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`ENCYCLOPEDIA OF
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`VOLUME2
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`ENCYCLOPEDIA OF CONTROLLED DRUG DELIVERY
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`Editorial Board
`Howard Bernstein
`Acusphere, Inc.
`Pravin R. Chaturvedi.
`Vertex Pharmaceuticals,Inc.
`Pierre M. Galleti (Deceased)
`Brown University
`Colin Gardner
`Merck Sharpe & Dohme
`Robert Gurny
`University of Geneva
`Yoshito Ikada
`Kyoto University
`Robert §. Langer
`Massachusetts Institute of Technofogy
`
`Rodney Peariam
`MegaBios
`Nicholas Peppas
`Purdue University
`Mark Saltzman
`Corneil University
`Felix Theeuwes
`ALZA Corporation
`
`Editorial Staff
`Publisher: Jacqueline [. Kroschwitz
`Editor: Glenn Collins
`Managing Editor: John Sollami
`Editorial Assistant: Susan O’ Driscoll
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`ENCYCLOPEDIA OF
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`VOLUME2
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`
`
`Edith Mathiowitz
`Brown University
`Providence, Rhode Island
`
`A Wiley-Interscience Publication
`John Wiley & Sons, Inc.
`New York / Chichester / Weinheim / Brisbane / Singapore / Toronto
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`This book is printed on acid-free paper. ©
`
`Copyright © 1999 by John Wiley & Sons, Inc. All rights reserved.
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`Published simultaneously in Canada.
`Nopart of this publication may be reproduced, stored in a retrieval system or transmitted in any
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`appropriate per-copy fee to the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA
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`For ordering and customerservice, call 1-800-CALL-WILEY,
`
`Library of Congress Cataloging-in-Publication Data:
`
`Mathiowitz, Edith, 1952—
`Encyclopedia of controlled drug delivery / Edith Mathiowitz.
`p- cm.
`Includes index.
`ISBN 0-471-14828-8 (set : cloth : alk. paper)—ISBN
`0-471-16662-6 (vol 1: alk. paper)-—ISBN 0-471-16663-4 tvol 2 :
`alk. paper)
`1, Drugs—Controlled release Encyclopedias.
`1. Title.
`[DNLM:1. Drug Delivery Systems Encyclopedias—English.
`Carriers Encyclopedias—English. QV 13 M43le 1999]
`RS201.C64M38 1999
`615.7—de21
`DNLM/DLC
`for Library of Congress
`
`2.Drug
`
`99-24907CIP
`
`Printed in the United States of America.
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`ww9s76é54321
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`3
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`592 (cid:9)
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`MUCOSAL DRUG DELIVERY, NASAL
`
`216. K.R. Liu et al., Ophthalmology 94, 1155-1159 (1987).
`217. G.A. Peyman et al., Retina 7, 227-229 (1987).
`218. M. Diaz-Llopis et al., Doc. Ophthalmol. 82, 297-305 (1992).
`219. S.K. Akula et al., Br. J. Ophthalmol. 78, 677-680 (1994).
`220. C. Le Bourlais et al., J. Microencapsul. 13, 473-480 (1996).
`221. S. Shakiba et al., Invest. Ophthalmol. Visual Sci. 34, 2903-
`2910 (1993).
`222. H.O.C. Gumbel et al., 2nd Int. Symp. Exp. Clin. Oral. Phar-
`macol. Pharm. Munich, Germany, September 11-14, 1997,
`p. 16.
`223. G. Besen et al., Arch. Ophthalmol. (Chicago) 113, 661-668
`(1995).
`224. B.D. Kuppermann et al., J. Infect. Dis. 173, 18-23 (1996).
`225. A.A. Alghadyan et al., Int. Ophthalmol. 12, 109-112 (1988).
`226. B.C. Joondeph, B. Khoobehi, G.A. Peyman, and B.Y. Yue,
`Ophthalmic Surg, 19, 252-256 (1988).
`227. K.K. Assil et al., Invest. Ophthalmol. Visual Sci. 32, 2891-
`2897 (1991).
`228. R.F. Gariano et al., Retina 14, 75-80 (1994).
`229. J. Garcia-Arumi et al., Ophthalmologica 211, 344-350
`(1997).
