REVIEW ARTICLE
`
`Clin Pharmacokinet 2003; 42 (13): 1107-1128
`0312-5963/03/0013-1107/$30.00/0
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Absorption Enhancers for Nasal
`Drug Delivery
`Stanley S. Davis and Lisbeth Illum
`Institute of Pharmaceutical Sciences, University of Nottingham, Nottingham, UK
`
`Contents
`
`Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
`1. Routes of Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
`2. Nasal Administration of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
`2.1 Peptide Drugs as Candidates for Enhanced Nasal Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109
`3. Enhancing the Nasal Absorption of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109
`3.1 Absorption Enhancers – ‘Literature’ Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
`3.2 Absorption Enhancers – Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
`3.3 Attributes of an ‘Ideal’ Absorption Promoter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114
`3.3.1 Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
`3.3.2 Phospholipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
`3.3.3 Nasal Powders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
`3.3.4 Chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1116
`3.3.5 Other Cationic Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
`4. Toxicity of Nasal Formulations Containing Enhancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119
`4.1 Methods to Assess Irritancy and Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119
`4.1.1 Erythocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119
`4.1.2 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119
`4.1.3 Protein Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
`4.2 Cilia Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
`4.3 Nondamaging but ‘Irritant’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
`4.4 Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121
`5. Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121
`5.1 Alniditan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121
`5.2 Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122
`5.3 Calcitonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122
`6. Nasal Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122
`6.1 Diphtheria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122
`6.2 Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123
`7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123
`
`Abstract
`
`This paper describes the basic concepts for the transmucosal delivery of drugs,
`and in particular the use of the nasal route for delivery of challenging drugs such
`as polar low-molecular-weight drugs and peptides and proteins. Strategies for the
`exploitation of absorption enhancers for the improvement of nasal delivery are
`discussed, including consideration of mechanisms of action and the correlation
`between toxic effect and absorption enhancement. Selected enhancer systems,
`such as cyclodextrins, phospholipids, bioadhesive powder systems and chitosan,
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`

`

`1108
`
`Davis & Illum
`
`are discussed in detail. Examples of the use of these enhancers in preclinical and
`clinical studies are given. Methods for assessing irritancy and damage to the nasal
`membrane from the use of absorption enhancers are also described. Finally, the
`mucosal use of absorption enhancers (chitosan) for the improved nasal delivery of
`vaccines is reported with reference to recent phase I/II clinical studies.
`
`1. Routes of Drug Delivery
`
`Drugs can be delivered by a wide variety of
`routes, the choice normally depending on factors
`such as clinical benefit, convenience, cost, the
`properties of the drug and the pharmacokinetic pro-
`file needed. In acute situations, an injectable form
`may be required, whereas for long-term therapy
`noninvasive procedures are preferred. Oral adminis-
`tration is usually the modality of choice. However,
`in some situations, the oral route may not be advan-
`tageous. For example, if rapid onset of effect is
`required, if gastric stasis occurs (e.g. migraine), or if
`a drug is poorly absorbed across the gastrointestinal
`tract or is largely degraded by endogenous pH con-
`ditions or enzymes within the lumen of the intestine,
`and/or by first-pass liver metabolism, then oral ad-
`ministration will not be possible.
`As a consequence, other noninvasive routes of
`delivery have been investigated in recent years.
`These include buccal, nasal and pulmonary routes.
`The buccal mucosa is normally poorly permeable
`and absorption can be slow. Delivery to the lungs
`can provide rapid onset of action but this route is
`often limited by dose, the irritant nature of certain
`compounds and effective administration to reach the
`alveolar region. The nasal route can be the route of
`choice for a wide range of drugs. This route of
`delivery will be discussed in more detail below.
`
`2. Nasal Administration of Drugs
`
`The nasal route has the advantage of providing
`rapid absorption of drugs into the systemic circula-
`tion with consequently little or no degradation (no
`first-pass effect). Many drugs display high bioavail-
`ability by this route, particularly if they have lipo-
`philic characteristics, and there is low inter- and
`intraindividual variability, similar to or lower than
`for a subcutaneous injection. The route is well re-
`
`ceived by patients. Disadvantages of nasal adminis-
`tration include problems associated with irritation,
`taste disturbance and perceived, rather than actual,
`difficulties with administration and absorption
`during attacks of colds and rhinitis. A variety of
`products for the delivery of drugs into the systemic
`circulation via the nose is available in the market
`place. These include treatments for pain, smoking
`cessation and hormone replacement therapy. Prod-
`ucts for erectile dysfunction are in development.
