2
`
`design
`
`Preservative-Free
`Nasal Drug-Delivery
`Systems
`
`René Bommer and Jochen Kern Ing. Erich Pfeiffer GmbH, Radolfzell, Germany
`Kilian Hennes and Walter Zwisler Qualis Laboratorium GmbH, Konstanz, Germany
`
`Unpreserved nasal sprays are the latest trend in nasal drug delivery. Different
`technologies are discussed here in the context of mechanically protected
`systems, which may provide additional benefits. New test protocols are
`suggested to evaluate the improved microbiological protection that can be
`achieved.
`
`contaminant to enter the system.The
`first is the orifice where the product
`is expelled; the second is an opening
`in the pump system that is dedicated
`to allowing ventilation into the
`container and maintaining the pres-
`sure balance. Both of these features
`need to be investigated to prevent the
`possibility of contamination.
`
`Figure 1:
`Multidose preservative-free
`nasal spray system.
`
`Improving on current designs
`A look at the driving forces behind
`the recent development of preserva-
`tive-free nasal formulations unveils a
`few interesting aspects. Nasal formu-
`lations intended for use over a long
`period of time are generally pre-
`served. However, it has now been
`recognised that preservatives have a
`negative effect on the ciliated tissue in
`the nasal cavity.1,2,3 The ciliary
`epithelium plays a decisive role in the
`function of the nose.The movement
`of the cilia is responsible for trans-
`porting inhaled particles that are
`trapped on the nasal mucosa; the
`debris is guided towards the throat
`and subsequently removed by swal-
`lowing.This clearing function pre-
`vents foreign particles from reaching
`the lungs.The effect of preservatives
`on the ciliary beat frequency can be
`described as cilio inhibiting. In the
`case of a nasal infection such as
`perennial rhinitis the mucus in the
`nasal cavity is highly contaminated
`and it is important to remove the
`infected mucus as quickly as possible.
`To treat the infection, the patient
`applies a preserved nasal spray up to
`three times a day over a period of up
`to three months in cases of a severe
`allergy. However, the preservatives do
`
`exactly the opposite and slow down
`the clearing of the mucus.
`The German health authority
`(BfArM) recently published a risk
`statement concerning the widely used
`preservative Benzalkoniumchloride.4
`The patient information leaflet must
`mention that frequent administration
`of Benzalkoniumchloride irritates the
`nasal mucosa and therefore alternative
`unpreserved products should be used.
`
`Determining efficiency
`Unpreserved nasal products are
`common in unit- and bi-dose deliv-
`ery systems, which deliver one or
`two doses into the nostril(s).These
`devices are disposable, thus, there is
`no risk of contamination during the
`period of use. Multidose systems are
`different in functional design and are
`to be used daily by the patient for a
`period of up to six months. In the
`case of unpreserved content, the
`drug-delivery product will certainly
`become contaminated during the
`period of use.
`A complete nasal drug product
`consists of a mechanical dispensing
`system and a container, which are
`both stationary and mounted together
`(Figure 1).This primary packaging
`exposes two flaws that could allow a
`
`october 2004 ❘ medical device technology
`
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`
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`IPR2019-00694
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`

`

`Orifice design
`An essential prerequisite in the devel-
`opment of preservative-free nasal
`spray systems is that they must be
`sterilisable. Polymeric materials can
`be selected that resist gamma irradia-
`tion and maintain their properties.
`To prevent any ingress of microbial
`contaminants into the system via the
`orifice, two basic options can be
`considered.The first option is to
`introduce a chemical additive into the
`nasal actuator that is in contact with
`the formulation and environment.
`Whether it makes sense to remove a
`preservative from the formulation
`and add a disinfectant into the pri-
`mary packaging is not within the
`scope of this discussion.Various
`bacteriostatic agents have already
`found their application in medical
`appliances. Most common is the
`implementation of materials that
`release silver ions into the device.
`However, the bacteriostatic activity
`largely depends on a high ratio of
`surface area to surrounding volume.
`In addition, efficacy in inhibiting
`bacterial growth depends on the
`microbiological burden and the
`nature of the contamination.There-
`fore, it is essential that the microbio-
`logical efficacy is challenged and
`validated using a variety of different
`bacteria in the test procedure.The
`chemically protected systems (with
`chemical additive in the actuator)
`discussed above are basically open
`systems, which means microorgan-
`isms can enter via the orifice and
`contaminate the formulation inside
`the nasal actuator.
`A different approach is adopted in
`preservative-free systems, which are
`based on mechanical principles.The
`main difference is that a mechanically
`protected dispensing system seals
`directly behind the orifice.The
`mechanical barrier inherently pre-
`vents any microorganism from
`entering the system. Figure 2 shows
`the different mechanisms of action.
