Dr. Richard Dalby, Ph.D., filed this expert report in Evans v. Matrixx Initiatives, Inc., a lawsuit filed in federal court in Florida in 2008. He doubts that Zicam could ever reach the olfactory area of the nose, which is at the top of the nasal cavity.
3. Based on existing data and experience with the delivery characteristics of other nasal products, what is the likelihood that Zicam gel, when used as directed, is deposited or distributed to the roof of the nasal cavity (i.e., the area at and above the upper portion of the superior turbinate) in any significant amount?
Research with other aqueous nasal sprays demonstrates that only droplets smaller than pm in diameter have a significant chance of reaching areas at and above the superior turbinate. Aside from nebulizer-derived aerosols, which typically produce droplets smaller than 10 ??m, commercially available aqueous nasal sprays do not deliver any significant amount of the formulation to the superior turbinate or olfactory region.
Zicam has even less potential to reach the roof of the nasal cavity in any significant amount compared to any other commercially available nasal sprays because of the comparatively large droplet size resulting from its higher viscosity. Due both to its viscosity and to the direction in which a user essentially directs the spray into the interior of the lateral nasal wall, it is highly unlikely that any significant amount of Zicam will reach the olfactory region when the product is used as directed. In many instances, most of the formulation will remain in the nasal opening. On rare occasions when Zicam passes the nasal valve, I expect Zicam to deposit mostly on the leading edge of the inferior turbinate and in the inferior airway (the meatus below the inferior turbinate and above the floor of the nasal cavity).
For these reasons, it is my opinion that no significant amount of the Zicam formulation is likely to come into contact with the superior regions of the nasal cavity when the product is used as directed.
I understand that some researchers have advocated the theory that the combined pump, actuator and formulation of Zicam are “over-powered” and that this would cause the normal protective function of the nose (described above) to be overwhelmed or in some way defeated and allow a significant fraction of the sprayed formulation to reach the olfactory region. This theory has no scientific basis and ignores the likelihood of inertial impaction enhanced by the large size of the droplets in combination with the anatomical obstacles. I am not aware of any scientific evidence that would support such a theory.
I have been asked to answer the following questions by attorneys from Drinker Biddle & Reath LLP, who represent Matrixx Initiatives, Inc., and Zicam, LLC. In doing so, I have drawn on my education, training, research, professional experience, and personal observation of a single unit of Zicam(R) Cold Remedy No-Drip Liquid Nasal Gel (“Zicam”, Lot B40118, Exp. 12/06).
Background and Qualifications
I, Richard Dalby, Ph.D., am a professor of Pharmacy at the University of Maryland School of Pharmacy in Baltimore, Maryland. A copy of my curriculum vitae containing a list of my publications for the past ten years is attached (as Exhibit A). I have been a professor at the University of Maryland since 1992. I have taught courses in various aspects of pharmacy, including the compounding, formulation and delivery of drug products since 1992. I continue to teach an annual Inhalation Aerosol Technology Workshop, started in 1992, that has educated over 400 industrial, government and academic scientists from the U.S. and worldwide, and I remain a co-organizer of Respiratory Drug Delivery, which attracts over 600 of the world's premier pharmaceutical aerosol researchers, executives and regulatory personnel to U.S. meetings and attracted more than 250 to our first European meeting last year. The focus of my research during this time has been on formulation and development of pulmonary and nasally inhaled pharmaceutical products, delivery device design and product evaluation. A particular focus of my work is evaluating how the device and formulation work together, making sure that the product reaches its target and performs as intended, including study of the patterns of drug deposition and distribution in the nasal cavity. My expertise in nasally inhaled pharmaceutical products covers aqueous nasal sprays and nebulizers. I have served as a consultant to over 40 pharmaceutical companies and made presentations at FDA and professional meetings on these topics. In addition, I have served on the FDA's Expert Committee on Pharmaceutical Sciences' subcommittee on Orally and Nasally Inhaled Drug Products (ONIDP).
I am being compensated for my time spent on this case at the hourly rate of $ 400.
The following materials were reviewed and considered by me in the course of forming my opinion. The were sent to me by the attorneys representing Matrixx Initiatives, Inc., and Zicam, LLC:
• Matrixx Pilot Study of Distribution of Zicam Spray in Nasal Passages by Patricia Hebda, Ph.D., Berrylin Ferguson, M.D., and Joseph Dohar, M.D., M.S., on 4/27/04.