`Nasal administration also has the potential of pro-
`viding direct access to the brain via the olfactory
`region. This aspect of nasal delivery has been re-
`viewed by one of us in detail elsewhere.[1]
`Lipophilic drugs can be expected to demonstrate
`rapid and efficient absorption when given nasally,
`but more polar compounds are poorly absorbed. The
`products of biotechnology in the form of peptides
`and proteins are good examples. In animal models
`and in humans, bioavailabilities of about 1% (versus
`subcutaneous) are to be expected for compounds
`such as insulin, calcitonin or leuprolide, and less for
`higher molecular weight species such as growth
`hormone, interferons and growth factors. Low-mo-
`lecular-weight polar compounds such as morphine
`and sumatriptan, and novel candidates for the treat-
`ment of migraine (e.g. alniditan, zolmatriptan), also
`show poor absorption across the nasal mucosa in the
`order of 10%. Benefit in terms of improved dose
`reliability, reduced dose and reduced adverse effects
`such as taste disturbance could be obtained if it was
`possible to increase the bioavailability of nasally
`administered drugs.
`The poor uptake of drugs from the nasal cavity
`can be associated with three major factors:
`• poor transport across the nasal membrane (as
`discussed above);
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (13)
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`Absorption Enhancers for Nasal Drug Delivery
`
`1109
`
`• possible (enzymatic) degradation in the nasal
`sician’s Desk Reference.[5] Nasal sprays of
`cavity/tissue;
`desmopressin are used for primary nocturnal enure-
`• rapid clearance from the absorption site.
`sis, haemophilia A, von Willebrand’s disease and
`central cranial diabetes insipidus. No figures for
`The second factor is of little consequence for
`bioavailability are quoted, but a statement is made
`most drugs so far studied to date[2] and will not be
`that desmopressin administered nasally has an an-
`discussed further here. However, mucociliary clear-
`tidiuretic effect about one-tenth that of an equivalent
`ance is an interesting problem in nasal drug delivery.
`dose administered by injection.[5] Calcitonin nasal
`In humans, the clearance of mucus from the nasal
`spray is used for the treatment of postmenopausal
`cavity by the mucociliary clearance mechanism has
`osteoporosis. Interestingly, the mean bioavailability
`a half-time of about 15 minutes. Thus, some drugs
`is quoted as approximately 3% of that for the inject-
`may not have sufficient time to be absorbed before
`able product in normal subjects, with peak plasma
`clearance occurs. Indeed, for some drugs adminis-
`concentrations appearing 31–39 minutes after ad-
`tered nasally, much of the dose is subsequently
`ministration (compared with 16–25 minutes after
`swallowed and is absorbed from the gastrointestinal
`parenteral administration). The quoted range of
`tract. Nasal sumatriptan, with a low nasal bioavaila-
`bioavailabilities
`is both broad and surprising
`bility of 16%,[3] is a case in point, where a second
`(0.3–30.6%).[5] The lower value appears reasonable
`peak in the plasma concentration-time profile is
`from studies in animals and literature reports on
`probably due to the gastrointestinal absorption of
`phase I studies and from our own work.[6,7] The
`material cleared from the nose. It is likely that two-
`higher value of over 30% appears to be extraordina-
`thirds of the drug reaching the circulation is ab-
`ry and can most probably be explained by the limita-
`sorbed from the gastrointestinal tract.
`tion in sensitivity of the current bioanalytical meth-
`Formulations that are able to slow down the
`ods of analysis. Naferelin nasal spray is used for
`clearance process of drugs from the nasal cavity can
`endometriosis and central precocious puberty; the
`therefore be advantageous. However, the critical
`quoted average bioavailability is 2.8% (range
`factor for most challenging drugs is one of absorp-
`1.2–5.6%). Nasal products for insulin, growth hor-
`tion across the nasal mucosa and, as a result, consid-
`mone, interferon and parathyroid hormone are re-
`erable effort has been directed towards the develop-
`ported to be in development by various pharmaceu-
`ment of technologies that can improve the rate and
`tical companies.[8]
`extent of transport of drugs across the membrane.
