Advanced Drug Delivery Reviews 29 (1998) 89–116
`
`L
`
`Effects of physicochemical properties and other factors on systemic nasal
`drug delivery
`
`*
`C.R. Behl , H.K. Pimplaskar, A.P. Sileno, J. deMeireles, V.D. Romeo
`Nastech Pharmaceutical Company, Inc.,45 Davids Drive, Hauppauge, NY 11788,USA
`
`Received 5 April 1996; accepted 4 March 1997
`
`Keywords: Nasal delivery; Physical chemical properties; Absorption factors; Intranasal drug delivery; Nasal solutions; Nasal
`gels; Nasal powders
`
`Contents
`
`1. Introduction ............................................................................................................................................................................
`2. List of nasal products ..............................................................................................................................................................
`2.1. Prescription nasal drug products ........................................................................................................................................
`2.2. Over the counter nasal drug products .................................................................................................................................
`2.3. Non-drug nasal products ...................................................................................................................................................
`2.4. Drugs currently under investigation ..................................................................................................................................
`3. Relevant anatomical features and rationale behind nasal drug delivery ........................................................................................
`4. Advantages and limitations of nasal drug delivery .....................................................................................................................
`4.1. Advantages of nasal drug delivery .....................................................................................................................................
`4.2. Limitations of nasal drug delivery .....................................................................................................................................
`5. Physicochemical properties of drugs which affect their nasal delivery .........................................................................................
`5.1. Drug molecular weight and size ........................................................................................................................................
`5.2. Drug solubility and dissolution rate ...................................................................................................................................
`5.3. pK and the partition coefficient of drug.............................................................................................................................
`a
`5.4. Chemical state: prodrugs ..................................................................................................................................................
`5.5. Physical state: particle size and morphology.......................................................................................................................
`5.6. Polymorphism .................................................................................................................................................................
`6. Formulation properties which affect nasal drug delivery.............................................................................................................
`6.1. Types of dosage forms and delivery systems ......................................................................................................................
`6.1.1. Nasal drops............................................................................................................................................................
`6.1.2. Solution sprays ......................................................................................................................................................
`6.1.3. Suspension sprays ..................................................................................................................................................
`6.1.4. Powders ................................................................................................................................................................
`6.1.5. Gels ......................................................................................................................................................................
`6.1.6. Emulsions and ointments ........................................................................................................................................
`6.1.7. Specialized systems, e.g. microspheres, liposomes, etc. .............................................................................................
`6.2. Drug concentration, dose and volume of administration ......................................................................................................
`6.3. Physical form of formulation ............................................................................................................................................
`6.4. Formulation pH ...............................................................................................................................................................
`6.5. Formulation osmolarity ....................................................................................................................................................
`
`90
`90
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`
`*Corresponding author. Tel.: 1 1 516 2730101; fax: 1 1 516 2730252.
`
`0169-409X/ 98/ $19.00 (cid:211)
`1998 Elsevier Science B.V. All rights reserved.
`P I I S0169-409X( 97 )00063-X
`
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`
`6.6. Formulation excipients .....................................................................................................................................................
`6.6.1. Solubilizers............................................................................................................................................................
`6.6.2. Buffer components .................................................................................................................................................
`6.6.3. Antioxidants ..........................................................................................................................................................
`6.6.4. Flavor/taste ...........................................................................................................................................................
`6.6.5. Preservatives..........................................................................................................................................................
`6.6.6. Humectants............................................................................................................................................................
`6.6.7. Gelling/ viscofying agents.......................................................................................................................................
`6.6.8. Absorption promoters .............................................................................................................................................
`7. Biological factors which affect nasal drug absorption.................................................................................................................
`7.1. Nasal blood flow ..............................................................................................................................................................
`7.2. Enzymatic activity in the nose...........................................................................................................................................
`7.3. Physical condition of the nasal mucosa ..............................................................................................................................
