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`PSTT Vol. 2, No. 11 November 1999
`
`Delivery of peptide and non-peptide
`drugs through the respiratory tract
`Stanley S. Davis
`
`The respiratory tract, and the nose in particular, offers opportunities
`
`for improved drug delivery. Many drugs are rapidly and efficiently ab-
`
`sorbed from the nasal cavity and, as a result, the nasal route may be
`
`used in crisis treatments (for example, for pain and nausea). Polar
`
`drugs, such as peptides and proteins, are not well absorbed across the
`
`nasal mucosa, unless they are delivered with an absorption enhancing
`
`material. Agents, such as the polysaccharide chitosan, that are able to
`
`open tight junctions between cells can offer important opportunities.
`
`The nasal route can also be used for the delivery of vaccines. This re-
`
`view makes a comparison between nasal and pulmonary delivery.
`
`Stanley S. Davis
`School of
`Pharmaceutical Sciences
`University of Nottingham
`University Park
`Nottingham
`UK NG7 2RD
`tel: 144 115 951 5121
`fax: 144 115 951 5122
`e-mail:
`stanley.davis@nottingham.ac.uk
`
`t In the 1960s, a lecturer on lung and pul-
`monary delivery claimed that ‘we are about to
`enter a new age of drug administration, where
`the lung will be used as a route to deliver a wide
`variety of drugs into the circulation’. It is now
`hoped that the lung could soon be used not only
`for the administration of drugs for local treat-
`ments but also for the delivery of biotechnology
`products, such as peptides and proteins, as well
`as conventional molecules such as analgesic
`agents. Certainly, up until the present time, drug
`delivery to the lung has largely been the domain
`of local treatments for asthma, respiratory dis-
`eases and infections. The use of the lung for sys-
`temic drug delivery has, in the main, been re-
`stricted to the administration of anaesthetic gases
`and nicotine administration from cigarettes (or
`drugs of abuse administered via smoking or in-
`halation techniques).
`This review will consider recent advances in the
`delivery of drugs to the respiratory system for im-
`proved systemic uptake. It will concentrate on the
`nasal administration of drugs, such as peptides
`and proteins, and non-peptide compounds, many
`of which are either difficult to administer by
`
`other routes, or require a faster onset of action or
`other advantage.The advantages and disadvantages
`of nasal administration will be considered and a
`comparison made with pulmonary delivery.
`
`The nose
`The nose has been used for the systemic admin-
`istration of drugs since ancient times. It remains
`a popular route for the administration of drugs
`of abuse such as cocaine, and in earlier times it
`was a favoured route for the administration of to-
`bacco in the form of snuff. Although the surface
`area of the nose is not as large as that found in
`the lung, it does provide an effective site for the
`efficient systemic absorption of many conven-
`tional drugs, and particularly those compounds
`that are relatively water soluble but also
`lipophilic in nature (as shown by their partition-
`ing properties)1. The nose is well vascularized
`and drugs absorbed from the nasal cavity will
`pass directly into the blood, without passing
`through the liver, where they would suffer from
`first-pass metabolism. The nose does contain
`metabolic enzymes; however, it has been found
`that degradation of compounds within the nasal
`lumen or in nasal tissues is not normally a prob-
`lem that limits systemic appearance. Compounds
`that are normally difficult to deliver orally, for
`example those with a high first-pass effect such
`as propranolol and steroids, are often well ab-
`sorbed from the nasal cavity without the need for
`sophisticated formulations and absorption en-
`hancers. Nicotine provides an example of a drug
`that is well absorbed from the nasal cavity.
`Indeed, in many cases, with such lipophilic com-
`pounds, the pharmacokinetics are similar to
`those found after intravenous administration2.
`This means that the nose can be used in so called
`‘crisis treatments’ for the rapid administration
`of compounds, such as in the treatment of pain,
`migraine, convulsions, seizures, sedation and
`
`450
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`1461-5347/99/$ – see front matter ©1999 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00199-6
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`PSTT Vol. 2, No. 11 November 1999
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`(a)
`
`150
`
`100
`
`50
`
`0
`
`Time for 50% clearance (min)
`
`Saline
`
`Chitosan
`solution
`
`Chitosan
`powder
`
`(b)
`
`Initial area of deposition
`
`Clearance via throat
`
`Pharmaceutical Science & Technology Today
`
`Figure 1. (a) Clearance of chitosan formulations from the nasal cavity
`of human subjects using gamma scintigraphy; (n 5 8), label 5
`technetium-99m. (b) Scintigraphic images showing deposition of
`formulation in the nasal cavity and clearance to the throat region.