`One strategy is to change the physicochemical
`Hence, low bioavailability can clearly be accept-
`properties of the drug by making it more lipophilic
`able for some marketed products, but advantage
`(e.g. prodrug approach),[4] but this results in a new would be gained in terms of reliability, reduced dose
`chemical entity and all the attendant consequences
`and reduced acquisition costs if nasal absorption
`for regulatory approval. Methods to enhance or pro-
`could be increased. The same situation holds for
`mote absorption by using formulation additives
`polar nonpeptide drugs that are poorly transported
`have therefore been a more popular alternative.
`across mucosal surfaces.
`
`2.1 Peptide Drugs as Candidates for
`Enhanced Nasal Delivery
`
`Various peptide drugs are currently available as
`nasal presentations, albeit often with low bioavaila-
`bility as compared with parenteral (subcutaneous)
`injection;
`examples
`include
`desmopressin,
`gonadorelin and its analogues, and calcitonin. Such
`nasal peptide preparations are described in the Phy-
`
`3. Enhancing the Nasal Absorption
`of Drugs
`
`A wide range of materials is known to modify the
`membrane transport of drugs. Some of these are in
`the form of ‘complexing’ agents that apparently
`alter the properties of the drug molecule and thereby
`aid its passage across the membrane (ion-pair sys-
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (13)
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`1110
`
`Davis & Illum
`
`3.1 Absorption Enhancers –
`‘Literature’ Perspective
`
`absorption of drugs. Many can be classed as mem-
`tems), but the majority have a direct effect on the
`membrane itself by modifying transport processes.
`brane active and have a disruptive effect on both
`transcellular and paracellular pathways. Although
`Drugs can cross biological membranes by two
`main pathways, transcellular (across the cell) and
`such disruption can be associated with increased
`paracellular (between cells). Lipophilic drugs are
`drug transport and increased bioavailability, effec-
`normally transported transcellularly by passive dif-
`tive compounds are often irritant or can be asso-
`fusion or receptor-mediated processes, whereas po-
`ciated with short- or long-term damage to mucosal
`lar drugs are believed to follow paracellular path-
`tissue. For example, some years ago, bile salts and
`ways. In the gastrointestinal tract, there are transport
`their derivatives were heralded as safe and effective
`pathways that facilitate or actively transport certain
`absorption promoters for peptides and proteins, and
`molecules and attempts have been made to exploit
`even today, surprisingly, one sees clinical investiga-
`these for drug delivery.[9] Whether such pathways
`tions using products containing bile salt derivatives.
`can be used for the nasal cavity is debatable. It is However, it is now appreciated that these promoters
`also known that particles can be transported across
`are damaging after long-term use. Similarly, fatty
`mucosal surfaces, often via specialised cells called
`acids and surfactants (detergents) such as Laureth-9,
`M-cells that are part of the immune surveillance while being effective in animal models, cause dam-
`system. Such processes can be important for the
`age and probably have little utility in clinical prac-
`development of particulate mucosal vaccines but
`tice. Newer surfactant materials, such as the acyl
`probably have no relevance for drug delivery.[10]
`carnitines and acyl maltosides, may be less damag-
`Thus, in order to increase the nasal uptake of polar
`ing but could well face regulatory hurdles. The
`drugs from the (human) nasal cavity, agents that can
`‘trick’ is to uncouple a desired improved delivery
`alter paracellular
`transport (and also modify
`from an unacceptable level of membrane damage.
`mucociliary clearance) would be beneficial.
`Even if this goal can be achieved, it will be impor-
`tant to demonstrate that the absorption promoter is
`not toxic if absorbed systemically.
`The older literature on the ‘damaging’ materials
`has been well reviewed elsewhere and will not be
`considered in detail in this article unless there are
`areas for future investigation or anomalies worth
`further consideration. For example, in 1994 Verhoef
`and Merkus[82] considered the relevance of nasal
`absorption enhancement to nasal drug delivery and
`listed various materials and their possible modes of
`action.
`Some materials, particularly surfactants, could
`have more than one effect, e.g. perturbing the cell
`membrane by leaching of membrane proteins, open-
`ing of tight junctions or preventing enzymatic degra-
`dation of the drugs. A review by Sayani and
`Chien,[83] on the systemic delivery of peptides and
`proteins across absorptive mucosae, contains a use-
`ful summary of the different enhancing agents. A
`listing was included specifically on the nasal deliv-
`ery of therapeutic peptides arranged by drug (16 in
`total) and year, beginning 1990 and ending 1993
`
`Readers of ‘popular’ fiction may recall a book by
`Arthur Hailey entitled Strong Medicine[11] that pur-
`ported to provide an expos´e of the pharmaceutical
`industry. Part of the story concerned the develop-
`ment of a new peptide drug that was to be delivered
`by nasal spray, with absorption rate improved by
`inclusion of a detergent. One character described
`how several detergents had been tested, with “the
`best non-toxic one, creating no irritation of nasal
`membranes, … found to be a new product recently
`available in the United States.”