`7.4. Volume of administration..................................................................................................................................................
`7.5. Site of deposit of formulation in the nose ...........................................................................................................................
`8. Profile of an ‘ideal’ drug candidate for nasal delivery.................................................................................................................
`9. Considerations in the design of a new chemical entity for nasal delivery .....................................................................................
`References ..................................................................................................................................................................................
`
`107
`107
`107
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`108
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`
`1. Introduction
`
`The most desirable and convenient method of drug
`administration is the oral route and the most favored
`dosage forms include tablets, capsules and solutions
`because of their ease of manufacture and administra-
`tion. Failure to systemically deliver select com-
`pounds through the oral route led to research on
`alternate routes of drug delivery. Lack of adequate
`absorption through the gastrointestinal tract was the
`single most predominant reason for such efforts.
`Researchers resorted to the parenteral route as an
`easy solution to the problem. Absorption through the
`intravenous route is not an issue and other parenteral
`routes, e.g. intramuscular and subcutaneous, provide
`satisfactory delivery of most drugs. For the past few
`decades, the transdermal route has been explored for
`a number of drugs. Much has been learned about this
`route, but its use is limited due to understandably
`low permeability of the skin to many drugs.
`Recently, focus has been on the nasal mucosa as
`an alternate route to achieve faster and higher drug
`absorption. Knowledge of the nasal mucosa’s high
`permeability and use of the nasal route for drug
`administration can be traced to ancient times. Reali-
`zation of the nasal mucosa as a therapeutically viable
`alternate route came in the last two decades. The
`nasal route was considered more seriously for sys-
`temic drug delivery with the early work of Hussain
`et al. [1] where the nasal absorption of propranolol
`was found to be comparable to the intravenous route
`in the Rat Perfusion Model. Convenient and practical
`experimental models were later developed to further
`
`study nasal absorption of drugs. This area of drug
`delivery received additional attention with a timely
`seminar organized by Dr. Y.E. Chien in 1984 [2].
`The seminar entitled ‘Intranasal Drug Administration
`for Systemic Medications’ was instrumental in plac-
`ing nasally administered medications at the forefront
`of drug delivery. Two books, one written by Chien
`[3] in 1985 and another by Chien et al. [4] in 1989
`provided a comprehensive review of the subject
`matter and a direction for other researchers to follow.
`The development of nasal drug products is still
`faced with many challenges. A better understanding
`of how the properties of drug molecules, formulation
`matrices,
`the nasal mucosa itself and the drug
`delivery systems affect drug absorption through the
`nasal route,
`is invaluable. The whole process of
`determining the feasibility of a drug candidate for
`nasal delivery begins with appropriate and adequate
`preformulation studies leading to the development of
`potential nasal products which are stable, safe and
`effective. This chapter will discuss some pertinent
`and important issues to be considered in this regard.
`
`2. List of nasal products
`
`2.1. Prescription nasal drug products
`
`Table 1 contains a list of marketed nasal prescrip-
`tion drug products. As can be seen, a total of 14
`brand products covering 12 drugs are on the market,
`of which half are for seasonal or perennial allergic
`rhinitis. The latest product, Miacalcin, was intro-
`
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`91
`
`Table 1
`List of prescription nasal products currently on the market
`
`Drug
`
`Indication
`
`Manufacturer
`
`Symptomatic treatment of seasonal
`and perennial allergic rhinitis
`Symptomatic treatment of seasonal
`or perennial allergic rhinitis
`Management of symptoms of
`seasonal and perennial allergic
`rhinitis and non-allergic perennial
`rhinitis
`Management of pain including
`migraine headache pain
`Post-menopausal osteoporosis
`Symptomatic prevention and
`treatment of seasonal or perennial
`rhinitis
`Prevention and control of
`polydipsia, polyurea, and
`dehydration in patients with
`diabetes insipidus
`Hemophilia A, von Willebrand’s
`disease (type 1)
`Treatment of inflammatory nasal
`conditions or nasal polyps
`Symptomatic treatment of seasonal
`or perennial rhinitis
`Management of seasonal and
`perennial rhinitis
`Central precocious puberty;
`endometriosis
`Promote milk ejection in breast
`feeding mothers
`Treatment of seasonal and perennial
`allergic rhinitis
`
`Allen and Hanbury’s/Glaxo
`Wellcome Inc.