`
`irritation in the nasal cavity. However, it is possible, through
`formulation options, such as the use of cyclodextrins and other
`complexation procedures, to minimize the irritation effects8.
`The measurement of irritation itself in non-human tests can
`present experimental challenges. If a compound is irritant
`through a mechanism of gross cell damage, then it is possible
`to screen for such effects in cell cultures, such as CaCO-2, or in
`animal models9. However, some compounds may be totally
`non-damaging but have irritant effects. Tolerance may be an
`important factor. Nicotine is a good example of this problem,
`where irritation occurs but the effect is transient and tolerance
`is soon obtained.The measurement of non-damaging irritation
`can be achieved in animal models using techniques such as the
`measurement of evoked potential or the measurement of
`
`451
`
`AQUESTIVE EXHIBIT 1035 page 0002
`
`nausea. The use of nasal administration for conditions such as
`erectile dysfunction is also under consideration3. However,
`nasal absorption can be too rapid and a modification of the
`pharmacokinetic profiles can be achieved through the use of
`controlled release technologies such as microparticles and ion-
`exchange formulations.
`On a commercial level, the nasal administration of migraine
`compounds has proved to be an effective and rapid way of pro-
`viding pain relief4. Although some migraine compounds may
`be given orally, the onset of action can be slow.This is not only
`governed by the transit time for arrival of the drug at the ab-
`sorption site in the intestines, but, in a large proportion of mi-
`graineurs, gastric stasis may mean that the drug does not arrive
`at its preferential site of absorption until two or more hours
`after oral administration. Such problems may be avoided with
`nasal formulations.
`
`Physiological factors
`When designing nasal products, it is worth considering some
`basic physiology. First, when a simple nasal formulation is
`placed in the nasal cavity (whether as a solution or powder), it
`will normally be cleared quite rapidly to the throat by a process
`of mucociliary clearance; the average half-time for clearance in
`man is approximately 15 minutes as measured by scintigraphic
`methods5.
`Moreover, it should be remembered that at any time, we pre-
`dominantly use only one side of the nose for breathing. Essen-
`tially, one nostril is open (patent) while the other side is ob-
`structed.A nasal cycle mechanism operates in switching a nostril
`from patency to obstructed, over a period of eight hours or so6.
`It is possible, through the use of bioadhesive and gelling
`formulations, to slow down the process of mucociliary clear-
`ance and retain a formulation within the nasal cavity for an ex-
`tended period of time (in excess of three to four hours). This
`can be particularly useful for the administration of drugs re-
`quired for local effect such as steroids, antihistamines, antialler-
`gics and decongestants, but such strategies can also be used for
`the prolonged delivery of a drug into the systemic circulation,
`using a suitable controlled release formulation. Particular advan-
`tage can be gained through using bioadhesive powder systems
`in the form of starch or chitosan microspheres (Fig. 1)7.
`
`Irritation
`As discussed above, some drugs can be well absorbed from the
`nasal cavity without the need for a specific delivery system.
`The main question with these compounds is often one of dose
`and the possibility of local irritation. Clearly, if a drug needs to
`be given at large dose, such as 50 mg or more, the nasal route
`will probably be unsuitable. Some drugs, by their very nature
`or the concentrations used (hyper osmotic solutions) can cause
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`PSTT Vol. 2, No. 11 November 1999
`
`immunocytochemical markers such as C-FOS protein10. Such
`studies can be performed as a prelude to the ‘best’ test for irri-
`tation, dose escalation studies in panels of human subjects.
`
`Polar molecules and enhancers (peptides and proteins)
`Despite the large surface area available in the nose and other
`features such as a lack of first-pass metabolism, the absorption
`of polar drugs from the nose is not normally good. For exam-
`ple, for peptide compounds such as parathyroid hormone
`(PTH), growth hormone, insulin, calcitonin and desmo-
`pressin, the bioavailability (rate and extent of absorption) from
`the nasal cavity of man is generally approximately 1% or less.
`This low uptake may be adequate for the development of some
`commercial products (such as desmopressin and calcitonin),
`because they have a wide therapeutic index and a relatively low
`‘cost of goods’, but it may be necessary to use novel formu-
`lation strategies in order to produce a product with an absorp-
`tion that can provide sufficient reliability in dosing (insulin),
`or an acceptable cost of goods for commercial viability.
