)
`tory nerve and the trigeminal nerve, pass through the nasal cavity. An intranasally
`delivered drug could use these pathways to reach tissue in the central nervous sys(cid:173)
`tem and achieve levels necessary to be of therapeutic benefit. Additionally, there are
`other potential vascular, cerebrospinal, or lymphatic pathways as routes to the cen(cid:173)
`tral nervous system (Dhuria et al. 2009).
`Currently, no marketed drug products exist that act via nose to brain. One chal(cid:173)
`lenge is targeting deposition of sprayed droplets in the regions where olfactory neu(cid:173)
`rons are located. However, there are research programs to treat Alzheimer's and
`Parkinson's diseases, some of which have shown some success (Dhuria et al. 2009).
`Given the overall difficulties with treating central nervous disease, nose to brain
`delivery could offer a promising way to achieve efficacy while minimizing side
`effects of drugs.
`
`5.3.4 Challenges of Nasal Drug Delivery
`
`Nasally delivering drugs to therapeutic areas of interest can make them more effec(cid:173)
`tive for local action, systemic action, and central nervous system action, at lower
`doses with minimum side effects. However, delivering drug to the specific regions
`of interest is challenging. As mentioned previously, these challenges arise because
`the winding and narrow geometry of the nasal airways filter most droplets into the
`anterior third of the cavity (Kimbell et al. 2007; Laube 2007; Hardy et al. 1985;
`Newman et al. 1987a; Suman et al. 1999; Vidgren and Kublik 1998). Most targets,
`though, are located in the posterior nasal cavity. Even less reach the access points
`for the nerves to the brain in the olfactory region. To overcome these challenges,
`new devices are in development to target drugs specifically to these regions
`(Djupesland et al. 2006). Also with these new devices come challenges to accu(cid:173)
`rately assess how well they deposit within specific areas of the nasal cavity.
`Another challenge with nasal drug delivery is mucociliary clearance. Most drop(cid:173)
`lets landing within the therapeutically beneficial posterior nasal cavity are removed
`by mucociliary clearance