`230. K.R. Liu et al., Ophthalmic Surg. 20, 358-361 (1989).
`231. T.D. Heath, N.G. Lopez, G.P. Lewis, and W.H. Stern, Invest.
`Ophthalmol. Visual Sci. 28, 1365-1372 (1987).
`232. B. Khoobehi et al., Ophthalmology 95, 950-955 (1988).
`233. B. Khoobehi, G.A. Peyman, M.R. Niesman, and M. Oncel,
`Jpn. J. Ophthalmol. 33, 405-412 (1989).
`234. Y. Ogura et al., Invest. Ophthalmol. Visual Sci. 32, 2351-
`2356 (1991).
`235. G.A. Peyman et al., Int. Ophthalmol. 12, 175-182 (1988).
`236. D. Sarraf and D.A. Lee, J. Ocul. Pharmacol. 10, 69-81
`(1994).
`237. J.M. Hill, R.J. O'Callaghan, and J.A. Hobden, in A.K. Mitra,
`ed., Ophthalmic Drug Deliver), Systems, Dekker, New York,
`1993, pp. 331-354.
`238. L. Hughes and D.M. Maurice, Arch. Ophthalmol. (Chicago)
`102, 1825-1829 (1984).
`239. M. Barza, C. Peckman, and J. Baum, Ophthalmology 93,
`133-139 (1986).
`240. T.B. Choi and D.A. Lee, J. Ocul. Pharmacol. 4, 153-164
`(1988).
`241. P.H. Fishman et al., Invest. Ophthalmol. Visual Sci. 25, 343-
`345 (1984).
`242. V. Baeyens et al., Adv. Drug Deliv. Rev. 28, 335-361 (1997).
`243. N.L. Burstein, I.H. Leopold, and D.B. Bernacchi, J. Oral.
`Pharmacol. 1, 363-368 (1985).
`244. M. Barza, C. Peckman, and J. Baum, Invest. Ophthalmol.
`Visual Sci. 28, 1033-1036 (1987).
`245. R.E. Grossman, D.F. Chu, and D.A. Lee, Invest. Ophthalmol.
`Visual Sci. 31, 909-916 (1990).
`246. M.O. Yoshizumi et al., J. Ocul. Pharmacol. 7, 163-167
`(1991).
`247. R. Grossman and D.A. Lee, Ophthalmology 96, 724-729
`(1989).
`248. T.T. Lam, D.P. Edward, X.A. Zhu, and M.O.M. Tao, Arch.
`Ophthalmol. (Chicago) 107, 1368---1371(1989).
`249. F.F. Behar-Cohen et al., Exp. Eye Res. 65, 533-545 (1997).
`250. T.T. Lam et al., J. Ocul. Pharmacol. 10, 571-575 (1994).
`251. D. Sarraf et al., Am. J. Ophthalmol. 115, 748-754 (1993).
`252. M.O. Yoshizumi et al., Am. J. Ophthalmol. 122, 86-90
`(1996).
`
`253. D.M. Maurice, Ophthalmology 93, 128-131 (1986).
`254. T.T. Lam, J. Fu, and M.O.M. Tso, Graefe's Arch. Clin, Exp,
`Ophthalmol. 223, 389-394 (1991).
`255. A. Albert, Nature 182, 421-423 (1958).
`256. L.L. Christrup, J. Moss, and B. Steffansen, in J. Swarbrick
`and J.C. Boylan, eds., Encyclopedia of Pharmaceutical Tech-
`nology, Dekker, New York, 1996, pp. 39-70.
`257. V.H.L. Lee and V.H.K. Li, Adv. Drug Delivery Rev. 3, 1-38
`(1989).
`258. B. Steffansen, P. Ashton, and A. Buur, Int. J. Pharm. 132,
`243-250 (1996).
`259. I. Taskintuna et al., Retina 17, 57-64 (1997).
`260. S. Shakiba et al., Antimicrob. Agents Chem. 39, 1383-1385
`(1995).
`261. A.S. Berger et al., Invest. Ophthalmol. Visual Sci. 37, 2318-
`2325 (1996).
