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`Pharmacology, Toxicology and Pharmaceutical Science » Drug Discovery » "Drug Discovery and Development - From
`Molecules to Medicine", book edited by Omboon Vallisuta and Suleiman Olimat, ISBN 978-953-51-2128-2, Published:
`June 3, 2015 under CC BY 3.0 license. © The Author(s).
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`Chapter 13
`
`Intranasal Drug Administration — An Attractive Delivery Route for Some Drugs
`
`By Degenhard Marx, Gerallt Williams and Matthias Birkhoff
`DOI: 10.5772/59468
`
`Read Chapter
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`1. Introduction
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`
`Figure 1. Multi-dose spray pumps can be fitted onto the bottles using a crimp ferrule, screwed-on or simply snapped on (from left to the right). In the forefront different
`types of nasal spray actuators.
`2. Evolution of multi-dose spray pumps
`
`
`Figure 2. Components of a typical multi dose pump. For a fully functional system a dip tube, fixture and actuator need to be added.
`3. A short introduction on intranasal administration
`
`
`Figure 3. Anatomy of the nasal cavity.
`4. Which technology is on the market?
`
`
`Figure 4. Spray tips for syringes which are used for the intranasal administration of naloxone, midazolam or some influenza vaccines.
`
`
`Figure 5. Examples of unit/bidose systems for liquids on the left with a glass vial which contains the one or two doses of the drug product and dry powder devices on
`the right.
`4.1. Bottles
`5. First steps to identify the right delivery system
`6. Formulation development
`7. Performance parameters
`
`
`Figure 6. Typical display from a spray pattern test using laser imaging, which can give information about the ovality of the emitted spray.
`
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`
`Figure 7. Typical display from a spray angle test using laser imaging, which can give information about the angle of the emitted spray.
`8. Trends for nasal drug administration
`8.1. Use of preservatives in multi-dose products
`8.2. Non-aqueous nasal formulations
`8.3. Side actuated spray pumps
`
`
`Figure 8. Example of a side actuated multi-dose spray pump
`8.4. Unit- and bi-dose sprayer
`9. Conclusion
`
`Intranasal Drug Administration — An
`Attractive Delivery Route for Some Drugs
`
`Degenhard Marx1, Gerallt Williams2 and Matthias Birkhoff1
`
`[1] Aptar Radolfzell GmbH, Radolfzell, Germany
`
`[2] Aptar France SAS, Le Vaudreuil, France
`1. Introduction
`
`Intranasal drug administration has a long tradition and was and is still used for medical as
`well as recreational purposes. The most common use is for treatment of local symptoms e.g.
`nasal congestion in the course of a common rhinitis or inflammation linked to allergic
`rhinitis. The medications intended for local activity are well established and can be found
`across the globe in every pharmacy and drug store. Examples for topical treatment of rhinitis
`are decongestants (oxymetazoline, xylometazoline, naphazoline), anti-histamines
`(azelastine, levocabastine, olopatadine) and glucocorticoids (e.g. mometasone, budesonide,
`fluticasone). For this particular indication, drugs should act fast and only locally while
`systemic absorption should be as low as possible; this to avoid systemic side effects which
`are linked with typical oral formulations of comparable drug substances.
`
`As described earlier [1] intranasal administration has much more potential. The nasal
`mucosa can be used for non-invasive systemic administration of drugs. The surface of the
`nasal mucosa in humans is around 150 cm2, a tissue which is well supplied by blood vessels.
`This ensures a rapid absorption of most drugs, can generate high systemic blood levels and
`avoids the first pass metabolism which needs to be taken into account following oral
`administration. This bypassing of the gastrointestinal system even enables the delivery of
`peptide hormones [1]. Calcitonin and desmopressin are on the market for years now; insulin
`and glucagon were under clinical development for this administration route [2].
`
`The rapid absorption of drugs via the nasal mucosa is also utilized for pain medications (e.g.
