Bibliography of Best Practices
Citations using Proveris Instrumentation
Characterization of Stability and Nasal Delivery Systems
for Immunization with Nanoemulsion-Based Vaccines
Makidon PE,
Nigavekar SS,
Bielinska AU,
Mank N,
Shetty AM,
Suman J,
Knowlton J,
Myc A,
Rook T,
Baker JR Jr.
Corresponding author: pmakidon@umich.edu
Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan , Ann Arbor, Michigan 48109-5648, USA.
Abstract
Background: Many infectious diseases that cause significant morbidity and mortality, especially in the developing world, could be preventable through vaccination. The effort to produce safe, thermally stable, and needle-free mucosal vaccines has become increasingly important for global health considerations. We have previously demonstrated that a thermally stable nanoemulsion, a mucosal adjuvant for needle-free nasal immunization, is safe and induces protective immunity with a variety of antigens, including recombinant protein. The successful use of nanoemulsion-based vaccines, however, poses numerous challenges. Among the challenges is optimization of the formulation to maintain thermal stability and potency and another is accuracy and efficiency of dispensing the vaccines to the nasal mucosa in the anterior and turbinate region of the nasal cavity or potentially to the nasopharynx-associated lymphoid tissue.
Methods: We have examined the effects of different diluents [phosphate-buffered saline (PBS) and 0.9% NaCl] on the stability and potency of nanoemulsion-based vaccines. In addition, we have determined the efficiency of delivering them using commercially available nasal spray devices (Pfeiffer SAP-62602 multidose pump and the BD Hypak SCF 0.5 ml unit dose AccusprayTM).
Results: We report the stability and potency of PBS–diluted ovalbumin–nanomeulsion mixtures for up to 8 months and NaCl-diluted mixtures up to 6 months when stored at room temperature. Significant differences in spray characteristics including droplet size, spray angle, plume width, and ovality ratios were observed between the two pumps. Further, we have demonstrated that the nanoemulsion-based vaccines are not physically or chemically altered and retain potency following actuation with nasal spray devices. Using either device, the measured spray characteristics suggest deposition of nanoemulsion-based vaccines in inductive tissues located in the anterior region of the nasal cavity.
Conclusions: The results of this study suggest that nanoemulsion-based vaccines do not require specially engineered delivery devices and support their potential use as nasopharyngeal vaccine adjuvants.
Keywords: nasal delivery of vaccines, nasal sprayer devices, mucosal adjuvant, aerosol transport and deposition,
nanoemulsion, effects of actuation
PMID: 19778268 [PubMed - in process]
Propagation of uncertainty in nasal spray in vitro performance models using Monte Carlo simulation: part I. Model prediction using Monte Carlo simulation
Guo C,
Doub WH,
Kauffman JF.
Corresponding author: changning.guo@fda.hhs.gov
Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, 1114 Market Street, Room 1002, St. Louis, Missouri 63101
Abstract
Design of experiment (DOE) methodology can provide a complete evaluation of the influences of nasal spray activation and formulation properties on delivery performance which makes it a powerful tool for product design
purposes. Product performance models are computed from complex expressions containing multiple factor terms and response terms. Uncertainty in the regression model can be propagated using Monte Carlo simulation. In this study, four input factors, actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of
surfactant were investigated for their influences on measured responses of spray pattern, plume width, droplet size distribution (DSD), and impaction force. Quadratic models were calculated and optimized using a Box-Behnken experimental design to describe the relationship between factors and responses. Assuming that the models perfectly represent the relationship between input variables and the measured responses, the propagation of uncertainty in both input variables and response measurements on model prediction was performed using Monte Carlo simulations. The Monte Carlo simulations presented in this article illustrate the propagation of uncertainty in model predictions. The most influential input variable variances on the product performance variance were identified, which could help prioritize input variables in terms of importance during continuous improvement of nasal spray product design. This work extends recent Monte Carlo simulations of process models to the realm of product development models. Copyright 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2114–2122, 2010
Keywords: Monte Carlo simulation; nasal drug delivery; design of experiment; in vitro test
PMID: 19902528 [PubMed - in process]
Evaluation of impaction force of nasal sprays and metered-dose inhalers using the Texture Analyser
Guo C,
Ye W,
Kauffman JF,
Doub WH.