`Schering Plough Corp.
`
`Astra USA, Inc.
`
`Bristol Myers Squibb
`
`Sandoz Pharmaceutical Corp.
`Fisons Corp. Prescription
`Products
`
`Rhone Poulenc Rorer
`
`Rhone Poulenc Rorer
`
`Merck and Co., Inc.
`
`Roche Laboratories
`
`Allen and Hanbury’s/Glaxo
`Wellcome Inc.
`Roche Laboratories
`
`Sandoz Pharmaceutical Corp.
`
`Rhone Poulenc Rorer
`
`No.
`
`1
`
`2
`
`3
`
`4
`
`5
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`Product
`Beconase(cid:210) AQ Nasal Spray
`
`Vancenase(cid:210) AQ Nasal Spray
`
`Rhinocort(cid:210) Nasal Inhaler
`
`Beclomethasone
`dipropionate monohydrate
`Beclomethasone
`dipropionate monohydrate
`Budesonide
`
`Stadol NS(cid:210) Nasal Spray
`
`Miacalcin(cid:210) Nasal Spray
`Nasalcrom(cid:210) Nasal Solution
`
`Butorphanol tartrate
`
`Calcitonin — salmon
`Cromolyn sodium
`
`DDAVP(cid:210) Nasal Spray
`
`Desmopressin acetate
`
`Stimate(cid:210) Nasal Spray
`
`Desmopressin acetate
`
`Decadron(cid:210) Phosphate Turbinaire(cid:210)
`
`Dexamethasone
`
`Nasalide(cid:210) Nasal Solution
`
`Flunisolide
`
`Flonase(cid:210) Nasal Spray
`
`Synarel(cid:210) Nasal Solution
`
`Syntocinon(cid:210) Nasal Spray
`
`Nasacort(cid:210) Nasal Inhaler
`
`Fluticasone propionate
`
`Nafarelin acetate
`
`Oxytocin
`
`Triamcinolone acetonide
`
`Sources: Physicians’ Desk Reference for Nonprescription Drugs, 1994, 15th ed., published by Medical Data Production Company, Montvale, NJ, and Handbook
`of Nonprescription Drugs, 1993, 10th ed., published by The American Pharmaceutical Association, Washington, DC.
`
`duced in 1995. Although the number of marketed
`nasal products for systemic effect
`is small,
`it
`is
`expanding. As advances are made in formulation
`science and technology, more drugs will become
`viable candidates for nasal delivery. From a market
`standpoint, current prescription nasal drug products
`approach sales in excess of one billion dollars per
`year. This amount is expected to increase dramatical-
`ly over the next several years.
`
`2.2. Over the counter nasal drug products
`
`Table 2 contains a list of marketed non-prescrip-
`tion nasal drug products. There are currently more
`than 30 such over-the-counter (OTC) nasal products
`for the symptomatic treatment of a variety of con-
`
`ditions. Several of these products were introduced in
`recent years. This number may increase as some
`nasal drug products are switched from prescription to
`OTC status.
`
`2.3. Non-drug nasal products
`
`A total of 12 non-drug nasal products are currently
`marketed which do not require FDA approval (Table
`3). These products are sodium chloride solutions.
`
`2.4. Drugs currently under investigation
`
`A review of the literature [5–15] [16–25] [26–36]
`[37–46] [47–52] indicates that at least 45 drugs have
`
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`
`Table 2
`List of over the counter (OTC) nasal drug products currently on the market
`
`Drug
`
`Indication
`
`Nasal decongestant
`Nasal decongestant
`Prompt and prolonged relief of nasal
`congestion due to common colds,
`sinusitis, hay fever etc.