`262. H. Guo et al., Invest. Ophthalmol. Visual Sci. 35, 1907 (1994),
`
`See also BIOADBESIVE DRUG DELIVERY SYSTEMS;
`MUCOSAL DRUG DELIVERY, BUCCAL; MUCOSAL DRUG
`DELIVERY, NASAL; MUCOSAL DRUG DELIVERY, OCULAR;
`MUCOSAL DRUG DELIVERY, VAGINAL DRUG DELIVERY
`AND TREATMENT MODALITIES.
`
`MUCOSAL DRUG DELIVERY, NASAL
`
`PAOLO COLOMBO
`University of Parma
`Parma, Italy
`
`KEY WORDS
`
`Butorphanol
`Calcitonin
`Desmopressin
`Drug delivery
`Enhancer
`Inhalation
`Insuffintor
`Insulin
`Nasal route
`Particle size
`Powder
`Spray
`Sumatriptan
`
`OUTLINE
`
`Introduction
`Nasal Delivery: Historical and Behavioral Use
`Anatomy and Physiology of the Nose
`Toxicological Considerations
`Dosage Forms and Materials
`Metering and Insufflators
`Qualitative and Quantitative Aspects of Nasal Dose
`Delivery
`
`AQUESTIVE EXHIBIT 1037 page 0005
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`

`

`Penetration Enhancers and Bioadhesion
`Drugs Developed for Nasal Administration
`Butorphanol
`Calcitonin
`Dihydroergotamine
`Sumatriptan
`Desmopressin
`Cromolyn Sodium
`Steroid Drugs
`The Insulin Case and Future Developments: Vaccines
`and Brain Targeting Through the Nose
`Acknowledgments
`Bibliography
`
`INTRODUCTION
`
`This article intends to update the state of the art of nasal
`drug delivery from a pharmaceutical and technological
`point of view. Many important contributions can be found
`in literature on the subject, focusing on different aspects
`of interest to researchers, such as the Proctor edited book
`(1), the edited and directly contributed books of Chien (2,3),
`and the reviews of Mum (4), Wilson (5), Edman (6), Merkus
`(7), Gizurarson (8), Duchene (9), Harris (10), Buri (11), and
`Alpar (12),
`A Nasal Drug Delivery Focus Group, organized in an
`American Association of Pharmaceutical Scientists section
`(13), has also been constituted as well as an Open Forum
`for free exchange and information in all R and D areas
`ranging from the formulation to the marketing of nasal
`preparations.
`
`NASAL DELIVERY: HISTORICAL AND BEHAVIORAL USE
`
`New materials and new technologies have stimulated
`pharmaceutical researchers to identify and use alterna-
`tives to the classical oral and injectable routes. One of the
`routes currently being studied is the nasal way, even
`though the physiological evolution of the nose followed the
`olfactive and respiratory necessity to provide humid,
`warmed, and filtered air for the lungs. In fact, nasal mu-
`cosa evolved in order to have a wide surface, large blood
`supply, and efficient filtering system. Because the mucosa
`is often affected by various diseases that alter its function-
`ality, the first nasal drug delivery system was for restoring
`normal nasal conditions. Man discovered the possibility of
`using nasal mucosa for absorbing substances giving sys-
`temic effects. Unfortunately, the most convincing examples
`of systemic effects obtained by administering active prin-
`ciples inside the nose were those which misused the nose,
`such as the behavioral habit of sniffing cocaine or tobacco.
`An instructive behavioral employment of the nose for drug
`absorption, usually in order to have hallucinations or more
`general mental effects, is the religious rite of the Amazo-
`nian population of Yanomamo to assume epeiza , that, is a
`Powdered mixture of different plant parts like Mimosa aca-
`cioides , Piptadenia peregrina, and others not identified
`(14). The interest of this rite for pharmaceutical research-
`ers is linked to the administration devices the natives use
`
`MUCOSAL DRUG DELIVERY, NASAL (cid:9)
`
`593
`
`in order to deposit the powdered drug in the nose (Fig. 1).
`The devices consist of an insufflator having the form of a
`long linear pipe activated by an assistant or, alternatively,
`a Y-shaped curved tube which allows for self-
`administration. These "medical devices" focalize the typi-
`cal aspect of nasal delivery that is the need for a nebulizer
`or an insuffiator for depositing solid or liquid formulations
`into the nose.