`It is well appreciated that it is possible to improve the trans-
`port of drugs across the nasal mucosa (and other mucous mem-
`branes) by using enhancer systems (Table 1). Unfortunately,
`with many of these systems that are largely based on surfactants,
`improvement in absorption is at the expense of tissue damage.
`Indeed, recent studies performed in Japan and the United States
`would suggest that, almost invariably, the high bioavailabilities
`achieved with absorption enhancers for the delivery of polar
`compounds across mucosal membranes can be associated with
`tissue damage11. Hence, a key goal in formulation development
`for nasal products is an ability to provide high bioavailability
`with minimum or no damage to the nasal mucosa. This can be
`achieved by using certain phospholipid compounds and, more
`particularly, cationic polymers such as chitosan12.
`
`Table 1. Nasal delivery–absorption enhancers
`
`Class
`
`Example
`
`Mechanism
`
`Opens tight junctions
`Disrupts membrane
`
`EDTA
`Sodium dodecyl
`sulphate
`Sodium deoxycholate Opens tight junctions
`Disrupts membrane
`Enzyme inhibition
`Mucolytic
`Disrupts membrane
`
`Oleic acid
`
`Amastatin
`Cyclodextrins
`N-acetyl cysteine
`
`Enzyme inhibition
`Disrupts membrane
`Mucolytic
`
`Chelators
`Surfactants
`
`Bile salts and
`derivatives
`
`Fatty acid and
`derivatives
`Enzyme inhibitors
`Non-surfactants/
`miscellaneous
`
`452
`
`Animal models
`Before it is possible to test novel approaches to nasal delivery
`in man, it is necessary to perform initial experiments in animal
`models.The rat is a useful way of screening initial concepts but
`the standard model, as described by Hirai, can greatly overesti-
`mate the absorption that will occur in man13. One of the rea-
`sons for this is that the model does not permit normal mu-
`cociliary clearance function, and, moreover, the animal needs
`to be anaesthetized and it is known that certain anaesthetics
`can significantly increase the nasal absorption of polar mol-
`ecules such as insulin14.The ovine model has a simple nasal ar-
`chitecture and can be used in a non-anaesthetized state and is
`also often predictive of results in man; not only qualitatively
`but also quantitatively, especially for peptides and proteins14.
`Although the shape of the ovine nose may be different to that
`of man, physiological processes, such as mucociliary clearance,
`are almost identical to those found in humans as assessed by
`the non-invasive technique of gamma scintigraphy. Recent
`studies on the clearance of gelling systems based upon poly-
`saccharides (pectin and chitosan) have shown close correspon-
`dence between sheep and human data5.
`
`Absorption enhancers
`Chitosan
`Over recent years, the nasal delivery of challenging drugs, such
`as peptides and proteins and polar molecules such as morphine
`and migraine compounds has been greatly improved using an
`approach that is not based upon ‘classical’ surfactant enhancers,
`but upon a cationic polysaccharide called chitosan. Chitosan is
`deacetylated chitin, and chitin is the second most abundant
`polysaccharide in the world. Below a pH value of approximately
`7.0, chitosan is water-soluble and, because of its cationic na-
`ture, can bind with mucosal surfaces and with mucin; the latter
`occurs through an interaction between the positively charged
`amine groups on the chitosan molecule and the negatively
`charged sialic acid groups on mucin. This interaction leads to
`bioadhesion and a reduced mucociliary clearance.
`However, interestingly, chitosan has another and more dra-
`matic effect in terms of providing improved nasal drug absorp-
`tion. Chitosan can alter the paracellular transport of drugs by
`direct effect on the tight junctions between cells. It has been
`shown that the presence of chitosan at a mucosal surface can
`lead to a transient opening of the tight junctions, and this has
`been demonstrated in CaCO-2 studies, where measurements of
`transepithelial resistance, mannitol transport and histological
`measurements have been made15. The opening of the tight
`junctions occurs for a period of approximately 15 minutes and
`could allow molecules as large as growth hormone (20,000 Da)
`to pass from the nasal lumen into the circulation. For drugs
`with molecular weights below approximately 10,000 Da, the
`
`AQUESTIVE EXHIBIT 1035 page 0003
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`PSTT Vol. 2, No. 11 November 1999
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`research focus
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`100
`
`80
`
`60
`
`40
`
`20
`
`Serum goserelin (ng ml-1)
`
`0
`- 100
`
`0
`
`100
`
`200
`
`300
`
`400
`
`500
`
`Time (min)
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`Pharmaceutical Science & Technology Today
`
`Figure 2. The chitosan effect as measured using a polypeptide
`(goserelin) in the sheep model (n 5 4). Bioavailability versus
`subcutaneous ranges from 1.5% for simple solution formulation (no
`chitosan) to 37% with a chitosan powder system. CHI powder 1
`(black); CHI powder 2 (blue); CHI solution (red); simple solution
`(green); subcutaneous (light blue). Reproduced, with permission, from
`L. Illum et al., submitted.