`If only it was that easy!
`
`3.2 Absorption Enhancers –
`Historical Perspective
`
`Table I lists some of the compounds that have
`been used previously as so-called absorption pro-
`moters for the nasal route. Some of these materials
`have also been evaluated for improving the oral
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (13)
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`

`

`Absorption Enhancers for Nasal Drug Delivery
`
`1111
`
`Table I. Materials used to enhance the nasal absorption of drugs
`
`Drug
`
`Species
`
`Comments
`
`Reference
`
`Enhancer
`Surfactants
`Laureth-9
`
`Laureth-9
`Laureth-9/sodium deoxycholate
`
`Granulocyte colony
`stimulating factor
`Insulin
`Insulin
`
`Laureth-9/glycodeoxycholate/
`lysophosphatidylcholine
`Poloxamer-407/sodium
`glycocholate/bacitracin
`Dioctylsulphosuccinate
`
`Insulin
`
`Tetracosactide
`(ACTH 1–24)
`Polysucrose 1500
`
`Brij 35 and Brij 96
`Polysorbate 80
`
`Insulin
`Ciprofloxacin
`
`Metroprolol
`Insulin
`
`Polysorbate 80
`Soybean-derived sterol and
`glucoside mixture
`Soybean-derived sterylglucoside Verapamil
`and β- sitosterol β-D-glucoside
`Soybean-derived sterylglucoside
`Alkylglycoside surfactants
`
`Insulin
`Insulin
`
`Insulin
`Insulin lispro
`Insulin
`Aminoglycosides
`(gentamicin,
`tobramycin)
`
`Alkylglycosides
`Dodecylmaltoside
`Quillaja saponin
`Quillaja saponin
`
`Bile salts and derivatives
`Sodium glycocholate and non-
`ionic, ionic and amphoteric
`surfactants
`Sodium glycocholate
`Sodium glycocholate
`Sodium glycocholate
`Sodium glycocholate
`
`Sodium deoxycholate
`
`STDHF
`STDHF
`
`STDHF
`
`STDHF
`
`Rat
`
`No effect using sodium glycocholate
`
`12
`
`13
`14
`
`15
`
`16
`
`17
`
`Type 1 diabetics
`Surfactants can make interferon aerosols more
`effective
`In combination with hydroxypropyl-β-cyclodextrin
`as protective agent
`Bacitracin gave best results
`
`Nasal pool device, epithelial damage. Polysucrose
`as permeation tracer
`
`18
`Bioadhesive systems based on cellulosic materials. 19
`Nasal as alternative to oral route
`Decrease in bioavailability
`Peanut oil formulation
`
`20
`21
`
`Perturbation of membrane lipid affects paracellular 22
`and transcellular pathways
`Powder formulation. No signs of inflammation
`Surfactants of different alkyl chain length. Various
`routes to include nasal
`Chain length dependence
`Possible effect on tight junctions
`Low concentration effective
`Various routes. No irritation observed
`
`25
`26
`27
`28
`
`23
`24
`
`Man
`Sheep
`
`Rat
`
`Rat
`
`Human
`
`Dog
`Rabbit
`
`Rat
`Rabbit
`
`Rabbit
`
`Rabbit
`Rat
`
`Rat
`Rat
`Rat
`Rat
`
`Interferon-β
`
`Rabbit
`
`Solution and powder systems
`
`Insulin
`Polyethylene glycols
`Insulin
`Keterolac
`tromethamine
`Morphine with
`nanoparticles
`Insulin
`Insulin
`
`hGH
`
`Insulin
`
`Rat
`Rat
`Human
`Rabbit
`
`Mice
`
`Rat, rabbit
`Human
`
`Rat, rabbit,
`sheep
`Sheep
`
`Various routes compared
`Structural changes to nasal tissue
`Type 2 diabetes
`Bioavailability greater than 80%. Minimal irritation
`
`No improvement in antinociceptive effect with
`enhancer
`Interspecies difference
`Healthy subjects. 7–9% bioavailability compared
`with intravenous
`Absorption animal-model-dependent
`
`Powder formulations
`
`29
`
`30
`31
`32
`33
`
`34
`
`35
`36
`
`37
`
`38
`
`Continued next page
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (13)
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`