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`due to the common cold, sinusitis,
`hay fever or other upper respiratory
`allergies
`Temporary relief of nasal congestion
`due to the common cold, sinusitis,
`hay fever or other upper respiratory
`allergies
`Temporary relief of nasal congestion
`due to the common cold, sinusitis,
`hay fever or other upper respiratory
`allergies
`Temporary relief of nasal congestion
`due to the common cold, sinusitis,
`hay fever or other upper respiratory
`allergies
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`
`Manufacturer
`
`Parnell
`Parke Davis
`Ciba Consumer
`Pharmaceuticals
`
`Schering Plough
`Healthcare Products
`
`Schering Plough
`Healthcare Products
`
`Schering Plough
`Healthcare Products
`
`Schering Plough
`Healthcare Products
`
`Schering Plough
`Healthcare Products
`
`Schering Plough
`Healthcare Products
`
`Roberts Pharmaceutical
`Corporation
`
`Schering Plough Healthcare
`
`Schering Plough
`Healthcare Products
`
`Bristol Myers Squibb
`
`Sterling Health
`
`Sterling Health
`
`Ciba Consumer
`Pharmaceuticals
`
`Proctor and Gamble
`
`Ciba Consumer
`Pharmaceuticals
`
`No.
`
`1
`2
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`Product
`Pretz-D(cid:210) Nasal Drops
`Adrenalin(cid:210) Chloride
`Privine(cid:210) Nasal Spray, Nasal
`Solution and Nasal Drops
`
`Afrin(cid:210) Cherry Scented
`Nasal Spray (0.05%)
`
`Afrin(cid:210) Nasal Spray
`Pump (0.05%)
`
`Afrin(cid:210) Extra Moisturizing
`Nasal Spray (0.05%)
`
`Afrin(cid:210) Menthol Nasal
`Spray (0.05%)
`
`Ephedrine
`Epinephrine hydrochloride
`Naphazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Afrin(cid:210) Nose Drops (0.05%)
`
`Oxymetazoline hydrochloride
`
`Afrin(cid:210) Children Strength
`Nose Drops (0.025%)
`
`Cheracol(cid:210) Nasal Spray
`Pump Cherry Scented
`
`Duration(cid:210)
`12 hour Nasal
`Spray (0.05%)
`
`Duration(cid:210)
`12 hour Nasal
`Spray Pump
`
`4-Way(cid:210) Long Lasting Nasal
`Spray
`
`NTZ(cid:210) Long Acting Nasal
`Spray and Drops (0.05%)
`
`Neo-Synephrine(cid:210) Maximum
`Strength 12 hour Nasal Spray
`and Nasal Spray Pump
`(0.05%)
`Nostrill(cid:210) Long Acting Nasal
`Decongestant
`
`Vicks(cid:210) Sinex(cid:210) Long Acting
`Decongestant Nasal Spray
`and Ultra Fine Mist
`Allerest(cid:210)
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`Oxymetazoline hydrochloride
`
`AQUESTIVE EXHIBIT 1039 page 0004
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`

`C.R. Behl et al. / Advanced Drug Delivery Reviews 29(1998)89–116
`
`93
`
`Table 2. Continued
`
`No.