`In an open system, two competing
`reactions take place: one is the
`growth of permeated microorgan-
`isms; the second is the release of the
`disinfectant to prevent growth. In
`contrast, in a mechanically protected
`
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`
`design 3
`
`system, a spring-loaded mechanical
`barrier is characterised by a Go or
`No-Go function and the one-way
`valve is either open during the spray
`or closed during storage time.
`Figure 3 shows a basic mechanical
`principle of a sealing mechanism. A
`small spring-loaded pin seals the
`orifice at the end of the nasal actua-
`tor. As soon as the patient actuates the
`dispensing system, the pressure inside
`the pump increases. At the moment
`the pressure in the pump system
`becomes higher than the spring force
`(as a result of incompressibility of the
`liquid formulation), the pin will
`retract and will release the metered
`dose. Depending on the volume of
`the dispensed dose, the velocity of the
`particles expelled from the orifice is
`50–70 km/h. After the dispensing
`act, the pressure in the volume
`chamber drops and the pin will reseal
`the orifice. In contrast to systems
`protected by a chemical additive
`where the growth-inhibiting effect
`depends on the nature of the contam-
`
`ination, a mechanical protection
`barrier behind the orifice remains
`independent of the contamination
`source.
`
`Controlling pressure balance
`As described above, the dispensed
`volume is generated under pressure
`in the container. In the most common
`preservative-free delivery systems, an
`embedded filter will prevent contami-
`nation entering the packaging.Two
`types of filter can be employed,
`depending on the design of the
`delivery system:
`■ A depth filter comprises pore sizes
`that are large enough for germs to
`penetrate; however, the travel distance
`is long enough to allow the microor-
`ganisms, which adhere to dust
`particles, to be retained.
`■ An absolute microbiological filter
`consists of a thin membrane with
`pores small enough to hold back any
`microorganism. Usually 0.2-µm
`membranes are used. An absolute
`filter may have some advantages
`
`Figure 2:
`
`Illustrated kinetic profiles of the protection principles.
`
`Figure 3:
`
`Function of a mechanical preservative-free system.
`
`medical device technology ❘ october 2004
`
`Opiant Exhibit 2071
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
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`

`4
`
`design
`
`because nonadhered bacteria and
`bacteria spores are more efficiently
`retained.
`
`Microbiological evaluation
`The Food and Drug Administration
`Guidance for Industry, “Nasal Spray
`and Inhalation Solutions, Suspensions
`and Spray Drug Products,” includes
`microbial requirements: “For device-
`metered, aqueous-based inhalation
`spray drug products, studies should
`be performed to demonstrate the
`appropriate microbiological quality
`through the life of the reservoir and
`during the period of reservoir use.
`Such testing could assess the ability of
`the container system to prevent micro-
`bial ingress into the formulation.”5
`A currently recommended test
`procedure was developed and pub-
`lished in Germany in 1998.6 The test
`should follow the daily, real-life use
`of a nasal spray and detect any devia-
`tion in quality. In addition, when
`employing this test procedure, it must
`be determined whether the microbio-
`logical test is to be regarded as a
`challenge of the system or as quality
`control. A challenge procedure uses a
`nutrient medium, wheras a quality-
`control test uses the real product.
`
`Test protocols
`This proposed test procedure, which
`is illustrated in Figure 4, has some
`
`Figure 4:
`
`Illustration of a test protocol.
`
`flaws and needs to undergo modifica-
`tions to allow a more meaningful
`interpretation of test results.The areas
`requiring change are described
`below.
`■ The pump is dipped into the
`bacteria suspension to allow contami-
`nation to be sucked into the nasal
`actuator. However, the pump’s valve
`closes after the spray as a result of a
`pressure drop in the volume chamber
`(either the actuator is kept in an
`actuated position or is released).This
`means that dipping the actuator into
`the contaminated medium after the
`spray has released has no significance
`because the valve is already closed.
`Therefore, the procedure must be
`modified to include “actuation and
`release” mode for immersion in the
`bacteria suspension, as illustrated in
`Figure 5.7
`■ Possible contamination in the nasal
`actuator must be checked at an earlier
`time than after three days otherwise it
`does not represent the real user
`situation. In an open but chemically
`protected system, examination after
`three days of storage time allows the
`residual volume in the pump system
`to evaporate. Under these dry condi-
`tions it is unlikely that contamination
`will survive and subsequently be
`detected.Thus, a kinetic profile of the
`inhibiting or bactericide action must
`be generated. After three days, the
`
`concentration of the released additive
`is high enough to inhibit some
`growth. However, it is important to
`look at the inhibiting kinetic during
`the first hours after contamination. In
`particular, following use by a real
`patient, the first eight hours of the
`inhibiting profile should be charac-
`terised in detail. A mechanical Go or
`No-Go system obviously does not
`need to consider a bactericide profile
`or sampling time point because there
`is no critical time for full activity to
`develop, as is the case with a bacteri-
`cide. Nevertheless the real user
`scenario must be applied in the same
`way.