`fentanyl nasal sprays), rescue medications like naloxone for opioid overdosing or
`midazolam for seizures in children. An important aspect for such medications is that
`intranasal administration is considered a non-invasive administration route and easy to do
`for self-administration or for care-givers. It has a low potential for injuries or disease
`transmission (hepatitis B, HIV). This is of special importance if fast relief from severe
`symptoms is required and patient’s ability to deal with injections is impaired. Intranasal
`triptanes for migraine treatment, fentanyl to stop cancer breakthrough pain and ondansetrone
`to relieve nausea are examples for this trend. For these indications, single dose systems or
`multi-dose pumps with counting or lock-out mechanisms are available to reduce the risk of
`unintended overdosing or misuse [1].
`
`Vaccines may also benefit from the intranasal route. Existing vaccines commonly utilize the
`intramuscular and oral administration route. While the respiratory and gastrointestinal tract
`is very immune competent and fights with microbes permanently, the muscle is not the first
`choice. Intramuscular vaccination primarily induces systemic immune response, mainly via
`formation of vaccine-strain specific circulating antibodies. Injections of vaccines were done
`since the early days and they are indeed effective. So for most people today vaccination is
`equal to getting an intramuscular injection which is linked to pain. For the health care
`professional it is linked to fears of needle stick injuries, risk of disease transmission and
`dangerous medical waste.
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`Figure 1.
`
`Multi-dose spray pumps can be fitted onto the bottles using a crimp ferrule, screwed-on or
`simply snapped on (from left to the right). In the forefront different types of nasal spray
`actuators.
`
`Intranasal vaccination provides a promising non-invasive and gentle alternative. The nasal
`mucosa is continuously exposed to dust and microbes and therefore extremely immune
`competent. Due to the presence of the so called nasal-associated lymphoid tissue (NALT),
`intranasal vaccination elicits broader protection. It induces mucosal (protection at the site of
`infection) and systemic immunity, which includes antibody formation as well as activation
`of circulating immune cells. It has also been reported that the nasal route induces cross-
`protection against variant strains of e.g. influenza viruses, an observation which may
`contribute to the development of so-called “universal vaccines”. There is also evidence that
`this administration route may enable the development of therapeutic vaccines for chronic,
`hard-to-treat diseases such as hepatitis B [3].
`
`Intranasal administration is an attractive route for a wide range of drugs and indications.
`With this review we will try to provide some insight into this technology and some
`considerations for a successful development of such drugs.
`2. Evolution of multi-dose spray pumps
`
`Multi-dose spray pumps represent the highest share of delivery systems for intranasal
`administration. This type of pumps was developed some 50 years ago and ousted step by
`step droppers and pipettes. These multi-dose spray pumps now dominate the market because
`they are very cost effective and convenient. The technical solution is quite simple: drug
`formulation is filled into multi-dose bottles made of glass or different plastic materials,
`which are closed by attaching the nasal spray pump including a dip tube. Nasal spray pumps
`are displacement pumps and when actuating the pump by pressing the actuator towards the
`bottle, a piston moves downward in the metering chamber. A valve mechanism at the bottom
`of the metering chamber will prevent backflow into the dip tube. So the downward
`movement of the piston will create pressure within the metering chamber which forces the
`air (before priming) or the liquid outwards through the actuator and generates the spray.
`When the actuation pressure is removed, a spring will force the piston and actuator to return
`to its initial position. This creates an underpressure in the metering chamber which pulls the
`liquid from the container by lifting up the ball from the ball seat above the dip tube at the
`bottom of the metering chamber [1]. The metering chamber ensures the right dosing and an
`open swirling chamber in the tip of the actuator will aerosolize the metered dose. In these
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`pumps systems no measures are taken to prevent microbial contamination when in use, thus
`the formulation must contain preservatives, in most cases benzalkonium chloride (BAC). To
`date, most of the medications administered nasally contain a preservative to support long
`storage times and proper in-use stability. For some years now, most manufacturers of
`delivery systems offer so called “preservative free systems” (PFS) which are designed in
`such a way that no preservatives have to be added. At least in Europe, authorities support the
`use of preservative-free nasalia and request it for children and adolescents [4]. A switch
`from preserved to unpreserved medications is also often used as a life-cycle management
`measure and the products are clearly labeled as “without preservatives” or “does not contain
`preservatives”. Today, preservative free systems are most widely used to moisturize the
`nasal mucosa using saline solutions or for nasal decongestants.
