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A look at the interconnected role of the formulation, formulation excipients, and nasal spray device

Introduction

Nasal sprays are drug/device combination products, as defined in FDA 21 CFR 3.2(e): “A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity”. Furthermore, the FDA identifies and describes nine different types of combination product – nasal sprays fall under type 2: “Prefilled Drug Delivery Device/ System”, where “drug is filled into or otherwise combined with the device AND the sole purpose of the device is to deliver drug”. For ease of reading, the drug formulation development and nasal delivery device development activities are treated separately in this article. In practice, the interplay between the formulation, device, and the patient will affect the emitted spray which will in turn affect the delivered dose and location of deposition.

Effect of nasal spray formulation attributes on spray characteristics

The parameters that affect how readily the formulation atomizes will be the ones that have the greatest effect on the spray characteristics:

• Viscosity. As the formulation viscosity increases, the formulation becomes more difficult to atomize. This leads to larger droplets, a narrower spray plume, and smaller spray area [1-3]. It should be noted, however, that the impact on the droplet size is influenced more by the type of viscosity enhancer used in the formulation than the viscosity itself. For example, doubling the formulation viscosity using ‘Thickener A’ will have a different impact on the droplet size compared to a similar increase in viscosity using ‘Thickener B’ due to, amongst other things, differences in shear thinning behavior [4]. The viscosity of the formulation has been shown to have the most significant influence on droplet size [5,6].
• Surface tension. As the surface tension of the formulation decreases, the formulation becomes easier to atomize and the droplet size decreases. Smaller droplets are usually accompanied by a broader spray plume and a larger spray area. Surface tension optimization should take into account that it does not result in a large proportion of droplets below 10 µm in size, so as to minimize deposition and uptake by the lungs. The inclusion of different co-solvents (e.g., alcohols) or surfactants will typically reduce the surface tension. However, they will also affect the viscosity and density of the formulation.
• Density. Formulation density has a similar effect to viscosity and surface tension – as the density decreases, the formulation becomes easier to atomize and the droplet size decreases. As was noted for surface tension, density optimization should avoid producing a large proportion of droplets below 10 µm in size.
• Particles. The presence of small solid particles within a nasal spray suspension typically has little effect on the spray characteristics. As the solid particles get larger, however, the spray characteristics can be affected producing a bimodal distribution of droplets – one peak corresponding to the liquid droplets, the other corresponding to the solid particles. Micronizing or milling the insoluble materials is one method that can be used to avoid this situation.

Nasal spray formulation development considerations

The physical and chemical attributes of the drug substance will drive the type of formulation to be developed. Typically, the choices of formulation are aqueous, hydroalcoholic, or co-solvent systems, non-aqueous, solution, and suspension. If the drug substance is readily soluble in water, an aqueous solution is preferred. In general, aqueous solutions with low viscosity atomize easily producing “elegant” spray plumes. If the drug substance is relatively insoluble in water, then one of the other formulation options can be considered:

• Aqueous suspension. To improve the physical stability of the formulation, an aqueous suspension will require the addition of a suspending agent (e.g., microcrystalline cellulose and sodium carboxymethyl cellulose) in conjunction with a surfactant (e.g., polysorbate 80), to reduce surface or interfacial tension between the solid particles and the liquid phase. Adding a suspending agent typically results in an increase in the viscosity of the formulation. Therefore, the concentration of the suspending agent needs to be optimized such that the viscosity is acceptable and appropriate for the desired spray characteristics of the drug product. The drug product might need to be shaken to homogeneously re-suspend the drug particles prior to use. While this is not a problem for multi-dose bottles, it is not possible with the micro-dose vials used in unit and bi-dose devices. Another drawback with the use of suspending agents is that they can also contain insoluble particles (e.g., microcrystalline cellulose). If the particle size of the drug substance needs to be determined in the final formulation, the morphology of the drug substance and suspending agent particles must be sufficiently different to enable particle identification.
• Hydroalcoholic or co-solvent formulations. Poor water solubility of drug substances is a topic that has received a lot of attention, particularly for oral dosage forms. It was reported in 2021 that maybe 70-80% of small molecule drug candidates could be classified as poorly water-soluble [7]. With nasal sprays, co-solvents and solubilizers (including ethanol, benzyl alcohol, phospholipids, cyclodextrins, surfactants, and polyethylene glycols) have been used or investigated to improve the solubility of the drug substance.
• Non-aqueous systems. Another formulation approach when dealing with a poorly soluble or insoluble drug substance is to use a non-aqueous formulation base. While the non-aqueous solvents might solubilize the drug substance, typically they do not atomize well when sprayed [8] due to their viscosity and inherent “stickiness”/surface tension.

