Assessment of the influence factors on in vitro testing of nasal sprays using Box-Behnken experimental design☆
Introduction
A nasal spray product combines a therapeutic formulation and a delivery device, where formulation characteristics and device capabilities must be coordinated to accomplish consistent delivery into the nasal cavity. The drug delivery performance of aerosols introduced via the nasal cavity depends on many factors, such as the design of the pump, the shape of the orifice, physical properties of the formulation, and patient handling (Harris et al., 1988, Cheng et al., 2001, Suman et al., 2002, Dayal et al., 2004). Formulation and pump designs appropriate to achieve the desired nasal drug release characteristics are the key to development of a good nasal product.
Traditionally, during product development and testing, actuation of nasal spray devices is performed manually. However, operator dependent force profiles lead to poor reproducibility. Since actuation parameters are critical to the aerosolization process, this variability can lead to problems when a submission is made to the FDA, because broad product specifications must be adopted to allow for patient bias. The FDA draft guidance (U.S. Food and Drug Administration, 2003) recommends the use of an automated actuation system, which delivers reproducible actuation performance for in vitro testing. The guidance also recommends that actuation parameters for spray drug products should be relevant to proper usage of the product by the target patient population. Changes in actuation parameters, although within the proper working range of the device, may still lead to changes in test results.
A nasal spray formulation is typically a mixture of active pharmaceutical ingredients (API), polymers, surfactants, and excipients. Polymeric gel vehicles are normally used to improve nasal bioavailability by increasing nasal residence times and controlling the rate of drug absorption. Surfactants are mainly employed to stabilize or solubilize active formulation components. During nasal product formulation design, it is important to consider molecular interactions between these ingredients that affect the rheological and physicochemical properties of the solutions, which, in turn, affect the ability of the formulation to be aerosolized into appropriately sized droplets.
The combined variability from device and formulation makes the development of nasal spray products more complicated than traditional pharmaceutical products. The influences of actuation parameters and formulation physical properties on in vitro test results for nasal products have been investigated previously by Guo and Doub (2006) and Dayal et al., 2004, Dayal et al., 2005, but in each study, targeted parameters were varied independently while keeping all other parameters constant.
Guo et al. used water to simulate nasal spray formulations, and actuation parameters were varied using an electronic automated actuation station (Guo and Doub, 2006). In that paper, the authors demonstrated that different actuation parameters affect the nasal spray characteristics in different ways and to different degrees. Among all the actuation parameters, stroke length and actuation velocity were shown to have significant effects on the nasal spray characteristics, while the other actuation parameters have little, if any, effect. Compared to spray pattern, plume geometry and DSD, shot weight provides very little characterization information.
Using various placebo solutions to simulate physical property changes in nasal spray formulations and controlling actuations via a pneumatic automated actuation station, Dayal et al. observed significant influence from actuation force and formulation viscosity (Dayal et al., 2004). Their spray pattern analysis revealed a power law relationship between viscosity and spray pattern area for CMC formulations. However, this relationship could not be obtained for carbopol formulations, which was attributed to differences in the rheological behavior of the two formulations. The addition of surfactant (0.5–5% Tween80) to a 2% CMC solution decreased the Dv50 values (16–26%) and altered the rheological properties. They concluded that the characteristic of nasal aerosol generation is dependent on a combination of actuation force, viscosity, surface tension and other rheological properties as well as pump design.
In another study, Dayal et al. used design of experiments (DOE) methodology to study the effects of formulation components (gelling agents and electrolytes) on formulation rheology, in vitro drug release, and droplet size distribution (DSD) generated from a high viscosity nasal pump using a 5-factor, 3-level Box-Behnken experimental design (Dayal et al., 2005). Gel formulations of hydroxyurea (HU) with surface-active polymers (hydroxyethylcellulose [HEC] and polyethylene-oxide [PEO]) and ionic excipients (sodium chloride and calcium chloride) were prepared using a Box-Behnken experimental design. The applications of Box-Behnken experimental design facilitated the prediction and identified major excipient influences on viscosity, DSD, and in vitro drug release.
While previous studies have identified the major factors that affect the physical properties of nasal sprays, their experimental designs were based on changing one variable at a time, and did not consider interactions between actuation parameters and formulation characteristics. DOE methodology can be used to improve understanding of the influence of actuation parameters, formulation characteristics and their interactions on nasal spray delivery performance. A properly designed set of experiments, in which all relevant factors are varied systematically can identify the factors having the greatest influence on the results, the existence of interactions between those factors, and the optimized factor values that yield the desired response.
The Box-Behnken design is one of the most efficient DOE methods (Ferreira et al., 2007). An advantage of the Box-Behnken design is that it does not contain combinations for which all factors are simultaneously at their highest or lowest levels. So these designs are useful in avoiding experiments performed under extreme conditions, for which unsatisfactory results are often obtained.
This paper describes experiments designed to elucidate interactions between four factors (actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant) with respect to their influences on nasal spray shot weight, DSD, and spray pattern and plume geometry (angle and width) properties. Box-Benkhen methodology was used to design a set of 27 experimental conditions that are capable of elucidating the influence of these factors on the nasal spray responses including second-order and interaction effects. The measured responses were fit to polynomial model functions, and an analysis of the polynomial coefficients and their standard errors was used to identify the factors and interaction terms that are statistically significant for each model.
Section snippets
Sample preparation
Pfeiffer (PFE) 0.10 mL nasal spray pumps (material number 62602, dip tube length 58 mm) and 20 mL bottles (material number 34473) were used in this project. Pump units are specified to deliver 100 μL of liquid per actuation (∼100 mg for water). Each nasal spray unit was filled with 18 mL deionized water or simulated formulations prior to testing and the first six actuations were fired to waste as priming shots.
Extra-low-viscosity-grade carboxymethylcellulose (CMC) was kindly provided by Aqualon North
Physical properties of the solutions
Measured values of the formulation physical properties are shown in Table 2. Based on three replicates of each measurement, the standard deviations for density, viscosity, and surface tension are 0.001 g/mL, 0.1 centipoise, and 0.1 mN/m, respectively. The physical properties between different samples showed statistically significant difference (p < 0.05), although most of the changes are very small.
Quadratic models of formulation physical properties (density, viscosity and surface tension) have been
Conclusion
In this study, the influence of four factors (actuation stroke length, actuation velocity, concentration of gelling agent and concentration of surfactant) on the in vitro characteristics of nasal sprays were investigated using a 3-level, 4-factor Box-Behnken design. The concentration of gelling agent (CMC) and surfactant (Tween80) are the dominant factors influencing the formulation viscosity and surface tension, respectively; therefore, their influences on nasal spray characteristics are most
References (8)
- et al.
Evaluation of different parameters that affect droplet-size distribution from nasal sprays using the Malvern Spraytec
Journal of Pharmaceutical Sciences
(2004) - et al.
Box-Behnken design: an alternative for the optimization of analytical methods
Analytica Chimica Acta
(2007) - et al.
The influence of actuation parameters on in vitro testing of nasal spray products
Journal of Pharmaceutical Sciences
(2006) - et al.
Effect of viscosity on particle size, deposition, and clearance of nasal delivery systems containing desmopressin
Journal of Pharmaceutical Sciences
(1988)
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The views presented in this paper represent those of the authors and do not necessarily reflect those of the U.S. Food and Drug Administration.