`
`Figure 2.
`
`Components of a typical multi dose pump. For a fully functional system a dip tube, fixture
`and actuator need to be added.
`
`In December 2012, the US Consumer Product Safety Commission (CPSC) issued a rule to
`require child resistant (CR) packaging for any over the counter or prescription product
`containing the equivalent of 0.08 milligrams or more of an imidazoline [5]. This class of
`drugs is widely used as decongestant for cough & cold medications. The reason for this
`request was the high number of accidental uptake of such medications by children and
`resulting serious health risks. The commission estimated that approximately 39 million units
`of nasal products containing imidazolines are sold annually in the US. A great proportion of
`the nasal products are presented with metering nasal spray pumps. In a comment [5] the
`CPSC stated that nasal spray pumps even when crimped onto the bottle are not considered
`CR and that either the pump action or the over cap must be child resistant. This forced the
`pharmaceutical industry to introduce child resistant features for nasal decongestants
`intended for the US market.
`3. A short introduction on intranasal administration
`
`Nasal sprays or drops are widely used and therefor easy-to-use and cost-effective solutions
`are already available for liquid or for dry powder formulated drug products. Also the basic
`requirements for the development of nasal sprays are well known. An important point when
`a development for nasal administration is considered: the product should have no unpleasant
`smell and should not be irritating or influence the sense of smell. There should be also no
`safety concern, if a dose is unintentionally shot into the eyes.
`
`For most nasal spray pumps the dispensed volume per actuation is set between 50 and 140
`µl, and an administered volume of 100 µl per nostril is optimum in adults. Higher volumes
`are prone to drip out immediately. So the anticipated dose should fit into a volume of
`roughly 100-200 µl when both nostrils are sprayed. Standard spray pumps will deposit most
`of the sprayed dose into the anterior region of the nasal cavity (see Fig. 3) [6]. Surface
`tension of the droplets and mucus layer will cause the immediate spread of the spray.
`Afterwards mucociliary clearance will distribute the liquid layer within the nasal cavity.
`Since the nasal mucus layer is continuously renewed and discarded into the throat, the nasal
`residence time of the administered drug depends on how fast it dissolves within the mucus
`layer and penetrates into the mucosa [7].
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`Figure 3.
`
`Anatomy of the nasal cavity.
`
`If a nasal spray is considered, authorities will require a lot of data to describe the nasal spray
`pump and its performance as part of the container closure system [8, 9]. Most of these
`required parameters are used for quality control purposes. For nasal deposition efficiency,
`the spray plume angle and administration angle are critical factors, while many other spray
`parameters, including droplet particle size, have relatively minor influences on deposition
`within the nasal cavity [10].
`
`The nose is a very effective filter and most particles and droplets will be caught within the
`nasal cavity. Only particles less than 10 µm median aerodynamic diameter, so called fine
`particles, can reach the lower airways during nasal breathing [11]. Most spray pumps will
`generate an aerosol with a mean particle size from 40-100 µm during the fully developed
`phase which is recognized as fine mist. Such an aerosol will deposit well in the nasal cavity.
`
`To date, nearly all drugs for intranasal administration are liquids and just some recreational
`drugs are used as powders. Of course dry powder preparations can be used without the need
`for reconstitution to a liquid. The particle size should be in the same range as droplets from a
`nasal spray and fine particles should be minimized to avoid pulmonary deposition. The size
`and structure of the particles must be a compromise between safe administration (no fine
`particles, good deposition) and fast speed of dissolution of the particles within the mucus
`layer [3]. Powders for nasal administration will most likely need protection from moisture
`uptake though the moisture sensitivity may be formulation-dependent. Long term use of
`powder formulations may result in mucosal irritation and chronic use should be considered
`with caution, but single administration should be of much lower risk.
`4. Which technology is on the market?