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`Product
`
`Drug
`
`Indication
`
`Benzedrex 12 hour Nasal
`Spray
`
`Oxymetazoline hydrochloride
`
`Dristan(cid:210)
`Spray
`
`12 hour Nasal
`
`Oxymetazoline hydrochloride
`
`Sinarest(cid:210) Nasal Spray
`
`Oxymetazoline hydrochloride
`
`Neo-Synephrine(cid:210) Nasal
`Sprays, Pediatric, Mild,
`Regular and Extra Strength
`
`Nostril(cid:210) Nasal Decongestant,
`Mild and Regular Strength
`
`Sinex(cid:210) Regular
`Vicks(cid:210)
`Decongestant Nasal Spray
`and Ultra Fine Mist
`Alconefrin(cid:210) Nasal Drops
`and Spray
`
`Benzedrex(cid:210) Nasal Spray
`
`Phenylephrine hydrochloride
`
`Phenylephrine hydrochloride
`
`Phenylephrine hydrochloride
`
`Phenylephrine hydrochloride
`
`Phenylephrine hydrochloride
`
`Dristan(cid:210) Nasal Spray
`
`Phenylephrine hydrochloride
`
`Dristan(cid:210) Menthol
`
`Phenylephrine hydrochloride
`
`Rhinall(cid:210) Nasal Spray and
`drops
`
`4-Way(cid:210)
`Fast Acting Nasal
`Spray (regular/mentholated)
`
`Phenylephrine hydrochloride
`
`Phenylephrine hydrochloride,
`naphazoline hydrochloride,
`pyrilamine maleate
`
`Benzedrex(cid:210) Nasal Inhaler
`
`Propyl hexedrine
`
`Otrivin(cid:210) Nasal Spray and
`Drops
`
`Xylometazoline hydrochloride
`
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`associated with colds, hay fever and
`sinusitis
`Temporary relief of nasal congestion
`due to the common cold, sinusitis,
`hay fever or other upper respiratory
`allergies
`Temporary relief of nasal congestion
`due to the common cold, sinusitis,
`hay fever or other upper respiratory
`allergies
`Temporary relief of nasal congestion
`due to colds, hay fever, upper
`respiratory allergies or sinusitis
`Temporary relief of nasal congestion
`due to colds, hay fever, upper
`respiratory allergies or sinusitis
`Temporary relief of nasal congestion
`due to colds, hay fever, upper
`respiratory allergies or sinusitis
`Temporary relief of nasal congestion
`due to colds, hay fever, upper
`respiratory allergies or sinusitis
`Temporary relief of nasal congestion
`due to colds, hay fever, upper
`respiratory allergies or sinusitis
`Temporary relief of nasal congestion
`due to colds, fever, upper respiratory
`allergies or sinusitis
`Temporary relief of nasal congestion
`due to the common cold, sinusitis,
`hay fever or other upper respiratory
`allergies
`Temporary relief of nasal congestion
`due to colds, hay fever, upper
`respiratory allergies or sinusitis
`Nasal decongestant
`
`Manufacturer
`
`Menley and James
`
`Whitehall Labs.
`
`Ciba Consumer
`Pharmaceuticals
`
`Sterling Health
`
`Ciba Consumer
`Pharmaceuticals
`
`Proctor and Gamble
`
`Polymedica
`
`Menley and James
`
`Whitehall Labs, Inc.
`
`Whitehall Labs, Inc.
`
`R P Scherer
`
`Bristol Myers Squibb
`
`Menley and James
`
`Ciba Consumer
`
`Otrivin(cid:210)
`Drops
`
`Pediatric Nasal
`
`Xylometazoline hydrochloride
`
`Nasal decongestant
`
`Pharmaceuticals
`Ciba Consumer Pharmaceuticals
`
`Sources: Physicians’ Desk Reference for Nonprescription Drugs, 1994, 15th ed., published by Medical Data Production Co., Montvale, NJ and Handbook of Nonprescription Drugs, 1993,
`10th ed., published by The American Pharmaceutical Association, Washington, DC.
`
`been or are being evaluated in humans for nasal
`delivery (Table 4). The list is not comprehensive
`because of ongoing investigational studies that are
`not always reported. Although most of these drugs
`
`may not reach the market place, it demonstrates the
`level of interest in the area of nasal drug delivery. A
`major focus of present research efforts is on the nasal
`delivery of injectable only peptide/protein drugs.