Corresponding author: changning.guo@fda.hhs.gov
U.S. Food & Drug Administration, Division of Pharmaceutical Analysis, 1114 Market Street, Room 1002,
St. Louis, Missouri 63101
Abstract
The impaction force from an inhalation product is an important characteristics by which to characterize the spray plume. It is one of the plume characteristics that can be perceived by a patient, and is expected to be good measures of local delivery equivalence for inhalation drugs. A Stable Micro Systems TA-XT.plus Texture Analyser equipped with 750 g load cell was used to measure the impaction force of several nasal sprays and metered-dose inhalers (MDIs). A survey of several commercial nasal spray and MDI products shows that impaction forces of these products varies from 1.5 to 6.5 g force and are significantly different from each other. A 3-level, 4-factor Box-Behnken design was applied to the study of impaction force of nasal sprays using placebo solutions. The influences of four factors: actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant, were investigated. Of those factors examined here, actuation velocity exerts the greatest effect on impaction force. Impaction force is a discriminative parameter for in vitro testing of nasal spray and MDI products. Since impaction force is more directly related to patient sensation and aerosol deposition in the nasal mucus than other, more traditional parameters, it may provide a better way to evaluate in vitro equivalence in support of abbreviated new drug applications (ANDAs) for orally inhaled and nasal drug products. Copyright 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2799–2806, 2009
Keywords: impaction force; nasal spray; MDI; Texture Analyser; design of experiment
PMID: 19097159 [PubMed - indexed for MEDLINE]
Spray pattern and droplet size analyses for high-shear viscosity determination of aqueous suspension corticosteroid nasal sprays
Pennington J,
Pandey P,
Tat H,
Willson J,
Donovan B.
Corresponding author: jennifer.willson@spcorp.com
Schering Plough Research Institute, Oral and Respiratory Product Development, Summit, NJ, USA.
Abstract
Aqueous suspension corticosteroid nasal sprays exhibit the rheological property of shear thinning, meaning they exhibit a decrease in viscosity upon application of shear. Most rheological methods are limited in the amount of shear that can be applied to samples (approximately 1,000 s(-1)) and thus can only approximate the viscosities at the high-shear conditions of nasal spray devices (approximately 10(5)-10(6) s(-1)). In the current work, spray area and droplet size were shown to demonstrate viscosity dependence. Three Newtonian fluids were used to determine equations to approximate viscosity at the spray nozzle from correlations to spray area and droplet size using a standard 100 microL Pfeiffer nasal spray pump. Several shear-thinning solutions, including four commercial aqueous suspension corticosteroid nasal sprays and three aqueous Avicel (1, 2, and 3%, wt/wt) samples, were analyzed to demonstrate the ability of spray area and droplet size analysis to estimate high-shear viscosities. The calculated viscosity values trend in accordance with the rheometer data along with the ability to distinguish differences between all samples analyzed.
Keywords: rheology; Avicel; spray area; droplet size; viscosity; shear thinning
PMID: 18800252 [PubMed - indexed for MEDLINE]
Assessment of the influence factors on in vitro testing of nasal sprays using Box-Behnken experimental design
Guo Ca,
Stine KJb,
Kauffman JFa,
Doub WHa.