`All these uses, or misuses, of the nose for systemic drug
`delivery have provided a lot of important information as to
`the employment of the nasal route for therapeutically drug
`delivery. The effects, and in particular, the toxicity mani-
`fested by the mucosa in response to drug deposition are of
`paramount importance for setting the therapeutical deliv-
`ery of drugs in terms of safety and efficacy. From these
`experiences it is worthwhile underlining some aspects that
`are particularly useful for the design of therapy and dosage
`form for the nose. The rapid onset of the effect is linked to
`high mucosa permeability and indicates using the nose for
`therapies requiring prompt response. Then, the maniacal
`use of the nose because of the effects involving the brain
`opens the possibility of directly reaching the brain after
`deposition on the olfactory mucosa. Finally, the fact that
`drugs are successfully administered in powder form in-
`creases the formulation possibilities for designing the ap-
`propriate dosage farm.
`
`ANATOMY AND PHYSIOLOGY OF THE NOSE
`
`The nose is characterized by two nasal cavities, separated
`by a septum and divided into three main regions: vestibule
`(nostril), atrium (or preturbinate region), and turbinate re-
`gion (15). The last region is composed of an olfactory upper
`part and of two respiratory medium and lower parts that
`join together in the rhinopharynx. The turbinate region is
`characterized by cornets and meati, gaps situated between
`cornets and the nasal external part. The nostrils are the
`entry of the nasal cavity.
`The nose presents sensitive, vegetative, and sensorial
`nervous conduction. The trigeminal nerves respond to al-
`
`Figure 1. Yanomano Indian tribe using the insufflator pipe for
`eperta, nasal administration.
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`594 (cid:9)
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`MUCOSAL DRUG DELIVERY, NASAL
`
`lergic stimulus causing sneezing; the vegetative system
`provides secretory and vasomobility functions, and partic-
`ular elements of the olfactory mucosa control the activity
`of sensorial nerves.
`Nasal cavities are covered by respiratory mucosa that,
`within the nostrils, is characterized by a stratified, squa-
`mous and keratinized epithelium, with hairs, called vi-
`brissae. Beyond the limen nasi, the epithelium loses its
`keratin cover and becomes the respiratory mucosa with
`pluristratified cylindrical epithelium. It is provided with
`vibratile cilia and other mucus secreting cells. Goblet cells
`and submucosa glands produce a high amount of mucus,
`which is the protective barrier against external agents.
`The continuous film of mucus is structured in two layers:
`the lower one is smooth with low viscosity, the upper one
`is more viscous and elastic and moves following the cilia
`movements.
`The nose, which has an extensive vascular network, has
`two main functions: the sense of smell given by the olfac-
`tory mucosa and the inspired air conditioning by purifica-
`tion, heating, and moisture regulation. The greatest par-
`ticles are removed by the vibrissae of the vestibule. Other
`particles are removed by the anatomic structures of the
`nasal cavities. The combined action of the cilia and mucus
`layer is called mucociliary clearance, an important defense
`mechanism against inhaled dust, allergens, and microor-
`ganisms. The coordinated beating of the cilia results in the
`movement of the upper mucus layer towards the naso-
`pharynx, where it is swallowed. Finally, there is an air flow
`control because the respiratory air volumes are monitored
`by the comets, which alternatively change their volume,
`giving a variable resistance to the breathed air.
`
`TOXICOLOGICAL CONSIDERATIONS
`
`The poor nasal bioavailability of many substances (in par-
`ticular, peptide and protein drugs) can be substantially im-
`proved by the use of absorption enhancers. The accepta-
`bility of these enhancers is not only dependent on their
`promoting effect but also on their safety profile for sys-
`temic and local adverse effects (16-21). Nasal drug for-
`mulations must not alter the histology and physiology of
`the nose in the sense that the mucosa must retain its func-
`tionality as a barrier toward external substances and mi-
`croorganisms. In any case, damage induced must be re-
`versible. The histological toxicity refers to the alteration of
`mucosa, including membrane protein removal, cell loss, ex-
`cessive mucus discharge, ciliotoxicity, and disturbance of
`the normal enzymatic balance (22,23). In addition, the dos-
`age form and its components should not interfere with the
`mucociliary clearance.