• Documents pertaining to University of Pittsburg Pilot Study To Assess The Intranasal Deposition Of Zicam.
• The patent filed 6/26/00 to Gel Tech, LLC, relating to Zicam, product and pump specifications.
• Botanical Laboratories, Inc., Product Master Formula dated 12/29/98 and 9/22/99.
• Botanical Laboratories, Inc., Interoffice Memo dated 10/2/99 from Rachel to Mary Beth, Jim C., and John regarding Zicam, Data on Proposed Sprayer.
• Zicam Cold Gel Material Safety Data Sheet dated 6/24/03.
• Certificate of Conformity for Gel Tech, LLC, from Valois Pharm.
• Certificate of Compliance from Calmar dated 4/5/00.
• Fax from Edward W. Baumann Jr. at Calmar Inc. to Jackie-Wilson dated June 22, 2000, regarding Zicam M-150 Nasal Sprayer Specification.
• Botanical Laboratories, Inc., Interoffice Memo dated 4/11/01 from Roger S. to Mary Beth W. and Carol C. regarding the evaluation of the nasal sprayers supplied by Gel Tech.
• Memorandum dated 12/19/01 from Mojdeh Vahid to Carol Childress regarding the Pfeiffer Sprayer compared to Calmar Sprayer.
• Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults by S.B. Mossad. QJM, Volume 96, number 1 (2003) pp 35-43.
• Zinc nasal gel for the treatment of common cold symptoms: A double-blind, placebo-controlled trial by Michael Hirt, MD, Sion Nobel, MD and Ernesto Barron, BS. Reprinted in the ENT Journal, October 2000, Volume 79, Number 10.
• Specifications of the Pfeiffer nasal pump and bottle.
• Effective Application of Nasal Steroid Spray in Common Practice by Richard Lebowitz MD, Suzanne Doud Galli MD, PhD. Operative Techniques in Otolaryngology-Head and Neck Surgery, Vol 12, No 2 (JUN), 2001; pp 112-114.
• Development of Nasal Delivery Systems: A review by Jack Aurora, PhD. Drug Delivery Technology.
• Controlled Particle Dispersion: Applying Vortical Flow to Optimize Nasal Drug Deposition by Marc Giroux, Peter Hwang MD and Ajay Prasad PhD. Drug Delivery Technology, March 2005, Vol 5, No 3.
• Comparison of Topical Medication Delivery Systems after Sinus Surgery by Timothy Miller MD, Harlan Muntz MD, M. Erik Gilbert MD, Richard Orlandi MD. Laryngoscope 114: February 2004.
• Radionuclide Imaging Studies in the Assessment of Nasal Drug Delivery in Humans by Stephen Newman and Lisbeth Illum. Am J Drug Deliv 2004: 2 (2): 202-112.
• Scintigraphic Assessment of the Oropharyngeal and Nasal Depositions of Fusafungine from a Pressurized Inhaler and from a Novel Pump Spray Device by $.P. Newman, K.P. Steed, G. Hooper and J. Brickwell. J. Pharm. Pharmacol. 1995, 47: 818-821.
• The Distribution of an Intranasal Insulin Formulation in Healthy Volunteers: Effect of Different Administration Techniques by S.P. Newman, K.P. Steed, J.G. Hardy, I.R. Wilding, G. Hooper and R.A. Sparrow. J. Pharm. Pharmacol 1994, 46: 657-660.
• The delivery of topical nasal sprays and drops to the middle meatus: a semiquantitative analysis by A Tsikoudas and J.J. Homer. Clin. Otolaryngol. 2001, 26, 294-297.
• Anosmia after Intranasal Zinc Gluconate Use by Bruce Jafek MD, Miriam Linschoten PhD and Bruce Murrow MD, PhD. American Journal of Rhinology, May-June 2004, Vol. 18, No. 3.
• Poster presentation by Bruce Jafek, Miriam Linschoten and Bruce Murrow.
• Study: Anatomic Distribution and Transport of a Topical Liquid Nasal Gel by Lawrence DeSanto MD and Jesus Herranz MD.
• Bottle of Zicam(R) Cold Remedy Nasal Gel.