Other drug substance attributes that will influence the choice of excipients used in the drug product formulation include its hydrophilicity, molecular weight, and size. Large molecular weight and water-soluble drugs (e.g., proteins and peptides) have a relatively low membrane permeability [9]. This, together with the limited residence time within the nasal cavity caused by mucociliary clearance necessitates formulation approaches to increase the contact time of the drug at the site of absorption and the permeability of the mucosal membrane, for example using mucoadhesives and penetration enhancers. Similar to suspending agents, mucoadhesives will increase the viscosity of the formulation.

Mucoadhesives are also used when formulating with drug substances that are intended to act locally within the nasal cavity, for example when the drug product is intended as a prophylactic treatment for respiratory diseases. These formulations are intended to be retained within the nasal cavity, the site of first infection. As such, it is important that the residence time of the drug within the nasal cavity is maximized – not to increase the time for absorption, but to increase the opportunity for the drug to interact with the virus within the nose and prevent it from entering deeper into the respiratory system.

Another important formulation consideration is whether the drug product will be manufactured sterile, or whether the formulation will contain a preservative [10]. Microbial growth can occur in a nasal formulation either during manufacture (from contaminated materials or equipment) or while in use by the patient (due to unhygienic handling or the intake of unfiltered venting air). Due to potential adverse events on the nasal mucosa associated with the use of preservatives (including discomfort, irritation, and alterations to the ciliary beat frequency [11]), their inclusion has been seen negatively by several regulatory agencies. Although preservative-free spray pumps are commercially available, due to the added complexity of aseptically manufacturing the drug product or the stresses exerted during terminal sterilization, the use of preservatives is still a commonly used formulation approach.

The pH, osmolality, and viscosity of the formulation also play an important role by affecting attributes such as the site of deposition, degree of absorption, and tolerability of the drug product.

• pH. The pH of the formulation will affect the fraction of the drug that exists as an uncharged species. The nonionized fraction of the drug is more permeable, and the extent of ionization depends on the drug pKa and the pH at and in the absorption site. Additionally, to avoid nasal irritation, the pH of the nasal formulation should ideally be adjusted to 4.5-6.5 because lysozyme in the nasal secretions is responsible for preventing the growth of certain bacteria at acidic pH. Under alkaline conditions, lysozyme is inactivated, and the tissue is susceptible to microbial infection [12,13].
• Osmolality. The osmolality of the formulation is one factor that will determine how well the drug product will be tolerated. The osmolality should whenever possible be adapted to the physiological situation. The further the formulation is from isotonic (280-300 mOsm/kg), local irritation and stinging are more likely to be experienced – especially in the case of chronic use. Higher osmolality values may be tolerable for emergency or single-application use [13], and there are studies showing that hypotonic nasal spray formulations improve drug permeability through the nasal mucosa. Some existing marketed products have reported osmolality in the range 300-700 mOsm/kg [14].
• Viscosity. Ingredients that increase the viscosity of the formulation will, in general, also increase the viscosity of mucus. Increasing the viscosity of mucus in the nasal cavity will inhibit the effect of ciliary beating, impair mucociliary clearance, and increase the residence time of the drug on the nasal mucosa to allow more time for passive diffusion. The narrower spray plume and larger droplets generated by more viscous formulations can play a part in controlling the whereabouts in the nasal cavity the spray droplets are deposited. It has been reported that low viscosity nasal spray formulations with a wider plume angle and small volume median diameter enhanced deposition in the anterior nasal passage and provided greater surface coverage of the nasal mucosa compared to higher viscosity formulations [4,15].

Typical formulation excipients
As mentioned previously, the pH, osmolality, and viscosity of the formulation are important considerations regarding the tolerability and effectiveness of spray drug products. In addition to pH adjusters, buffer salts, viscosity modifiers/mucoadhesives, solvents/co-solvents/solubilizers, suspending agents and preservatives, several other classes of excipients have been used to produce stable and effective formulations. These include:

• Antioxidants – in cases where the drug substance is susceptible to oxidation
• Penetration enhancers – to aid absorption and increase the speed of action of the drug substance, particularly with larger drug molecules
• Surfactants and/or emulsifiers – if the formulation is an emulsion
• Humectants – to prevent nasal dehydration and offset some of the irritancy associated with other excipients (e.g., preservatives, antioxidants)
• Flavors and sweeteners – to mask any bitterness or unwanted odor in the formulation resulting from the drug substance or excipients

When choosing the formulation excipients, it is important to note that the possibility of undesirable biological effects is a major concern with the use of new or novel materials. Additionally, certain classes of excipients will, by their nature, have an adverse effect on the spray characteristics (e.g., viscosity modifiers). While not being a showstopper, these factors should be taken into consideration early in the product development process to ensure that costly and time-consuming reformulation activities are not required down the line.

The Inactive Ingredient Database (IID) [16] provides information on excipients used in FDA-approved drug products and can be used as a starting point when considering formulation additives.