Corresponding author: changning.guo@fda.hhs.gov
aDivision of Pharmaceutical Analysis, U.S. Food and Drug Administration, 1114 Market Street, Room 1002, St. Louis, MO 63101, United States
bDepartment of Chemistry and Biochemistry and Center for Nanoscience, University of Missouri at St. Louis, 315 Benton Hall, One University Boulevard, St. Louis, MO 63121, United States
Abstract
The purpose of the research was to investigate the influences of actuation parameters and formulation physical properties on nasal spray delivery performance using design of experiment (DOE) methodology. A 3-level, 4-factor Box-Behnken design with a total of 27 experimental runs was used in this study. Nine simulated aqueous formulations with different viscosities and surface tensionswere prepared using carboxymethylcellulose sodium (CMC, gelling agent) and Tween80 (surfactant) each at three concentration levels. Four factors, actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant were investigated for their influences on measured responses of shot weight, spray pattern, plume geometry and droplet size distribution (DSD). The models based on data from the DOEwere then optimized by eliminating insignificant terms. Pfeiffer nasal spray pump units filled with the simulated formulations were used in the study. Nasal pump actuation stroke length exerts a strong, independent influence on shot weight, and also slightly affects spray pattern and plume geometry. Actuation velocity and concentration of gelling agent have significant effects on spray pattern, plume geometry and DSD, in a complicated manner through interaction terms. Concentration of surfactant has little, if any, influence on nasal spray characteristics. Results were fitted to quadratic models describing the inherent relationships between the four factors evaluated and nasal spray performance. The DOE study helped us to identify the source of variability in nasal spray product performance, and obtained better understanding in how to control the variability. Moreover, the quadratic models developed from the DOE study quantitatively describe the inherent relationships between the factors and nasal spray performance characteristics. With the assistance of the response surfaces developed from the DOE model, the time and labor in designing a nasal spray product to achieve desired product performance characteristics can be reduced.
Keywords: Nasal drug delivery; In vitro testing; Automated actuation; Shot weight; Spray pattern; Plume geometry; Droplet size distribution; Viscosity; Surface tension; Box-Behnken experimental design
PMID: 18832029 [PubMed - indexed for MEDLINE]
Comparison of delivery characteristics from a combination metered-dose inhaler using the Andersen cascade impactor and the next generation pharmaceutical impactor
Guo C,
Gillespie SR,
Kauffman J,
Doub WH.
Corresponding author: changning.guo@fda.hhs.gov
U.S. Food and Drug Administration, Division of Pharmaceutical Analysis, 1114 Market Street, Room 1002, St. Louis, Missouri 63101
Abstract
The purpose of this research was to compare two cascade impaction devices for the aerodynamic particle size assessment of a combination metered-dose inhaler (MDI) product, Combivent1. Particle size analysis was performed using an Anderson Mark II cascade impactor (ACI) and a Next Generation Pharmaceutical Impactor (NGI), both fitted with a preseparator and either a 1 L glass chamber or USP throat, and operated at various flow rates. Particle size distributions (PSDs) and dose delivery profiles were assessed by means of the mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle fraction <5 micron aerodynamic diameter (FPF<5 mm), and induction port deposition fraction (IPF). Under their normal operating conditions, the ACI (28.3 L/min) and the NGI (30 L/min) yield similar PSDs and dose delivery profiles. However, this equivalent performance for the ACI and the NGI no longer exists at a higher flow rate of 60 L/min. Furthermore, changes in PSD results may also be obtained between different operators and/or when different induction port designs were employed. Thus, it is strongly recommended that special care be taken to eliminate variation in experimental parameters and/or selection of ancillary devices such as the preseparator, induction port or throat, to insure good repeatability and reproducibility when testing inhalation drugs. Copyright 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3321–3334, 2008
Keywords:Andersen Cascade Impactor; Next Generation Pharmaceutical Impactor; Combivent; particle size distribution; dose delivery profile; flow rate; induction port; albuterol sulfate; ipratropium bromide
PMID: 17932959 [PubMed - indexed for MEDLINE]
The Influence of Actuation Parameters on In Vitro Testing of Nasal Spray Products
Guo C,
Doub WH.