`Various methods have been used to test the toxicity of
`drugs and additives on the nasal mucosa and the mucocil-
`iary system. Traditionally, histopathological examination
`of a prefixed membrane specimen by light and scanning
`electron microscopy is regarded as the indicator of cytotox-
`icity. These methods suffer from inspector subjectivity and
`the impossibility of highlighting subtle changes in nasal
`mucosa and do not provide the nasal sensitivity tolerance
`measurement in response to a particular formulation.
`
`Therefore, in order to determine minute changes occurring
`in the mucosal tissue due to exposure to formulations, a
`biochemical approach has been developed (24). The extent
`of the release of total proteins, although not very specific
`as to the type of damage, provides a general indication
`about the extent of irritation.
`The release of enzymes lactate dehydrogenase (LDH)
`and 5'nucleotidase (5'-ND), directly indicate the extent of
`damage suffered by the mucosa. Membrane-bound 5'-ND
`release in the nasal perfusate gives an indication of the
`level of membrane perturbation, whereas the cytosolic en-
`zyme LDH indicates cell leaching and/or lysis (25).
`Mucociliary transport and clearance interferences can
`be measured in vivo (26,27) or in vitro (28). Determination
`of ciliary beat frequency in vitro has been carried out on
`explants of ciliated mucosa from human adenoid tissue
`(29), from the trachea of different animal species (30,31),
`or from chicken embryo trachea (32). The frog palate prep-
`aration as an ex vivo model for the mucociliary transport
`velocity study has also been proposed for the indication of
`topical tolerability of different substances (83). Effects on
`the ciliary beat frequency detected in vitro may be more
`pronounced than the influence in vivo. In vitro experi-
`ments directly expose ciliated epithelia to test solution,
`whereas in vivo the cilia are protected by mucus (34).
`Therefore, in vitro ciliary beat frequency tests should be
`used as indicators for potential damage to nasal epithe-
`lium, rather than proof of such damage occurring in the in
`vivo situation. One of the best known in vivo tests is the
`saccharin transit time, i.e., the time required for the sub-
`ject to taste a saccharin particle placed on the inferior tur-
`binate of the naris (35). However, the most powerful
`method used for measuring the deposition and clearance
`of drugs in the nasal cavity remains scintigraphy.
`
`DOSAGE FORMS AND MATERIALS
`
`Nasal dosage forms consist of preparations containing dis-
`persed or dissolved drugs, filled in a container designed to
`be squeezed or spray activated (36). The aim of delivery is
`to deposit the formula on the mucosa and coat the available
`surface, in particular the respiratory part, which is the ma-
`jor absorption site for drugs. Other therapeutic situations
`must require a localized accumulation of the. product in
`certain districts of the nasal cavity. This can be achieved
`through an appropriate design of the insufflator and of the
`formulation to produce a fine dispersion of droplets or par-
`ticles capable of sticking to the mucosa (37). This avoids
`the coalescence of the mist with a backflow of product and
`limits a fast transport to the pharynx by mucociliary clear-
`ance. Therefore, dispersion pattern and bioadhOsion are
`the two key factors to be considered during the develop-
`ment phase of the formulation.
`At present, the application of the product by spraying
`is very elegant and accepted. Therefore, the objective of
`formulation design is to obtain an aerosol useful for inspi-
`ration and deposition in the upper airways. In the past,
`drops were often instilled in the nose, but the advancement
`of insufflator technology has made this form obsolete and
`limited to pediatric use or to patients less able to perform
`
`AQUESTIVE EXHIBIT 1037 page 0007
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`

`the insufflative maneuvers. Liquid preparations are com-
`mon dosage forms for nasal delivery. Because the nasal
`epithelium is essentially a lipophilic transport barrier,
`transnasal transport is related to the nasal mucosa tissue—
`water partition coefficient, suggesting also an important
`role of the stereochemical conformation during membrane
`transport (38). Therefore, aspects such as formula pH,
`ionic strength, surface active agents, viscosity, and drug
`concentration have to be considered in order to facilitate
`the transport (39). However, from a technological point of
`view, the liquid preparations present problems linked to
`formula stability, low drug concentration at the absorption
`site, and short residence time in nasal cavity.