`
`AQUESTIVE EXHIBIT 1039 page 0005
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`

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`
`Table 3
`List of over the counter (OTC) non-drug products on the market
`
`No
`
`1
`
`Product name
`Afrin(cid:210)
`
`Saline Mist
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`8
`9
`10
`11
`12
`
`AYR(cid:210)
`Saline Mist
`and Nose Drops
`
`Nasal Moist(cid:210)
`
`TM
`NaSal Moisturizer AF
`Nasal Spray and Drops
`Ocean Mist
`
`Salinex(cid:210) Nasal Mist
`and Drops
`
`Dey-Vial(cid:210)
`Sodium Chloride Solution
`Dristan(cid:210)
`Saline Nasal Spray
`Humist(cid:210)
`Saline Nasal Spray
`Nebu-Sol(cid:210)
`Sodium Chloride Solution
`Pretz(cid:210) Nasal Solution
`Sodium Chloride Nasal Solution 3% and 10%
`
`Indication
`
`Provides soothing moisture to dry
`inflamed nasal membranes due to
`colds, allergies, low humidity and
`other minor nasal irritations
`Restores vital moisture to provide
`prompt relief for dry, crusted and
`inflamed nasal membranes due to
`chronic sinusitis, colds, low
`humidity, overuse of nasal
`decongestant drops and sprays,
`allergies, and other minor
`nasal irritations
`Used for dry nasal membranes caused
`by chronic sinusitis, allergy,
`asthma, dry air and oxygen therapy
`Immediate relief of dry nose
`
`Rhinitis Medicamentosa, Rhinitis
`Sicca and Atrophic Rhinitis
`Temporary relief of nasal congestion,
`sneezing, itchy and watery eyes and
`running nose due to cold, hay fever
`or other upper respiratory allergies
`Immediate relief of dry nose
`Immidiate relief of dry nose
`Immediate relief of dry nose
`Immediate relief of dry nose
`Immediate relief of dry nose
`Immediate relief of dry nose
`
`Manufacturer
`
`Schering Plough
`Healthcare Products
`
`B.F. Ascher
`and Company
`
`Blairex Laboratories,
`Inc.
`
`Sterling Health
`
`Fleming and Company
`
`Muro Pharmaceutical
`Inc.
`
`Dey Laboratories
`Whitehall LaboratoriesInc.
`R P Scherer
`Dey Laboratories
`Parnell
`Dey Laboratories
`
`3. Relevant anatomical features and rationale
`behind nasal drug delivery
`
`Researchers became interested in the nasal route
`for the systemic delivery of medication due to the
`high degree of vascularization and permeability of
`the nasal mucosa. Cauna [53] reported that the blood
`supply to the nasal cavity was studied and accurately
`described, at least in general terms a long time ago.
`Kolliker [54] in 1852, Kohlrausch [55] in 1853, and
`Zuckerkandl [56] in 1884 identified a rich capillary
`network in the subepithelial zone and around the
`nasal glands, and a cavernous plexus deep to the
`glandular zone. It was not until 1935 that additional
`information was added to this knowledge base
`[57,58]. Several researchers have studied the ana-
`tomical and physiological aspects of the nasal mem-
`brane, including its vascular nature, as they relate to
`drug delivery [53,59–66]. The nasal cavity is highly
`vascularized and its membrane can be classified into
`
`two types: olfactory and non-olfactory. The olfactory
`epithelium is a pseudostratified columnar structure. It
`consists of specialized olfactory cells, supporting
`cells, serous and mucosal glands. The non-olfactory
`part is a vascular membrane. Its surface is covered
`by ciliated pseudostratified columnar epithelium.