• Guidance for Industry, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - Chemistry, Manufacturing, and Controls Documentation. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2002. (FDA to GOV reference).
• The Effect of Formulation Variables and Breathing Patterns on the Site of Nasal Deposition in an Anatomically Correct Model. Yang Guo, Beth Laube and Richard Dalby. Pharmaceutical Research (Published online, August 2005).
• Drug Delivery to the Nasal Cavity: In Vitro And In Vivo Assessment. Stephen P. Newman, Gary R Pitcairn and Richard N. Dalby. Critical Reviews in Therapeutic Drug Carrier Systems, 21 (1), 21-66, 2004.
• Nasal Nebulizers Versus Nasal Spray Pumps: An Investigation Of Deposition And Mucociliary Clearance. Julie Suman, Beth L. Laube and Richard N. Dalby. Pharmaceutical Research, 16 (10): 1648-1652 (1999).
• Deposition Transcript of Terence M. Davidson M.D. dated March 14, 2005 in Susan Nelson v. Matrixx Initiatives, Inc.
• Deposition Transcript of Terence M. Davidson M.D. dated May 3, 2006 in Julie Gillespie v. Matrixx Initiatives, Inc.
• Deposition Transcript of Terence M. Davidson M.D. dated September 15,
• 2006 in Dennis O'Hanlon v. Matrixx Initiatives, Inc.
• Deposition Transcript of Terence M. Davidson M.D. October 5, 2007 in Angelo Bruno v. Matrixx Initiatives, Inc.
• Report of Terence M. Davidson M.D. dated October 15, 2007 in concerning William Seckman
• Report of Terence M. Davidson M.D. dated February 7, 2008 in concerning William Seckman
• Alexander and Davidson, Intranasal Zinc and Anosmia: The Zinc-Induced Anosmia Syndrome, Laryngoscope 116: February 2006 217-220
• J. Herranz Gonzalez-Botas, N. Galindo Campillo, L.W. DeSanto, M. Garcia Simal, Anatomical distribution and transport of a liquid nasal gel, Acta Otorrinolaringologica Espanol 57(3):130-133 (2006) (as translated)
• David G. Laing, Natural sniffing gives optimum odour perception for humans, Perception 12:99-117 (1983)
• Isabelle A. Torbier and Richard Doty, Sniff magnitude test: Relationship to odor identification, detection, and memory tests in a clinic population, Chem. Senses May 2007
• Julie D. Suman, Beth L. Laube, Ta-chun Lin, Guillaume Brouet, and Richard Dalby, Validity of in vitro tests on aqueous spray pumps as surrogates for nasal deposition, Pharm. Research 19(1):1-6 (2002)
• Sinus Drug Delivery: Science Versus Anecdotes. Beth L. Laube. Respiratory Drug Delivery Europe 2007 (ISBN 1-933722-07-X), p159-198, Davis Healthcare International Publishing, River Grove, IL, April 2007.
• Numerical Modeling of Turbulent and Laminar Airflow and Odorant Transport during Sniffing in the Human and Rat Nose. Kia Zhao, Pamala Dalton, Geoffery C. Yang and Peter W. Scherer. Chemical Senses. 31(2):1-7-18, 2006.
• An impairment in sniffing contributes to the olfactory impairment in Parkinson's disease. Noam Sobel, Moriah E. Thomason, Iris Stappen, Caroline M. Tanner, James W. Tetrud, James M. Brower, Edith V. Sullivan and John D.E. Gabrieli. Proceedings of the National Academy of Sciences of the United States of America. 98(7):4154-9, March 2001.
I have been asked by attorneys from Drinker Biddle & Reath LLP to list trials or depositions in which I have participated:
• On December 19, 2007, I was deposed in a patent dispute between MEDPOINTE HEALTHCARE INC. (Plaintiff) and APOTEX INC. and APOTEX Corp. (Defendants). I was hired by Kirkland and Ellis LLP, who represent MEDPOINTE. The deposition occurred in New York, NY, and I believe the case fell under the jurisdiction of the United States District Court For The District Of Delaware.
• On February 6, 2007, I gave testimony in a case involving Barbara Lusch (Plaintiff) and Matrixx Initiatives, Inc. (Defendant). I was hired by Drinker, Biddle and Reath LLP, who represent Matrixx Initiatives. The trial (Case No. CV-05-292-HA) occurred in Portland in the US District Court, District of Oregon.