`These drawbacks accelerated the development of nasal
`powders as alternative nasal dosage forms with improved
`chemicophysical and microbiological stability. Further-
`more, drug dissolution on nasal mucosa provides elevated
`drug concentration at the deposition site, giving rise to a
`high flux of active ingredient. In many cases the superi-
`ority of nasal powder compared with nasal liquid was dem-
`onstrated, in particular with peptidic drugs (40-42). Ad-
`ministration of powders requires a nasal insufflator for
`dose emission and deposition of particles in the nose. It has
`been assessed that the site and pattern of inhalatory pow-
`der deposition in the respiratory tract are affected by the
`aerodynamic properties of the powder (43). Moreover, the
`formalities of dose delivery control the deposition mecha-
`nisms, i.e., inertial impacting, sedimentation, and diffu-
`sion. It could be postulated that efficient nasal delivery of
`powder from a spraying device requires impacting with ad-
`hesion and/or sedimentation of particles on nasal mucosa;
`therefore, powder properties such as particle size, shape,
`surface, density, and flow must be optimized to activate the
`proper mechanism for therapeutic treatment. The number
`of drugs directly administrable to the nose in powder form
`is limited because of unsuitable characteristics such as
`large particle size, low solubility, poor absorption, and ir-
`ritability. These limits can be overcome through the use of
`a suitable solid excipient as carrier. Such a carrier must
`be compatible, hydrophilic, soluble, and of an aerodynamic
`particle size favorable to nasal deposition. The most com-
`mon material used are sugars, pcyclodextrin, cyclodextrin
`derivatives, phospholipids, starches, cellulose derivatives,
`poly(vinylpyrrolidone) and others. Swellable polymers
`proved very useful as nasal carriers, because the swelling
`phenomenon was added as a transport enhancing effect.
`Particle size is the main parameter affecting nasal drug
`delivery. It was found that powders around 100 pm in size
`are efficiently delivered in terms of amount and type of
`delivery, when an insufflator device using a gelatin capsule
`as reservoir was used (44). In the particle size range be-
`tween 150 and 50 /um there was an evident change in the
`insufdation behavior: for size over 150 ?rim, the spray pat-
`tern suggested more favorable conditions for impacting the
`nasal mucosa; below 50 ,um, a more uniform deposition by
`sedimentation is expected, but the possibility of particle
`respirability can increase as well. Other formulations used
`for nasal delivery involve nasal gels; one example is vita-
`min 13„ gel, which provides a superior bioavailability com-
`pared with oral delivery (45). A scopolamine gel is expected
`to be filed soon for approval (46).
`
`MUCOSAL DRUG DELIVERY, NASAL (cid:9)
`
`595
`
`METERING AND INSUFFLATORS
`
`Devices for nasal delivery differ according to the formula-
`tion to be dispensed. Liquid solutions are delivered using
`metered atomizing pumps, metered-dose pressurized na-
`sal inhalers, rhinal tubes for variable volume delivery, and
`plastic spray or squeeze bottles (47). Pumps and squeeze
`bottles operate by mechanical actuation to sample a liquid
`volume from a reservoir and to produce a mist cloud having
`the shape of alt inverse cone or of a sagittal plume. The
`use of these devices is usually extensively explained in the
`product leaflets, and the intervention of a pharmacist for
`assembling the nasal spray device is often requested.
`Quantity dispensed and reproducibility are the major
`points to be assessed. Pumps, both mechanically or gas
`actuated, are very precise and accurate in delivery, pro-
`vided that they are primed according to the indications of
`the producer. The delivery rate is very fast because emis-
`sion is usually completed in less that one second. The size
`of droplets produced with these devices prevents the en-
`trance of the preparation into the lung, and their size and
`velocity provide an impacting on the nasal mucosa with a
`distributed deposition. The multidose preparations require
`preservatives in the solution that can alter the mucosa.