`It should be stressed that the blood supply to the
`nasal mucosa is pertinent with regard to systemic
`drug delivery. The arterial blood supply to the nasal
`cavity is derived from both the external and internal
`carotid arteries. The terminal branch of the maxillary
`artery supplies the sphenopalatine artery, which in
`turn supplies the lateral and medial wall of the nasal
`chamber. The anterior and posterior ethmoid branch-
`es come from the ophthalmic artery, which is a
`branch of the carotid artery. These vessels supply the
`anterior portion of the nose. Additionally, twigs from
`the facial artery supply the vestibule and the anterior
`portion of the septum. Some vessels from the greater
`palatine artery pass through the incisive canal of the
`
`AQUESTIVE EXHIBIT 1039 page 0006
`
`

`

`Table 4
`List of investigational nasal products
`
`C.R. Behl et al. / Advanced Drug Delivery Reviews 29(1998)89–116
`
`No.
`
`Drug
`
`Status
`
`Indication
`
`95
`
`Reference
`
`1
`
`2
`3
`4
`5
`6
`7
`
`8
`
`9
`
`10
`
`11
`12
`13
`14
`
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`25
`26
`
`27
`
`28
`29
`
`30
`
`31
`32
`
`33
`34
`
`Adrenocorticotropic hormone (ACTH)
`
`Human studies
`
`Atropine sulfate
`Azelastine nasal spray
`Buprenorphine hydrochloride
`Chlorpheniramine maleate
`Chlorprophenpyridamine maleate
`Clonazepam
`
`Human studies
`FDA advisory committee approval
`Human studies
`Human studies
`Human studies
`Human studies
`
`Cocaine hydrochloride
`
`Human studies
`
`Cyanocobalamin (vitamin B12) nasal gel
`
`NDA submitted
`
`Deferoxamine mesylate
`
`Human studies
`
`Diphenhydramine hydrochloride
`Doxylamine succinate
`Ergotamine tartrate
`17-Beta estradiol
`
`Fenoterol
`Gentamicin
`Glucagon
`Gonadotropin releasing hormone agonists
`Gonadotropin releasing hormone
`Growth hormone (GH)
`Hexarelin
`Interferon
`Insulin
`Ipratropium bromide
`
`Leuprolide acetate
`Luteinizing hormone releasing
`hormone (LHRH)
`Meclizine hydrochloride
`
`Metoclopramide hydrochloride
`Midazolam
`
`Mupirocin
`
`Neostigmine bromide
`Nicotine
`
`Nifedipine
`Nitroglycerin
`
`Human studies
`Human studies
`Human studies
`Human studies
`
`Human studies
`Human studies
`Human studies
`Human studies
`Human studies
`Human studies
`Human studies
`Human studies
`Human studies
`Human studies
`
`Human studies
`Human studies
`
`Human studies
`
`Human studies
`Human studies
`
`Human studies
`
`Human studies
`Recently approved drug
`product in the USA and
`Europe
`Human studies
`Human studies
`
`Diagnostic of adrenocortical
`insufficiency, anti-inflammatory
`and immunosuppressant
`Treatment of peptic ulcer disease
`Seasonal allergic rhinitis
`Relief of moderate to severe pain
`Antihistaminic agent
`Antihistaminic agent
`Treatment of Lennox-Gastaut Syndrome
`(Petit Mal Variant), akinetic and
`myoclonic seizures
`Local anesthesia of accessible mucus
`membranes of the oral, laryngeal,
`and nasal cavities
`Maintainance and replacement treatment
`of patients with vitamin B12 malabsorption
`Treatment of acute iron intoxication
`and of chronic iron overload due to
`transfusion dependent anemias
`Antihistaminic and antitussive agent
`Nighttime sleep aid
`Treatment of migraine
`Management of moderate to severe
`vasomotor symptoms associated
`with menopause
`Beta 2 agonist for the treatment of asthma