• On May 26, 2006, I was deposed in a case involving Susan Wyatt (Plaintiff) and Matrixx Initiatives, Inc. (Defendant). I was hired by Drinker, Biddle and Reath LLP, who represent Matrixx Initiatives. The deposition was in Baltimore, MD, and I believe the case fell under the jurisdiction of the United States District Court, Northern District of Alabama, Southern Division.
• On December 6, 2005, I was deposed in a patent dispute (Case Numbers SACV 04-00079 CJC (FMOx) and SACV-04-00243 CJC (FMOx)) between DEY, L.P (Plaintiff) and Ivax Pharmaceuticals, Inc. and Eon Labs, Inc. (Joint Defendants). I was hired by Cohen, Pontani, Lieberman & Pavane and Mayer, Brown, Rowe & Maw LLP, who represent Eon and Ivax respectively. The deposition occurred in Washington, D.C., and I believe the case fell under the jurisdiction of the United States District Court, Central District Of California.
• On January 13, 2005, I was deposed in a patent dispute (Patent Interference No. 105,219) between Quadrant Drug Delivery Ltd. (U.S. Patent No. 6,290,991 B1, Junior Party) and Nektar Therapeutics (U.S. Patent Application No. 10/245,722, Senior Party). I was hired by Morrison & Foerster LLP, who were representing Quadrant. The deposition occurred in California, and I believe the case fell under the jurisdiction of the United States Patent and Trademark Office, Board of Patent Appeals and Interferences.
• On December 19, 2002, I participated in a hearing before the European Patent Office in Munich, Germany. I was hired by Simmons and Simmons, who were representing Glaxo Group Limited in a patent opposition dispute (European Patent No. 0616524) against Rhone-Poulenc Rorer Limited.
Answers
All of the opinions expressed in this report are held to a reasonable degree of scientific probability.
1. What are the factors and variables that affect the extent of nasal drug deposition and distribution for aqueous nasal sprays?
When compiling my answers, I have defined a nasal spray drug product (using the FDA description in the “Guidance for Industry” cited above) as a system containing “therapeutically active ingredients (drug substances) dissolved or suspended in solutions or mixtures of excipients (e.g., preservatives, viscosity modifiers, emulsifiers, buffering agents) in nonpressurized dispensers that deliver a spray containing a metered dose of the active ingredient.” Nasal sprays of this type contain drugs and excipients in a mostly water-based formulation and are described as “aqueous.” Such nasal spray units consist of a bottle to hold the formulation to be sprayed, a valve which meters out a specific volume of formulation each time it is pressed (or “actuated”) by the patient, and an actuator that both allows pressure to be exerted on the stem of the valve by the patient's applied finger force (which discharges the formulation) and directs the resulting spray from the tip of the actuator's nozzle into the nose. Zicam is a nasal spray drug product as I have defined it.
Several features of nasal spray drug products have the potential to influence the initial deposition site and the ultimate locations reached by the droplets that comprise the spray. These are (1) nasal anatomy and physiology, (2) the design of the nasal spray unit hardware (sometimes called the “delivery system”), (3) the formulation and (4) the manner in which the spray is generated and administered by the patient.
The anatomy and physiology of the nose play a critical role in determining where nasal sprays ultimately deposit following self-administration by a patient. This assertion is easily understood when the internal structure of a typical nose is considered. The nasal cavity is divided by the nasal septum into left and right halves. Beyond the entrance to each nostril (“the nasal opening”) is a constriction in the airway (sometimes called “the nasal valve”) located adjacent to the internal ostium. The constriction has an internal diameter of approximately 0.3 cm beyond which the airway bends through approximately 90 degrees before reaching the turbinates, which are folds of the nasal lateral wall that project into the airway. Typically, anatomists identify an inferior (lower), middle and superior (upper) turbinate with a narrow airway or meatus between each one. Above the superior turbinate, a portion of the ceiling of the nasal cavity is densely covered by olfactory receptors. This area is termed the olfactory region. During normal use, the tip of the actuator (“the nozzle”) of a nasal spray cannot be inserted into the nostril deeper than the nasal valve. The angle of insertion of the tip of an actuator nozzle cannot be varied beyond the angle permitted by the interior dimensions of the nostril, constraining placement of the nozzle.