`
`12000
`
`10000
`
`8000
`
`6000
`
`4000
`
`2000
`
`Plasma G-CSF conc (pg ml-1)
`
`0
`
`0
`
`100
`
`300
`
`500
`
`700
`
`900
`
`1100
`
`Time (min)
`
`Pharmaceutical Science & Technology Today
`
`Figure 3. The use of a phospholipid, lysophosphatidyl-glycerol (LPG),
`to enhance the nasal absorption of G-CSF in the sheep model (n 5 4).
`The protein was combined with starch microspheres (SMS), with LPG
`in solution, and as a mixture of LPG and SMS as a nasal powder.
`SC 10 mg kg21 (black); SMS 40 mg kg21 (blue); SMS 1 LPG 40 mg kg21
`(red); LPG 40 mg kg21 (green).
`
`453
`
`AQUESTIVE EXHIBIT 1035 page 0004
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`use of chitosan can lead to an improvement in bioavailability of
`from 5–10-fold. It has been demonstrated that this chitosan ef-
`fect with various polypeptides, that include desmopressin, in-
`sulin, leuprolide, calcitonin, PTH, CCK-8, as well as with polar
`compounds for the treatment of migraine, such as alniditan,
`and analgesic agents such as morphine.These studies have been
`performed in an ovine model and in man4.
`Chitosan is, by its very nature, a high molecular weight ma-
`terial that is not itself absorbed. Chitosan is non-toxic and has a
`reversible effect on ciliary function. Therefore, chitosan repre-
`sents a new approach to improving the transmucosal delivery
`of challenging molecules. It has also been shown that the so-
`called chitosan effect of improving drug absorption across mu-
`cosal surfaces can be realized, not only in the nasal cavity but
`also in the gastrointestinal (GI) tract and vagina15. Modified
`chitosans that are soluble above pH 7 could be useful in the GI
`tract. Further improvement of drug absorption can be obtained
`by using powder formulations of chitosan, either as chitosan
`alone or in combination with gelatin in the form of micro-
`sphere systems. With some drugs, such as PTH, it is not poss-
`ible to use liquid (chitosan) formulations of the drug because
`of stability problems, and thus powder formulations are essen-
`tial. PTH formulations based on chitosan powder have per-
`formed well in the ovine model and in Phase I testing in
`human subjects. A representative example is shown in Fig. 2.
`
`Phospholipids
`The nasal administration of large protein molecules, such as
`G-CSF and erythropoietin, can also be achieved via the nasal
`routes. However, not surprisingly, the quantities delivered will
`be less than those achieved for molecules of lower molecular
`weight, such as calcitonin and insulin. In general terms, the
`larger the molecule the less drug that can be safely and reli-
`ably delivered across the nasal mucosa using novel formu-
`lation. For these higher molecular weight polypeptides, phos-
`pholipid-based systems or combinations of phospholipid
`with chitosan or other bioadhesive materials have been shown
`to be effective, either in solution or as powder formulations
`(Fig. 3)16.
`
`Vaccines
`The concept of improved delivery of a therapeutic agent via
`the nose by the transient modification of a paracellular-trans-
`port process can also be applied to the delivery of certain vac-
`cine antigens. As the reader will appreciate, there is currently
`increasing interest in the use of the nose for mucosal vaccina-
`tion. Such an approach is entirely sensible for prophylaxis
`against respiratory diseases, such as influenza, measles and RSV.
`Nasal administration of vaccines is itself an interesting area and
`space does not permit further detail here. Suffice to say that a
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`PSTT Vol. 2, No. 11 November 1999
`
`variety of vaccine systems, both liquid and particulate, is under
`current consideration.