`
`For intranasal administration of drugs a lot of delivery systems are available, simple and low
`cost as well as highly sophisticated. It ranges from droppers, to sprayers to be attached to a
`syringe, to so called unit- and bi-dose systems as well as multi-dose solutions for liquids.
`This wide range of available systems opens the door to tailored packaging.
`
`There are some considerations to choose the right solution in a competitive environment.
`Convenient and safe use and cost of goods need to be balanced. Also the availability of high
`speed filling and packaging equipment for the selected presentation should be evaluated.
`There are of course some other considerations for the different types of systems which
`should be discussed here.
`
`Droppers are the simplest and -just looking on packaging costs- the cheapest way to deliver
`medication into the nose. The blow-fill-seal (BFS) technology is widely used. The BFS
`droppers made of polyethylene or polypropylene are cheap but require special filling
`equipment. Also the material for the dropper (e.g. adhesion profile, evaporation rate) as well
`as processing temperatures during the BFS process may set some limitations. Splitting half
`doses from one single container may be a challenge and so for each nostril (if the medication
`requires this) one dropper needs to be considered. To deliver the right dose, some substantial
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`overfilling is required which can be neglected for cheap formulations but may be important
`for expensive drugs.
`
`Droppers for multi-dose presentations are still on the market but can be considered to be
`obsolete. A preserved formulation for multi-dose presentations is mandatory but
`preservatives will not solve all hygienic jaundices. Precise dosing is also close to impossible
`so that only drugs with a wide safety margin can be used with such systems. Intranasal
`administration using droppers is not very convenient. To get a good nasal deposition, the
`recipient should lie down or bend the head backwards to improve deposition.
`
`For some rescue medications like naloxone or midazolam or some intranasal vaccines spray
`tips (see Fig. 4) attached to standard Luer-syringes are used to deliver the drug. The
`handling is somehow inconvenient, because in most cases the drug must be transferred from
`a vial into the syringe. Then the spray tip is attached and the system is ready for
`administration. The generated spray and the quality of the nasal deposition depend much on
`the characteristics of the spray tip and the smooth displacement movement of the plunger of
`the syringe. If no mechanical aid is employed (e.g. removable clips to split 2 half doses), it is
`difficult to separate doses for each nostril. Also, depending on the handling procedure, a
`dead volume of 70-130 µl for the spray tip + syringe combination must be considered. A
`concern for such kits may be a possible confusion of the administration route. The used
`syringes are easily fitted with a needle and there is some risk in real life, that the drug
`intended for intranasal administration is injected. Most of these disadvantages can be
`avoided if prefilled systems are used.
`
`So called unit/bidose systems (see Fig. 5) for liquid formulations are state of the art for the
`intranasal administration of drugs requiring exact dosing. They have been on the market for
`more than 10 years for intranasal breakthrough pain and migraine management. The systems
`contain one or two separated half doses ready for administration. They are optimized for
`easy intuitive and safe handling. These systems will also ensure an optimal nasal deposition
`of the drug. These advantages are linked to a somehow higher price. The filling is similar to
`the procedure used for prefilled syringes and requires appropriate equipment.
`
`Figure 4.
`
`Spray tips for syringes which are used for the intranasal administration of naloxone,
`midazolam or some influenza vaccines.
`
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`Figure 5.
`
`Examples of unit/bidose systems for liquids on the left with a glass vial which contains the
`one or two doses of the drug product and dry powder devices on the right.
`
`Dry powder systems: In the near future, some drugs and vaccines will probably focus on
`dry powder formulations to take advantage of improved storage conditions. It may be a
`challenging task to generate a powder with the right particle size. As mentioned before, the
`particles must be designed for safe administration (no fine particle fraction), good deposition
`and fast dissolution within the mucus layer. For dry powders, electrostatic charge and
`moisture ingress must be considered. Systems which actively drive out the powder, using
`compressed air generated by a pump-like mechanism, seem to be better accepted than
`passive ones, where the powder is taken up by the nasal air flow. Dealing with dry powder
`needs of course different manufacturing and filling technologies, which are already available
`for other medications.