Corresponding author: changning.guo@fda.hhs.gov
Division of Pharmaceutical Analysis, U. S. Food and Drug Administration, 1114 Market Street, Room 1002, St. Louis, Missouri 63101
Abstract
Nasal spray drug products are normally characterized via measurement of shot weight, spray pattern, plume geometry, and droplet size distribution (DSD). In this project, the actuation parameters, such as stroke length, actuation velocity, and actuation acceleration, were investigated to ascertain how they affect nasal spray characteristics. Pfeiffer nasal spray pump units filled with water were used in the study. Actuation parameters were adjusted using an electronic automated actuation system, SprayVIEWTM NSx. Spray pattern and plume geometry measurements were carried out using a high speed optical spray characterization system, SprayVIEWTM NSP, and DSD analysis was performed using a Malvern 2600 laser diffraction system. Our results show 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 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. The findings from this work suggest that, for in vitro bioavailability (BA) and bioequivalence (BE) studies of nasal spray products, the actuation parameters, stroke length, and velocity must be carefully selected. Spray pattern, plume geometry, and DSD appear to provide critical data for assessment of nasal pump performance. Copyright 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2029–2040, 2006
Keywords: nasal drug delivery;in vitro test; automated actuation; spray pattern; plume geometry; droplet size distribution; laser diffraction; SprayVIEWTM
PMID: 16865693 [PubMed - indexed for MEDLINE]
Spray Pattern Analysis for Metered Dose Inhalers: Effect of Actuator Design
Smyth H1,7,
Brace G2,6,
Barbour T6,
Gallion J3,6,
Grove J4,6,
Hickey AJ5.
1College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA.
2Straightforward Solutions, LLC, Raleigh, NC 27609, USA.
3Tyco Healthcare, Raleigh, NC 27616, USA.
4Straightforward Solutions, LLC, Raleigh, NC 27609, USA.
5School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
6Bespak Inc., Apex, NC 27502, USA.
7To whom correspondence should be addressed. (hsmyth@salud.unm.edu)
Abstract
Purpose. This study was conducted to identify the device factors influencing spray pattern and particle
size to gain a more complete understanding of spray plume measurements.
Methods. A statistically designed experiment was used to investigate the influence of three actuator
features (orifice diameter, expansion chamber depth, and orifice length) on spray pattern and particle
size profiles. Custom-built actuators were manufactured and analyzed with laser light sheet illumination
methods for spray patterns and laser diffraction for particle size analysis.
Results. In addition to orifice size, spray patterns were significantly influenced by the actuator orifice
length and sump depth. Particle size analysis of the plumes generated from actuators used in these
studies showed that all actuator features (orifice size, length, and sump depth) were significant factors
influencing particle size.
Conclusions. The performance of propellant-based metered dose inhaler aerosols seems to be
significantly related to sump depth and orifice length, in addition to orifice size. Rational design of
propellant-based metered dose inhalers should therefore consider these variables in addition to
formulation strategies and simply modifying orifice diameter.
Keywords: aerosol plume; actuator; laser diffraction; pMDIs; spray pattern.
PMID: 16783475 [PubMed - indexed for MEDLINE]
Spray Pattern Analysis for Metered Dose Inhalers I: Orifice Size, Particle Size, and Droplet Motion Correlations
Smyth H1,
Hickey AJ1,
Brace G2,
Barbour T3,
Gallion J4,
Grove J5.
Corresponding author: hsmyth@unm.edu
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
2Straightforward Solutions, LLC, Raleigh, North Carolina
3Bespak Inc., Apex, North Carolina
4Polyzen, Inc. Apex, North Carolina
5AXON Corporation, Raleigh, North Carolina
Abstract
Factors that influence spray pattern measurements of pressurized,
metered-dose inhalers have been evaluated. Spray patterns were correlated with
changes in actuator orifice diameter, particle size profiles, and calculated estimates
of particle-size dynamics of plumes during a spray. Spray patterns, regardless of
actuator orifice size, were ellipsoid in the vertical direction. Measures of elliptical
ratio, major axis, and minor axis were significantly influenced by orifice size in a
non-linear fashion over the range of orifice sizes investigated. Spray patterns also
correlated with particle size profile and spray geometry measurements. Spray distribution
asymmetry may be related to droplet evaporation and sedimentation
processes. However, the spray patterns did not appear sensitive to changes in gravitational
force acting on the plume. Instead, it is postulated that elliptical spray
patterns may have dependence on fluid dynamic processes within the inhaler actuator.
Developing an understanding of these processes may provide a basis for
developing spray pattern tests with relevance to product performance.
Keywords: Aerosol, actuator, laser diffraction, pMDI, respiratory drug delivery
PMID: 17012116 [PubMed - indexed for MEDLINE]