`As with any issue in drug delivery, the choice of the delivery
`system needs to take into account the properties of the drug or
`antigen, particularly its size, stability and physicochemical char-
`acteristics.The chitosan concept has been applied to several dif-
`ferent antigens, to include those used for vaccines against
`influenza, whooping cough (pertussis) and other respiratory dis-
`eases. By the use of chitosan (in solution and powder form), it
`has been possible to obtain improved immune responses as
`measured in terms of antibody titres (IgG and IgA) as well as
`dramatic improvements in challenge tests in appropriate animal
`models17.
`
`Advantages of nasal delivery
`The nose can be used for the delivery of several compounds,
`either because it affords rapid administration of the drug into
`the systemic circulation (without the need for injection) or
`permits the delivery of challenging molecules such as peptides
`and proteins, which are difficult to administer via routes other
`than by injection. The choice of a nasal delivery system will be
`dictated by the dose of the drug, the potential for irritation and
`precision of dosing. In our experience, and those of other
`groups, with the right type of delivery device and appropriate
`patient training, the nasal route of administration is able to
`provide equal or better precision of dosing compared with
`subcutaneous administration. This is far better than can be
`achieved through oral dosing or via the pulmonary route, un-
`less one is using one of the more recently developed breath-ac-
`tivated or computer-controlled systems (see later). Total quan-
`tities of drug that can be given nasally will depend upon
`whether a liquid or powder formulation is being used.
`Normally, 150 ml is the maximum volume that can be applied
`at any one time into one nostril. For a powder formulation, the
`maximum quantity is approximately 50 mg, depending upon
`the bulk density of the material.
`
`Reproducibility
`The nasal administration of drugs can be relatively reliable and
`reproducible. Studies in man have shown that the coefficient of
`variation can be as good as or better than that achieved by sub-
`cutaneous administration. For example, Drejer et al.18 reported
`that the intranasal administration of insulin in man resulted in
`a faster time course of absorption than subcutaneous injection
`with a significantly reduced inter-subject variation.
`
`Nasal and pulmonary administration
`The lung
`The lung represents another part of the respiratory system that
`can be used for the effective delivery of drugs into the general
`
`454
`
`circulation. For a long time, the lung has been used for the ad-
`ministration of drugs for the treatment of local conditions.
`However, more recently, spurred on by the advent of novel de-
`livery devices, there is growing interest in the use of the lung
`for the systemic delivery of challenging molecules, such as
`peptides and proteins, as well as analgesic agents and even vac-
`cines19. The lung can provide an excellent means for the rapid
`delivery of peptide drugs into the blood, providing that the
`drug can reach deeper regions. The large surface area of the
`lung is well known, although, interestingly, the permeability of
`the lung tissue in itself is not that different from other mucosal
`surfaces; it is the large area that provides for the rapid absorp-
`tion. Small molecules, such as nicotine, and more polar
`species, such as morphine, are apparently relatively well ab-
`sorbed from the central as well as the peripheral lungs.
`However, polypeptide molecules, such as insulin, are only well
`absorbed if they are delivered into the deep (alveolar) regions.
`Data from animal models would suggest that, for a typical
`polypeptide, 50% or more of the dose can be absorbed from
`the alveolar region.Thus, in contrast to the nose, the main issue
`in lung delivery is not one of improving absorption, but
`achieving drug delivery to the correct region of the lung.
`
`Pulmonary delivery
`In the field of nasal delivery, irrespective of whether one is using
`solution or a powder formulation, it is not difficult to deliver the
`whole dose into the nasal cavity. However, in the case of pul-
`monary delivery, the ability to deliver large quantities of drug
`selectively into the lung, and, more particularly, to the deep lung,
`presents problems. Scintigraphic data obtained in man would
`suggest that with conventional multidose inhaler systems and
`dry powder inhalers most of the drug does not reach the lung at
`all20. Some of the dose may be left in the device, some may be
`left in a spacer system (if used), but the majority impacts at the
`back of the throat and is then swallowed. For example, for a typi-
`cal dry powder inhaler (DPI), one would expect approximately
`only 10–20% of the dose to reach the lung, and normally only
`half of this to reach the peripheral region. As discussed above,
`for a peptide molecule one would expect approximately only
`half of this dose, that reached the alveolar region, to be absorbed.
`A simple calculation indicates that for a conventional pulmonary
`delivery system, the probable achieved bioavailability, with refer-
`ence to the original dose, will be relatively small (10% or less).
`Importantly, some of the more recent concepts in delivery, in
`the form of dry powder systems and liquids, should permit
`larger quantities of drug to be delivered into the lung and, sig-
`nificantly, into the deep lung with greater dosing precision21.