Nasal spray device considerations

Two of the most important considerations when selecting a nasal spray device are the number of doses that will be contained in the device (the fill volume) and whether the drug product will be sterile or preserved.

• Number of doses per device – nasal spray devices for liquid formulations come in unit dose, bi-dose, and multi-dose formats, with spray volumes ranging from 25 to 140 µL. The selection of the fill volume (number of doses per device) is generally driven by the intended frequency of use of the drug product. For a chronic-use product (e.g., for nasal allergies), a multi-dose device containing 1 month’s supply might be selected. For an acute-use product (e.g., for pain management, controlling seizures, or rescue medication), a unit dose or bi-dose device might be chosen [10].
• Sterile or preserved – whereas there are very few limitations regarding devices that can be used for preserved formulations, this is not the case with all sterile formats. Sterile unit and bi-dose products can be aseptically manufactured and assembled, or terminally sterilized, with no modifications needed to the devices. Multi-dose devices, however, require that the sterility of the formulation is maintained throughout the in-use life of the product. Several different approaches have been used to address this problem. (1) Conventional devices have been designed with a special tip seal and 0.2 µm filter to ensure that any venting air introduced during product use is filtered to remove any potential microbial contamination. (2) “Bag-on-valve” containers, where the formulation is aseptically filled into an inner “pouch” inside a pressurized container. The inner pouch collapses as the product is expelled without the need for venting air, thereby preventing the possible ingress of contamination.

Nasal Spray Device Selection
When selecting the device itself, currently there are only a few unit and bi-dose options to choose from. With multi-dose devices, however, there are numerous different pumps, actuators, and suppliers competing in the marketplace, so evaluating the spray characteristics of the formulation from several of the device options is a critical aspect of the product development program. It is important that the actual formulation is used during the device selection study because water, placebo, or any other solution will probably spray differently when compared to the drug product. All the tests in the study are performed on several samples from each device type to assess both the variability of each of the options, as well as to provide a direct comparison across the different options. The spray characteristics that will aid in the device selection are:

• Priming – the number of actuations required before the target dose weight is obtained for two successive sprays.
• Pump delivery – the dose weight of the expelled spray. This is evaluated at various points throughout the in-use life of the samples (e.g., every 10th spray) to assess the inter- and intra-sample variability. All the dose weights must comply with the target delivery specification for the product.
• Droplet size distribution – this testing is performed using laser diffraction and characterizes the size of the droplets within the plume in terms of cumulative volume distributions Dv10, Dv50 and Dv90 (values indicating that 10%, 50%, and 90% of the spray volume is contained in droplets less than this size), as well as the spread of the droplet size distribution (the “Span” = Dv90-Dv10/Dv50) and the % of droplets less than 10 µm in diameter (representing a risk estimate of droplets that may be inhaled into the lung). These parameters are evaluated for multiple actuations (e.g., 10 actuations) throughout the in-use life of the samples. Values for Dv50 of 30-70 µm, Dv90 < 200 µm, a narrow Span (e.g., 1.0-2.0), and a low % < 10 µm (e.g., less than 5%) are considered optimal [17].
• Spray pattern – this testing is performed using a non-impaction laser sheet-based instrument and characterizes the shape of the plume when looking downward on the nasal spray unit as the product is emitted from the nasal spray device. The ovality ratio (the ratio of the maximum to minimum cross-section diameter of the plume) is evaluated for multiple actuations throughout the in-use life of the samples. A uniform circular/oval pattern with an ovality ratio close to 1 is optimal. Additionally, a spray pattern cross-sectional area within the range of 250 to 600 mm² is generally considered acceptable. Other parameters that are obtained from this testing are Dmin and Dmax (the length of the shortest and longest lines respectively that pass through the weighted center of mass drawn within the perimeter of the spray pattern), and the ellipticity (the ratio of the major and minor axes of the ellipse).

Nasal cast deposition and computational fluid dynamics (CFD) are two other methods that have been used to aid in the device selection process. In the nasal cast method, the in vitro deposition patterns are evaluated using an anatomically correct nasal cast combined with a color-based image analysis method [4,18]. The nasal cast is coated with a paste that changes color on contact with water. The color density in the different regions of the “nose” gives an indication of the amount of spray deposited. With CFD, three-dimensional simulations of the nasal cavity are generated, and algorithms are used to model aerosol transport and quantify the delivered dose to the specific regions of the nasal cavity [19].

In Summary – Nasal Spray Formulation and Development

Nasal sprays are drug/device combination products. The formulation development and selection of the device must be aligned and cannot be performed in isolation because both will determine how the medication dose is delivered and the location of deposition within the nasal cavity.

References

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3. Kulkarni VS, Shaw C, Smith M, Brunotte J. Characterization of plumes of nasal spray formulations containing mucoadhesive agents sprayed from different types of device. Poster at AAPS annual meeting (2013)
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