`■ The test procedure is missing an
`investigation of the microbiological
`filter.The efficacy of the ventilation
`filter can be evaluated in a simple test
`method.7 A sleeve is put over the
`pump system and appropriately
`sealed to avoid any exchange with the
`outside environment (Figure 6).The
`air space inside the sleeve is highly
`contaminated. Dispensing is actuated
`and released several times.The low
`pressure inside the system will be
`balanced by the ventilation flow
`through the filter. After appropriate
`incubation time a possible microbial
`growth is checked according to
`Chapter 71, “Sterility Tests,” as
`described in the United States Phar-
`macopeia 25.
`
`september 2004 ❘ medical device technology
`
`visit www.medicaldevicesonline.com
`
`Opiant Exhibit 2071
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`design 5
`
`Figure 5:
`
`Illustration of an optimised test protocol.
`
`Market outlook
`The nasal drug delivery market is
`valued at US$7billion. It is not as
`saturated as the oral drug-delivery
`market and enjoys a two-digit annual
`growth rate.The development of
`preservative-free nasal sprays is much
`more complex than traditional
`dispensing systems and requires close
`co-operation of various disciplines in
`the drug-delivery business. Preserva-
`tive-free systems were developed in
`response to changes in the nasal
`market. In addition to the general
`lack of new molecules, major nasal
`products are losing their patent
`
`Figure 6:
`Experimental setup for the
`evaluation of the filter efficacy.
`
`protection. Driven by the increasing
`generic threat, pharmaceutical com-
`panies are advised to reformulate
`their products to receive further
`patent protection. From the user’s
`perspective, a less irritating therapy
`through the application of preserva-
`tive- and additive-free nasal sprays is
`appreciated.
`
`Greater yet economic protection
`Unpreserved nasal sprays are the latest
`major trend in the nasal device
`business.The two existing principles
`of the microbiological protection of
`the content are present in the market,
`but a mechanically protected system
`may reveal additional benefits. Direct
`sealing at the orifice also protects the
`system from evaporation and subse-
`quently from crystallisation of the
`ingredients. In particular, with
`steroidal nasal formulations, which
`mostly exist as suspensions, the
`potential for clogging is dramatically
`reduced.
`From the medical device supplier’s
`viewpoint, a shift in responsibilities
`can be observed. Microbiological
`protection in a preserved nasal drug
`product has depended on the effective-
`ness of the preservative in the formula-
`tion.With the removal of
`preservatives, microbiological integrity
`depends on the delivery device and
`therefore becomes the responsibility of
`the medical device supplier.
`In the course of a product life-cycle
`
`management and fuelled by regula-
`tory authorities’ and patient aware-
`ness, preservative-free nasal sprays are
`gaining market share.This increasing
`market penetration is an example that
`economical issues and patient-related
`factors do not necessarily have to be
`mutually exclusive, but can be inline
`with the interests of industry and
`patients.
`
`Acknowledgement
`This article is written in memory of
`our late colleague Alex Stihl.
`
`References
`1. P. Merkus et al., “Classification of
`Cilio-Inhibiting Effects of Nasal
`Drugs,” Laryngoscope, 111, 4,
`pp. 595–602 (2001).
`2. H.J.M. van de Donk et al., “The Effects
`of Preservatives on Cilliary Beat
`Frequency of Chicken Embryo
`Tracheas” Rhinology, 18, pp. 119–130
`(1980).
`3. H.J.M. van de Donk et al.,“The Effects
`of Nasal Drops and their Additives on
`Human Mucociliary Clearance.”
`Rhinology, 20, pp.127–137 (1982).
`4. www.bfarm.de/de/Arzneimittel/
`am_sicher/stufenpl/Benzalkoniumchl
`orid.pdf (6 January 2004).
`5. FDA Guidance for Industry: Nasal
`Spray and Inhalation Solution,
`Suspension and Spray Drug Products
`— Chemistry, Manufacturing and
`Controls Documentation.
`6. B. Wiedemann and B. Kratz,
`“Konservierungsmittelfreie Nasalia,”
`Deutsche Apotheker Zeitung, 138, 7,
`pp. 529–533 (1998).
`7. K. Hennes and W. Zwisler, Qualis
`Laboratorium (2003), integrity-1.pdf,
`mdt
`www.qualis-laboratorium.com
`
`Dr René Bommer,*
`is the Director Business Development and
`Jochen Kern
`is Product Manager at Ing. Erich Pfeiffer GmbH,
`Pharma Division, Oeschlestr. 54–56, D-78315
`Radolfzell, Germany,
`e-mail: rene_bommer@pfeiffer.de
`Dr Kilian Hennes
`is Site Manager and
`Dr Walter Zwisler
`is Study Director at Qualis Laboratorium
`GmbH, Blarerstr. 56, D-78462 Konstanz,
`Germany.
`
`* To whom all correspondence should be
`directed.
`
`visit www.medicaldevicesonline.com
`
`medical device technology ❘ october 2004
`
`Opiant Exhibit 2071
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`