`Metered unidose insufflator devices are the technological
`solution to avoiding preservative use. An example of these
`is reproduced in Figure 2. However, considering that there
`are two nostrils and that deposition carried out in both
`nostrils doubles absorption, bidose devices have been de-
`veloped and marketed both by the Pfeiffer (48) and Valois
`(49) companies.
`Powder delivery requires different types of insufflators,
`which can be mechanically or respiratory actuated. The
`user requests are for a small-sized portable device, with
`high spraying performance and visible feedback, moisture
`protected and easy to handle. The mechanically designed
`devices consist of a rubbery bulb connected through the
`dose reservoir to a nasal adapter (Fig. 3). The squeezing of
`the rubbery bulb provides a stream of air capable of emit-
`ting the appropriately loaded powder in the insufflator.
`The insufflators designed to be used by breathing through
`
`Figure 2. Monospray systems for nasal administration of mono-
`close of liquid formulation (Valois Pharm, France).
`
`AQUESTIVE EXHIBIT 1037 page 0008
`
`

`

`5% (cid:9)
`
`MUCOSAL DRUG DELIVERY, NASAL
`
`Figure 3. Different insufflators for nasal administration of pow-
`dered formulations. From left to right: Rinofiatore® (Fisons, Rome,
`Italy), Mint Nasal Insufflator® (Miat, Milan, Italy), Puvlizer ® (Tei-
`jin, Tokyo, Japan).
`
`the nose are a nose adapted version of the dry powder in-
`halers, designed for lung delivery. With both types of de-
`vices, the drug unidose is loaded in a gelatin capsule that
`is pierced just before activation. Because the capsule is lo-
`cated between the air jet producer and the nose adapter,
`the air stream that flows through creates a turbulence in-
`side the capsule, capable of aerosolizing and emitting the
`amount of powder contained. This phenomenon, called
`"dancing cloud" by the Hovione company (50), causes a
`complete, gradual, and efficient emission of the powder
`content of the motionless capsule. The devices loaded with
`gelatin capsule can deliver different amounts of powder
`without adversely affecting their behavior (51).
`
`QUALITATIVE AND QUANTITATIVE ASPECTS OF NASAL
`DOSE DELIVERY
`
`Nasal delivery of a drug requires metering of the dose and
`its emission by means of a device capable of producing an
`aerosol suitable for deposition on nasal mucosa. The words
`cloud, plume, or puff are used indifferently for indicating
`the nasal aerosol. The goal of puff production is to appro-
`priately deposit the drug according to the pathology to be
`treated, which could be for localized or systemic effects. For
`example, a disease such as rhinitis requires a deposition
`on the total area of the mucosa, whereas a targeting to the
`brain would require localized deposition at the roof of the
`nose. Other therapeutic possibilities require the adapta-
`tion of the puff for deposition at different sites.
`In any case, nasal delivery of drug involves both quali-
`tative and quantitative aspects of drug delivered. The
`qualitative aspect refers to the aerodynamic behavior of
`the cloud produced and is described by the spray pattern
`and the cloud geometry, whereas the quantitative aspect
`is linked to the dose of drug sprayed per puff. The quali-
`tative aspect is assessed by photographic technique in or-
`der to obtain the sequence of dose emission from the pump
`or insufflator and to collect information on spray pattern
`and geometry. Plume shape, height, area, density, particle
`
`size, and velocity are the parameters involved in the spray
`pattern and geometry determination.
`In the case of liquid preparations, the qualitative aspect
`is primarily dependent on the device used for insufflation.
`The spray geometry in the case of pump metered-dose in-
`sufflators or squeeze plastic bottles is totally different. It
`is not surprising to find that different geometry can result
`in different bioavailability of the drug. This is probable not
`only when comparing two different types of nasal insuffla-
`tors but also in the case of the same type manufactured by
`different producers. As an example, Figure 4 shows two
`mists of the same liquid formulation produced using two
`similar pumps manufactured by different producers. The
`two preparations were not bioequivalent, because delivery
`with one pump gave a bioavailability 30% lower than the
`reference (C. Vecchio and R. Bettini, University of Parma,
`Department of Pharmacy, personal communication, 1998).
`Registrative health authorities require for droplet size dis-
`tribution determination using two different methods, such
`as laser scattering and cascade impactor. In addition, the
`spray pattern and plume geometry must be compared for
`bioequivalence studies.