`However, bioavailabilities for peptide drugs, even from an opti-
`mized dry powder system that provides good deposition in the
`lung, will range from 10–20%.
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`AQUESTIVE EXHIBIT 1035 page 0005
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`PSTT Vol. 2, No. 11 November 1999
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`reviews
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`110
`
`100
`
`90
`
`Plasma glucose (% Basal)
`
`80
`- 100
`
`0
`
`100
`
`200
`
`300
`
`Time (min)
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`Pharmaceutical Science & Technology Today
`
`Figure 4. Effect of pulmonary administered insulin on plasma glucose
`levels in human subjects (n 5 8), insulin dose 5 25 i.u. Insulin incor-
`porated into hydroxyethyl starch microspheres using spray drying. The
`administration device was a Valois Prohaler (Valois, Marly-Le-Roi,
`France). Formulations were labelled with technetium-99m to allow
`lung deposition to be followed (45% of estimated dose).
`
`Table 2. A comparison of polypeptide delivery across
`mucosal surfaces
`
`Route
`
`Maximum dose (mg)
`
`F (%)a
`
`Amount delivered
`systemically (mg)
`
`Oral (g.i.t.)
`Lung (DPI)
`Nasal – sol
`– pdr
`
`500
`5 3 3
`30
`50
`
`5
`12.5
`25
`40
`
`25
`2
`7.5
`20
`
`aBioavailabilities that can be obtained using formulations acceptable for long-term human
`dosing.
`
`455
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`AQUESTIVE EXHIBIT 1035 page 0006
`
`Insulin
`Pulmonary delivery systems for the systemic administration of
`insulin are in an advanced stage of development and have been
`shown to perform well in Phase II investigations. It is probable
`that such delivery systems can also be applied to other appro-
`priate peptide molecules, such as calcitonin and PTH, and per-
`haps even to larger species such as erythropoietin22. It should
`be remembered, however, that with some peptide therapeutics
`delivery to the lung may be inappropriate, simply because of
`the nature of the drug and its potential effect on lung tissues.
`Thus, growth factors, for example growth hormone and cyto-
`kines such as G-CSF, could be inappropriate for pulmonary de-
`livery to man on such grounds, notwithstanding the fact that
`relatively good absorption could be obtained by using this
`route. It should also be appreciated that the lung has a large
`surface area and that local concentrations will be low, thereby
`minimizing any potential undesired effect.
`As one would expect, pulmonary systems for insulin have
`been well received by patients who prefer this method of drug
`delivery to the normal process of injection. Importantly, Phase II
`studies have demonstrated that the product is well tolerated
`with no evidence of any effect on lung function over an ex-
`tended period of time. Figure 4 contains data from recent stud-
`ies on the use of hydroxyethyl starch microspheres in the de-
`livery of insulin to the human lung using a ‘conventional’ DPI
`that provides good lung deposition23.
`
`Crisis treatment
`In terms of the nose, the lung can be used for the rapid admin-
`istration of drugs, particularly in the area of pain management.
`Morphine and Fentanyl appear to be good candidates, provided
`the drug itself does not cause local problems in the lung, such
`as bronchospasm. It would appear that inhalation systems –
`pulmonary or nasal – may soon be in development for
`cannabinoid delivery as part of a drive in the UK to establish
`whether these compounds could provide benefit in the treat-
`ment of pain and other conditions such as multiple sclerosis. It
`is clear that a molecule that can be delivered via the lung could
`also be delivered via the nose if an appropriate formulation
`strategy is used.
`
`Comparison
`The quantity of drug that can be delivered into the lung may
`be more limiting than that given nasally, but, of course, it is
`possible to give more than one dose. Table 2 offers a compari-
`son of the relative merits of nasal, pulmonary and oral admin-
`istration in terms of drug dosage. As would be expected, each
`route has its advantages and disadvantages.The final choice will
`depend on a variety of factors, but, in particular, the nature of
`the drug to be delivered, the dose of active material and the
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`PSTT Vol. 2, No. 11 November 1999
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`nature of treatment (acute or chronic). Any decision over
`choice will also need to consider patient convenience and cost.
`
`References
`Illum, L. and Fisher, A.N. (1997) in Inhalation Delivery of Therapeutic Peptides and
`1
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`Update– latest news and views
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`456
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`AQUESTIVE EXHIBIT 1035 page 0007
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