`
`Multi-dose solutions are by far the most widely used package solution. In Asia, simple
`squeeze bottles are on the market which can be considered obsolete because exact dosing is
`not possible and during use mucus may be sucked back into the bottle. The current standard
`multi-dose solutions are metering nasal spray pumps attached to bottles containing 10-30 ml
`of a liquid formulation. For this reason we would like to provide a closer insight into the
`technology of spray pump systems. As mentioned earlier the manufacturer fills the drug
`formulation into multi-dose bottles made of glass or Pharma-grade plastic materials. These
`are then closed by attaching the spray pump including a dip tube. The pump may be fixed by
`a screw closure, crimped on or simply snapped onto the bottle [1]. Now the system should
`be tight and no leakage should be observed during subsequent handling. This filling process
`is done on high-speed lines which can easily fill and close 60-200 bottles per minute.
`
`Before the system can be used, the pump must be primed. This is normally done by the
`patient just before first use. A number of priming strokes is required to purge the air off the
`system and dip tube and to deliver the product at the intended dose volume. Spray pumps are
`displacement pumps. When actuating the pump, a piston moves downward inside the
`metering chamber. A valve mechanism with a ball sealing the metering chamber against dip
`tube and container at the bottom of the metering chamber will prevent backflow into the dip
`tube. So the downward movement of the piston will create pressure within the metering
`chamber which forces the air (before priming) or the liquid outwards through the actuator
`and generates the spray. When the actuation pressure is removed, a spring will force the
`piston and the connected actuator to return to its initial position. This creates an
`underpressure in the metering chamber which pulls the liquid from the container by lifting
`up the ball from the ball seat above the dip tube at the bottom of the metering chamber [1].
`For a proper repeated function the spray pump should be held in upright positions to ensure
`that the end of the dip tube is always submersed in the formulation.
`4.1. Bottles
`
`Bottles or containers are an integral part of multi-dose container closure systems and will
`also influence the general appearance of the final product. Special shapes may be used to
`differentiate a product from competitors. Glass bottles are less prone to cause interactions
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`and will give good protection to the formulation even for long storage intervals. Sometimes
`the glass can influence the stability of the formulation (change in pH, release of trace
`metals). This depends of course on the quality of the glass which is described by its
`hydrolytic class (classes I-III are normally used for pharmaceutical products). The
`disadvantages which glass bottles may have are the higher weight and the risk to breakage
`when dropped [1].
`
`Bottles are also made of plastic material (e.g. polyethylene, polypropylene, polyethylene
`terephthalate). A pump supplier will most likely not manufacture these bottles because a
`complete different technology is used. Parts for spray pumps are quite exclusively made by
`injection moulding which gives high precision. Bottle manufacturers use a process referred
`to as blow-moulding. The general principle is to make a hollow raw part and then blowing
`up the material to the final dimensions. The most important disadvantage for all bottles
`made of plastic material is evaporation/weight loss during storage. Plastic materials are not a
`perfect barrier for gas or water evaporation. This problem can be tackled using laminated
`materials but these are more expensive. Another potential risk has to be considered: inks and
`adhesives from labels may migrate through the bottle wall and leach into the formulation
`[1].
`
`Pure mechanics but critical for all types of bottles: the bottle opening must fit the pump
`exactly. It needs to be tested and dimensions need to be controlled because variations may
`cause leakages or damage the housing of the pump during final assembly. To avoid any
`issues, consultation of the pump system supplier is highly recommended as these companies
`are experienced in managing this interface. The pump supplier should be able to recommend
`a range of suited bottles from suppliers which provide reliable quality. Before switching to
`another bottle or bottle supplier, the compatibility with the pump system should be checked
`in advance [1].
`5. First steps to identify the right delivery system
`
`One of the first steps in approaching the development of an intranasal drug administration
`project is to select the appropriate system for delivering the drug formulation. The selection
`of the delivery system is strongly governed by the type of formulation envisaged for
`delivery. Most likely the formulation will be liquid (solution or suspension), but also powder
`or gel formulations are possible. Of course the dosing frequency as well as legal restrictions
`(e.g. for controlled substances) will influence the decision for a single or multi-dose
`presentation. Once the basic type of system has been selected, it is then prudent to do some
`basic compatibility investigation or studies in order to avoid any obvious incompatibilities
`between the components and the proposed active pharmaceutical ingredient (API) and any
`known excipients before moving on to the formulation development stage.