Based on this anatomy, it seems improbable that without intentional tissue shrinkage and/or anaesthesia one could insert a rigid rod with a diameter of greater than about mm more than approximately 1.5 cm into either nostril on a straight path between the nostril and the olfactory region - which is usually at least 5-6 cm away at an angle of around 45 degrees to the horizontal in a standing patient - without its path being blocked by the bony projections described above. Changes in insertion angle of the rod would not reduce the validity of this observation. It is of course possible to direct a flexible object or a thinner rigid rod, such as a nasal scope, around the internal structures.
Not only do the bony projections of the nasal cavity deny direct, straight line access to the olfactory region for rigid objects or liquid streams, such as that delivered by a high viscosity nasal spray such as Zicam (because neither can easily change course once started in a given direction), but the nasal valve and the leading surfaces of the turbinates collectively produce conditions known to trap airborne particles inhaled via the nose, primarily by a process called “inertial impaction.” This is unsurprising since one of the functions of the nose is to prevent airborne particles from reaching the lungs during inhalation. Droplets of nasal spray directed into the nose are likely to be trapped in the anterior part of the nose very efficiently, and I have seen no evidence to suggest that more than 2-3% of the output from a nasal spray reaches the lungs.
In brief, the reason for this is that particles moving in an air stream develop momentum in their direction of travel, and the more momentum they have, the more difficult it is for them to stop or change direction if a solid object is placed in their path. Momentum is highest when the particles are large (this increases their mass) and/or their velocity is high. Both conditions exist in aqueous nasal sprays as the formulation exits the nozzle - whether or not the patient is inhaling through their nose at the time. Large, fast moving droplets exiting the nozzle of the nasal spray are forced to change direction as they pass from the nostril into the airway between the turbinates. Most are unable to make this direction change and impact on the leading edge of the turbinates.[FN1] In my opinion, most impaction will occur on the inferior turbinate. Impaction theory is generally accepted and supported by observations in nose models, healthy volunteers and patients. Because sprayed droplets are wet, and the turbinates are covered with mucous, droplets adhere to the turbinates, and the action of cilia that line this region of the nasal cavity carries them towards the back of the nasal cavity (the nasopharynx), from where they are ultimately swallowed. Cilia beat in a highly directional and coordinated way and do not carry particles towards the olfactory region.
FN1. While inertial impaction can seem complex, it is easily understood if one considers a car attempting to drive through a hairpin turn. If the car is travelling too fast or it is a large, heavy SUV, it is likely to hit (or impact) the crash barrier. If the car travels more slowly or is a smaller, lighter sports car, it is likely to make the turn successfully.
From the above description, it is clear that anything which influences the size, speed or direction of droplets in a nasal spray can potentially influence where they deposit. This includes design features of the pump, particularly those of the swirl chamber and the internal diameter of the spray orifice. Because the patient's finger force is used to drive formulation out of the metering chamber of the pump and extrude it via the nozzle orifice as droplets or a liquid stream, characteristics of the patient actuation can influence the resulting spray. Such patient variables include (1) applied force, (2) displacement, (3) acceleration during displacement stroke, (4) hold time, (5) acceleration during metering chamber refilling and (6) the delay between successive actuations. The fate of the spray will additionally depend on other patient variables, such as (1) the angle of tip insertion, (2) the depth of tip insertion and (3) any airflow through the nose at the time of spraying.
The components of the formulation also exert an influence on the size, speed or direction of droplets. The most profound influence is mediated by dissolved and/or dispersed polymers added to increase the viscosity of the formulation in an attempt to minimize dripping and/or increase the retention time of the formulation in the nose. Formulations with the highest viscosities are associated with the largest droplets and the narrowest spray patterns (closely approximating a stream of liquid rather than a cone of droplets). All other factors being equivalent, such formulations would be expected to have a lower velocity at the point of extrusion from the nozzle tip, in view of the additional energy needed to force the viscous formulation in the container through the narrow spray orifice.