`Antibiotic
`Treatment of hypoglycemia
`Treatment of ovarian endometriosis
`Maintenance of spermatogenesis
`Induce growth
`Growth hormone releasing agent
`Antiviral agent
`Diabetes mellitus
`Treatment of bronchospasm associated
`with chronic obstructive pulmonary
`disease, including chronic
`bronchitis and emphysema
`Prostatic cancer, endometriosis
`Diagnostic of hypothalamic pituitary
`gonadal axis
`Management of nausea, vomiting
`and dizziness associated with
`motion sickness
`Antiemetic
`Preoperative sedation,
`general anesthetic
`Temporary elimination of nasal
`carriage of S.aureus
`Treatment of myasthenia gravis
`Smoking cessation
`
`Management of vasospastic angina
`Prevention of angina pectoris due
`to coronary artery disease
`
`[5]
`
`[6]
`[7]
`[8]
`[9]
`[10]
`[11]
`
`[12]
`
`[13]
`
`[14]
`
`[15]
`[16]
`[17]
`[18]
`
`[19]
`[20]
`[21]
`[22]
`[23]
`[24]
`[25]
`[26]
`[27]
`[28]
`
`[29]
`[30]
`
`[31]
`
`[22]
`[33]
`
`[34]
`
`[35]
`[36]
`
`[37]
`[38]
`
`AQUESTIVE EXHIBIT 1039 page 0007
`
`

`

`96
`
`C.R. Behl et al. / Advanced Drug Delivery Reviews 29(1998)89–116
`
`Table 4
`List of investigational nasal products
`
`No.
`
`35
`36
`
`37
`
`38
`39
`
`40
`41
`42
`
`43
`44
`45
`
`46
`
`Drug
`
`Norethisterone
`Octreotide acetate
`
`Progesterone
`
`Prophenpyridamine maleate
`Propranolol hydrochloride
`
`Prostaglandins
`Ranitidine hydrochloride
`Scopolamine hydrobromide
`
`Sufentanil citrate
`Tixocortol pivalate
`Vaccines (e.g. influenza,
`para-influenza,measles,
`poliovaccine etc.)
`Vasopressin
`
`Status
`
`Human studies
`Human studies
`
`Human studies
`
`Human studies
`Human studies
`
`Human studies
`Human studies
`Human studies
`
`Human studies
`Human studies
`Human studies
`
`Human studies
`
`palate to reach the anterior part of the nose. The
`veins
`of
`the
`nasal
`cavity
`drain
`into
`the
`sphenopalatine foramen and then into the pterygoid
`plexus. Some other veins accompany the ethmoid
`arteries and join the superior ophthalmic vein. Veins
`which are anterior in the nose drain into the facial
`vein.
`The richly supplied vascular nature of the nasal
`mucosa, coupled with its low barrier to drug permea-
`tion, makes the nasal route of administration attrac-
`tive for a number of drugs, both non-peptide and
`peptide drugs.
`In addition,
`the olfactory region
`provides a potential advantage where by a drug may
`be exposed to neurons that may facilitate its access
`into the cerebral spinal fluid when administered
`intranasally. This topic, however, is still not well
`understood and remains controversial.
`
`Indication
`
`Reference
`
`Contraceptive agent
`To reduce blood levels of growth
`hormone and IGF-I in acromegaly
`patients
`Treatment of amenorrhea and abnormal
`uterine bleeding
`Antihistaminic agent
`Management of hypertension and
`angina pectoris
`Abortive agent
`Treatment of duodenal ulcers
`Prevention of nausea and vomiting
`induced by motion sickness
`Analgesic agent
`Anti-inflammatory agent
`Immunological
`
`Prevent or control polydepsia,
`polyurea and dehydration withdiabetes insipidus
`
`[39]
`[40]
`
`[41]
`
`[10]
`[42]
`
`[43]
`[9]
`[6]
`
`[44]
`[45]
`[46–50]
`
`[51,52]
`
`agents. Some of the major advantages offered by the
`nasal route include:
`
`• rapid absorption, higher bioavailability, therefore,
`lowe