`

`1112
`
`Davis & Illum
`
`Table I. Contd
`
`Drug
`Enhancer
`Phenol red, FITC-
`Sodium glycocholate, sodium
`salicylate, sodium caprate, EDTA dextran
`STDHF
`hGH
`
`Glycocholate and methylcellulose Insulin
`PEG 300, sodium glycocholate
`Melatonin
`Glycofurol and sodium
`Peptide T
`glycocholate
`STDHF, EDTA, β-cyclodextrin
`
`Model peptides
`(enkephalin and TRH)
`
`Phospholipids
`DDPC
`
`DDPC
`DDPC
`DDPC
`DDPC
`
`Insulin
`
`Insulin
`Insulin
`hGH
`hGH
`
`Species
`Rat
`
`Human
`
`Human
`Rabbit
`Rabbit
`
`Rat
`
`Human
`
`Human
`Human
`Human
`Human
`
`Dimyristoyl phosphatidylglycerol
`
`Salmon calcitonin
`
`Rabbit
`
`Reference
`39
`
`Comments
`Bile salts and EDTA were most effective.
`Molecular weight of ‘drug’ important
`No adverse effects other than irritation. Plasma
`levels similar to physiological endogenous peak
`Gellified system. Type 1 diabetics. Irritant system 41
`55% bioavailability without additives
`42
`Coadministration of two enhancers
`43
`
`40
`
`Perfusion method. STDHF toxic, EDTA nontoxic
`but poor effect, cyclodextrin inhibited absorption of
`some peptides
`
`Healthy subjects. Slight irritation. 8.3%
`bioavailability compared with intravenous
`Healthy subjects
`Type 2 diabetics. Well-tolerated system
`GH-deficient patients
`GH-deficient patients. Significant absorption
`without adverse effects
`No benefit from increasing viscosity and
`formulation
`Powder systems. Differences between species
`
`44
`
`45
`
`46
`47
`48
`49
`
`50
`
`51
`
`Desmopressin
`
`Rat, sheep
`
`Insulin
`
`Rabbit
`
`Liposome membrane fluidity considered important
`
`52
`
`Lysophosphatidylcholine and
`starch microspheres
`Liposomes (dipalmitoyl
`phosphatidylcholine) with soy-
`derived sterol and its
`sterylglucoside
`
`Cyclodextrins
`Cyclodextrins (α, β, γ)
`Dimethyl-β-cyclodextrin
`Dimethyl-β-cyclodextrin
`Methylated-β-cyclodextrin
`Modified cyclodextrins
`Dimethyl-β-cyclodextrin
`
`Cationic polymers
`Chitosan
`Chitosan
`Chitosan
`Modified chitosans
`Poly-L-arginine chitosan
`
`Insulin
`Insulin
`rhG-CSF
`Salmon calcitonin
`Buserelin
`Glucagon
`
`Insulin
`Alnitdan
`Goserelin
`Peptide drugs
`FITC-dextran
`
`Rats
`Rabbit
`Rabbit
`Rat, rabbit
`Rats
`Rabbit
`
`Sheep
`Human
`Sheep
`Rat
`Rat
`
`Dimethyl-β-cyclodextrin gave best result
`Powder more effective than liquid formulations
`
`Dimethyl-β-cyclodextrin well tolerated
`Liquid and powder system
`
`Phase II
`Solutions and powders
`
`Sodium deoxycholate, lysophosphatidylcholine
`as controls. Good absorption from cationic
`compounds without damage
`Comparison with cyclodextrins
`
`53
`54
`55
`56
`57
`58
`
`59
`60
`61
`62
`63
`
`64
`65
`
`Continued next page
`
`Chitosan
`Aminated gelatin
`
`Opioid dipeptide
`Insulin and FITC-
`dextran
`
`Rat
`Rat
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (13)
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
`
`

`

`Absorption Enhancers for Nasal Drug Delivery
`
`1113
`
`Table I. Contd
`
`Enhancer
`Hyaluronan chitosan
`
`Drug
`Gentamicin
`
`Species
`Rabbit
`
`Comments
`Microparticle formulations – mucoadhesion and
`penetration enhancement
`
`Reference
`66
`
`Lipids and miscellaneous systems
`Oleic acid/monoolein
`Renin inhibitor
`
`Oleic acid
`
`Buserelin
`
`Lauroylcarnitine
`Acylcarnitines
`Palmitoyl-DL-carnitine,
`lysophosphatidylcholine
`Carbopol, chitosan
`
`Salmon calcitonin
`TRH analogue
`hGH
`
`FITC-dextran
`