`In the case of nasal powder, the powder cloud, which
`looks like a plume emerging from a chimney, grows in di-
`mension during emission, with a maximum height and
`width depending on the characteristics of the product
`sprayed and the device used. The cloud aspect is mainly
`dependent on the formulation's characteristics and, par-
`ticularly, on the fundamental (size and shape) and derived
`(packing and flow) properties of the powder (44). Using a
`rubbery bulb insufflator, the clouds originating from small
`particle size powder are fluffy and homogeneous in density,
`whereas the clouds obtained from large particle size pow-
`ders are characterized by visible individual particle trajec-
`tories (Fig. 5). The rate of particle delivery decreased with
`decreasing size, whereas the time needed to completely
`emit the dose through the nose adapter of the insufflator
`increased with decreasing size. For nasal impacting, the
`powder cloud should remain as compact as possible to
`
`(a)
`
`(h)
`
`Figure 4. Nasal puffs obtained by spraying the same desmopres-
`sin nasal solution through two different metered-dose pumps. Puff
`(a) provided a superior bioavailability compared with puff (b). The
`amounts emitted were not significantly different.
`
`AQUESTIVE EXHIBIT 1037 page 0009
`
`

`

`6.3 - BB (cid:9)
`
`08-125 (cid:9)
`
`125.190 (cid:9)
`
`HBO-250 (cid:9)
`
`250. 355
`
`- 0
`
`Particle size range (,1111)
`
`Figure 5. Influence of nasal powder particle size on the puff ap-
`pearance (Miat Nasal Insufflator).
`
`achieve an efficient shot of powder to the nasal mucosa,
`whereas for sedimentation a larger cloud would be pre-
`ferred. The measurement of the expansion area of the axial
`section of the clouds during emission evaluates the packing
`of the cloud: as the particle size decreased below 100 gm,
`the area of the puff increased (44). Serum progesterone
`levels following nasal administration in rabbits of two
`powder mixtures containing co-ground progesterone-fi-
`cyclodextrin or co-lyophilized progesterone and fi-
`cyclodextrin showed rapid increase (52). Progesterone co-
`grounded powder exhibited a significantly higher extent of
`bioavailability, without a significant difference in rate com-
`pared with the co-lyophilized powder. The progesterone-fl-
`CD co-ground powder was ejected by the insufflator at
`higher speed and as a compact cloud.
`The quantitative aspect of nasal delivery is different ac-
`cording to the physical state of the preparation, i.e., liquid
`or solid, and it is largely dependent on the type of device
`used for spraying. In the case of liquid preparations, there
`are obviously different delivery behaviors according to the
`device used. Metered pumps are designed for delivering a
`very precise and accurate amount of nasal solution. The
`alternative, the squeeze bottle, suffers from a strong de-
`pendence on the energy used in squeezing the bottle in
`order to emit the dose. Therefore, the device affects the
`accuracy of delivery. As an example, a solution of xylome-
`tazoline was delivered in different amounts from squeeze
`bottle by different patients. Figure 6 shows the behavior
`of successive sprays performed by male or female patients:
`it is evident that the males exert more strength in spraying
`than females, because they sprayed out more product per
`shot. The same solution charged in a metered pump device
`is less dependent on the varying strength of the patient,
`as Figure 6 shows as well. Finally, metered pumps are reg-
`ularly used in prescription preparations, and the squeeze
`bottle is the choice for over-the-counter preparations.
`The quantitative aspect of a nasal solution filled in mul-
`tidose reservoir is first tested by the labeled number of
`sprays that must be available using the preparation com-
`pletely. It is also required that the number of priming
`operations to be performed before the device is ready for
`use should be declared. After this preliminary character-
`istic, the content uniformity per spray is a regulatory req-
`uisite. This must be checked from dose to dose, from con-
`tainer to container, and from batch to batch, considering
`
`0.3
`
`0.25
`
`0.2
`
`0 w
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`(T..) 0.15
`0
`
`0.1
`
`0.05
`
`0.3
`
`0.25
`
`01D
`13 0.2
`cu
`c7-; 0.15
`
`C
`
`0.1