`
`The materials used for the systems are selected by the manufacturer to warrant proper
`mechanical function and low likelihood of chemical interactions. In practice potential
`interactions between the formulation and parts of the spray pumps due to sorption or
`swelling should be excluded. Typical tests that could be considered at this stage include
`immersion tests of the functional parts of the pump in the formulation to detect swelling or
`discoloration. First tests with assembled pumps from this immersion test will provide data
`on potential effects on mechanical function (e.g. friction, metering).
`
`Typical functions
`Functional parts of the pump, actuator
`and fixtures, dip tube, bottles
`Functional parts of the pump, actuator
`and fixtures, dip tube, bottles
`Functional parts (may release
`formaldehyde!)
`
`Material
`Polyethylene
`(PE)
`Polypropylene
`(PP)
`Polyoxy
`methylene
`(POM)
`Rubber or
`Gaskets, seals, stopper
`elastomers
`Stainless steel Springs, balls for valve mechanism
`Aluminum
`Ferrules for crimped connections
`Bottles, vials, balls for valve
`Glass
`mechanisms
`
`Table 1.
`
`Typical classes of materials used for nasal spray systems
`
`A simple test for spray performance will assure that the formulation can be aerosolized by
`the considered pump and the delivered particle size is appropriate for effective nasal
`deposition. As mentioned earlier, the particle size should be in the range from at least 10 to a
`maximum of 150 µm. Particle sizes above 10µm assure that no product passes in to the
`lungs and impact in the nasal cavity. Droplets greater than 150 µl should be avoided as they
`are prone to run out of the nasal cavity immediately. It is not unwise to perform such
`preliminary compatibility tests with a certain range of different pumps to get an impression
`which may provide the best performance.
`
`Type of materials
`
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`Type of materials
`Chemical name / identity of the material
`Chemical name of any monomer used
`Supplier name
`Compliance with relevant standards in relation to their intended use (e.g.
`pharmacopeias)
`Complete qualitative composition when:
`The material is not described in the European or national pharmacopeias
`The monography authorizes the use of several additives (from which the
`manufacturer may choose)
`Specifications
`Identification
`Reference to European Pharmacopeia or Member State monographs or in-house
`monograph (if not described in EP or Member State monographs)
`Non-compendial methods (with validation) should be included where
`appropriate
`
`Table 2.
`
`General information on the container closure system related to materials of construction
`which should be provided by the supplier of the system
`
`At the end of the whole development process the requirements from authorities are straight
`forward: “For the final product (=formulation in combination with the whole container
`closure system) the suitability of the container closure system used for the storage,
`transportation (shipping) and use of the drug product should be discussed. This discussion
`should consider, e.g., choice of materials, protection from moisture and light, compatibility
`of the materials of construction with the dosage form (including sorption to container and
`leaching) safety of materials of construction, and performance (such as reproducibility of the
`dose delivery from the system when presented as part of the drug product)” [12].
`6. Formulation development
`
`Nasal drug formulations are broadly categorized into several types including solutions,
`suspensions, powders or gels. A key factor in selecting the type of nasal formulation to be
`developed is whether the therapy is intended for local or systemic application. Depending on
`the application, factors such drug absorption rate from the nasal mucosa into the systemic
`blood circulation and residence time in the nasal cavity become key elements in the
`formulation development process.
`
`Taking as examples spray solutions and suspension type formulations, the following factors
`should be considered during nasal formulation development:
`
`Drug, particles: consideration should be given to the desired therapeutic concentration for
`each dose, keeping in mind whether the total dose to the nasal cavity will be one (single
`nostril delivery) or two (one delivery into each nostril). For aqueous solutions and
`suspensions the typical dosing volume ranges are 50-140µl and for solution or suspension in
`pressurized metered dos