`Starch-maltodextrin/carbopol 974 Insulin
`mixtures
`Oily suspensions (peanut oil,
`liquid paraffin, sesame oil)
`Lipid emulsions
`
`Insulin
`
`Insulin
`
`Microparticle resins
`
`Insulin
`
`rhG-CSF
`
`Rat
`
`Rat
`
`Rat
`Rat
`Rat
`
`Rabbit
`
`Rabbit
`
`Rabbit
`
`Rats
`
`Rabbits
`
`Rabbit
`
`Oleic acid emulsion system effective. No damage
`to mucosa
`Oleic acid solubilized and stabilised by hydroxy-β-
`cyclodextrin
`C-12 chain length optimal
`Acyl chain length important
`Mucolytic agents and enzyme inhibitors also
`examined
`Microsphere formulations reduced clearance as
`major mechanism
`Dry powder system
`
`Perfusion model. Water in oil and oil in water
`systems
`Fractionated sodium polystyrene sulphonate
`powder
`Low toxicity in cell culture model
`
`67
`
`68
`
`69
`70
`71
`
`72
`
`73
`
`74
`
`75
`
`76
`
`77
`
`78
`
`79
`80
`
`Nitric oxide donor (S-nitroso-N-
`acetyl-DL-penicillamine)
`HPE-101 + 2-hydroxypropyl-β-
`cyclodextrin
`Polyacrylic acid gel
`Hyaluronate sodium solutions
`
`Buserelin acetate
`
`Rat
`
`Cyclodextrin solubiliser potentiates effect of
`HPE-101
`
`Rat
`Rat
`
`Viscous solutions
`
`Calcitonin (eel)
`Vasopressin and
`analogue
`81
`No irritation of nasal membrane
`Rat
`Insulin
`Glycyrrhetinic acid
`DDPC = didecanoyl-L-α-phosphatidylcholine; EDTA = ethylene diamine tetra-acetic acid; FITC = fluorescein isothiocyanate; hGH = human
`growth hormone; HPE-101 = 1-[2-(decylthio)ethyl]azacyclopentane-2-one; Laureth-9 = polyoxyethylene 9-lauryl ether; PEG = polyethylene
`glycol; rhG-CSF = recombinant human granulocyte colony-stimulating factor; STDHF = sodium tauro-24,25-dihydrofusidate; TRH =
`thyrotropin-releasing hormone.
`
`(except for one reference from 1995). A selection of
`absorption promoting additives was described, in-
`cluding chelating agents such as EDTA, bile salts
`and derivatives (sodium tauro-24,25-dihydrofusi-
`date [STDHF]), cyclodextrins, phospholipids and
`fatty acids. Lutz and Siahaan[84] recently reviewed a
`list of various materials including absorption en-
`hancers and how these materials perturb tight junc-
`tions and thereby improve paracellular drug deliv-
`ery.
`Behl et al.[8] have reviewed the optimisation of
`systemic nasal drug delivery with pharmaceutical
`excipients and have described the various mechan-
`isms for nasal drug enhancement to include both
`
`physicochemical effects and membrane effects.
`They classified so-called ‘nasal drug delivery op-
`timisers’ under the following headings: cyclodex-
`trins, fusidic acid derivatives, phosphatidylcholines,
`microspheres and liposomes, and bile salts and sur-
`factants (in reality, fusidic acid derivatives are simi-
`lar to bile salts). The pros and cons of using optimis-
`ers in nasal formulations were then discussed. This
`useful review has a listing of 27 different types of
`enhancer with details of the drug, the method used to
`evaluate the enhancer (in vivo, in vitro), and the
`model (human, rat, rabbit, etc.), with references up
`to 1995.
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (13)
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
`
`

`

`1114
`
`Davis & Illum
`
`The general literature on mucosal penetration
`enhancement, often involving other routes of drug
`administration, is also instructive. The excellent edi-
`torial by Sezaki[85] on mucosal penetration enhance-
`ment deals specifically with penetration enhancers.
`He concludes that, unfortunately, enhanced permea-
`bility has often been associated with membrane irri-
`tation or damage and despite the fact that underlying
`mechanisms have been actively investigated using
`various methods, only rectal suppositories of anti-
`biotics containing the fatty acid salt sodium caprate
`have gained regulatory approval. Seven years on,
`the situation is little changed.
`Other useful reviews covering specific materials
`include those by Donovan and Huang[86] on particle
`uptake (largely relevant to vaccine delivery) and by
`Pereswetoff-Morath[87] on microspheres.
`The present review will concentrate on those
`enhancer systems that are deemed likely to proceed
`to successful nasal products.
`
`3.3 Attributes of an ‘Ideal’
`Absorption Promoter
`
`In hindsight, is perhaps not surprising that many
`‘effective’ enhancers were less than acceptable for
`long-term clinical use. For an enhancer to gain regu-
`latory approval, careful consideration will need to
`be given to its intended use – limited acute use could
`permit the use of a surfactant material, whereas
`long-term repeated administration would probably
`necessitate the use of a material that has a very
`different performance specification.
`An ‘ideal’ absorption promoter should have the
`following characteristics. It should carry the drug
`molecule across the cell from apical to basolateral
`surface. The carrier should be potent, pharmacologi-
`cally inert at the concentration used (nontoxic and
`nonallergenic), and have no irritant or disruptive
`effect on the cell membrane. The carrier should be
`compatible with drugs and physically rather than
`covalently associated with the molecule. The mode
`of action of the carrier should be known, preferably
`involving a natural process such as ion transport/cell
`signalling. The carrier should remain in contact with
`
`the mucosa long enough to achieve maximal effect.
`The effect should be transient and reversible. The
`carrier should have no taste or offensive odour,
`should be readily available and inexpensive. If the
`carrier is absorbed together with the drug it should
`be metabolised to provide acceptable breakdown
`products.
`
`Few absorption enhancers intended for nasal ad-
`ministration have all these attributes. However, we
`have found that various cationic polymers can have
`this function, and one in particular, chitosan
`(polyglucosamine), apparently satisfies all
`the
`above criteria.[2,88] Moreover, it is a natural material
`present in the diet and is approved as a food additive
`in many countries. As an additional benefit, the
`material is also bioadhesive and interacts with nega-
`tively charged cell surfaces and the negatively
`charged sialic acid residues in mucus.[2] Conse-
`quently, chitosan can slow down mucociliary trans-
`port. As an absorption promoter it acts by two
`different but complementary mechanisms. Further
`details will be given below in section 3.3.4.
`
`Ongoing research work directed to the gastroin-
`testinal tract could provide future leads. For exam-
`ple, the acetylated non-α amino acid materials being
`investigated for the improved oral delivery of pep-
`tides and heparin have some of the characteristics
`listed above, but the dose (stoichiometry) is less than
`attractive.[89] According to presentations made at
`scientific meetings, this type of material is also
`effective when applied nasally, but as far as we are
`aware no data have yet been published.
`
`Recent studies on peptide transporters might also
`be possibly exploited for nasal administration. The
`amphipathic 21-residue peptide pep-1 described by
`Morris et al.[90] apparently forms noncovalent com-
`plexes with peptides and proteins and allows im-
`proved delivery into cell lines. As yet, no in vivo
`data have been reported.
`
`Other carrier systems based on natural carriers, to
`include those involved in bacterial and viral trans-
`port, are also under investigation. However, these
`almost invariably involve the covalent attachment of
`the drug to the carrier.
`
`© Adis Data Information BV 2003. All rights reserved.
`
`Clin Pharmacokinet 2003; 42 (13)
`
`Opiant Exhibit 2075
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`

`

`Absorption Enhancers for Nasal Drug Delivery
`
`1115
`
`3.3.1 Cyclodextrins
`fects on long-term administration and/or provided
`and
`of Merkus
`The
`pioneering work
`low bioavailability and clinical failures in diabetic
`others[53,91,92] has shown that certain cyclodextrin
`patients.[98] Studies on the mechanism of effect[99]
`derivatives have an absorption promoting effect in
`have suggested that DDPC inhibits apical mem-
`animal models, particularly the rat, which provided
`brane sodium channels and causes structura