Not withstanding the above sources of variability, in my experience and in the literature, most aqueous nasal sprays have a droplet mass median aerodynamic diameter exceeding 50 pm (micrometer or micron). They produce a very small percentage of droplets smaller than 10 pm. Hence, deposition in the anterior (front) part of the nasal cavity is probable (more likely than not), and penetration into the more distal and superior parts of the nasal cavity, or through the nose and into the lungs, is unlikely no matter how a patient breathes. Even smaller droplets (such as produced by a nebulizer and in the 2-7 ??m size range) are unlikely to reach the distal and superior regions, which include the olfactory region. When these smaller particles and volatile molecules do reach the olfactory region, it is because they can follow the inhaled air stream (with less deposition attributable to inertial impaction or other deposition mechanisms) or diffuse to regions with only minimal air flow. This is the reason we can smell fragrant oils - odorant molecules or small particles (less than 10 ??m) dispersed in air - but not large particles (around 50 ??m), which do not reach the olfactory region. For this reason, researchers with an interest in targeting drugs to the brain via the olfactory region do so using nebulizers, not aqueous spray pumps. Little has been published on the influence of the angle of spray nozzle insertion or the angle of the patient's head during spraying on deposition site, and the labelled instructions on commercial products describe several orientations. In my view, ordinarily, inertial impaction of larger droplets is not likely to be sensitive to these variables because they do not influence the size, velocity or relative direction of the emerging spray as it enters the nose. However, in the extreme case in which a patient sprays directly towards the wall of the nasal cavity, this reduces the distance available for droplets to turn into the airway and would lead to a high probability of impaction in the nasal opening.
According to the labelling of commercial products, there is no generally accepted way in which patients are instructed to breathe during use of a nasal spray. Patients may be instructed to inhale through the open nostril (the one not occluded by the tip of the nasal actuator) or to hold their breath during spraying. With a constant inhalation flow rate of 125 ml/s (7.5 I/min), the flow pattern in the nasal cavity is reported to be laminar with regions of highest velocity in the nasal valve and the inferior airway (consistent with droplet impaction in these regions). Very little air flow has been reported in the olfactory region at this flow rate, and certainly none would be expected if a patient is not inhaling through their nose. In either case, it is difficult to envision a mechanism by which 50 pm droplets might reach the olfactory region.
2. How do they apply in the context of Zicam(R) Cold Remedy Nasal Gel delivered via the nasal pump when the pump is used according to the package directions?
Zicam has a viscosity much higher than other commercially available nasal sprays. Zicam produces large droplets, easily visible to the eye. Formulations like Zicam will enter the nasal opening as a liquid stream or large droplets and be extremely resistant to changes in direction, making it highly likely that droplets will impact and adhere to surfaces in the lower region of the nasal cavity.
Attached as Exhibit B is a copy of the side of the box in which Zicam is supplied. The relevant instructions of Zicam's labelling that might affect the location of deposition read as follows:
4. “Place tip of nozzle just past nasal opening (approximately 1/8”).”
5. “While inside nasal opening, slightly angle nozzle outward.” (In addition, the side of the box in which Zicam is supplied (Exhibit B) shows a schematic diagram which further illustrates the intended angle of nozzle tip insertion into the nasal opening.)
6. “Pump once into each nostril. To avoid possible irritation, do not sniff up gel.”
Instructions 4 and 5 would aim the fast moving sprayed stream or droplets directly into the interior lateral wall of the nasal opening. Close to the spray orifice, the liquid stream or droplets will have their maximum velocity, and there will be either little or no distance from the orifice to the interior lateral wall of the nose. These are conditions conducive to maximal impaction of formulation (which means there are likely to be few droplets introduced into the nasal opening or deeper into the nose). In addition, instruction 5 makes it extremely unlikely that the emerging liquid stream would be directed towards the opening to the nasal valve.
Following instruction 6 ensures that the patient is not inhaling when Zicam is sprayed into the nose. This removes the possibility that any small droplets that were produced (an unlikely eventuality) would be carried deeper into the nose. The last sentence in instruction 6 warns a patient against sniffing after the formulation has been deposited in the nose, which precludes the possibility that formulation could be dislodged from the nasal opening and transferred to a deeper region of the nose.
Taken together, the recommended insertion depth and angle instructions essentially direct the spray into the lateral nasal wall in the lower part of the nasal opening. Under these circumstances, the liquid stream or droplets will most likely impact and adhere to the surfaces in the lower nasal opening and remain there.
As referenced above, Zicam's labelling does not direct the patient to inhale while using the product and specifically warns, “To avoid possible irritation, do not sniff up gel.” Even if a patient ignores the labelled instructions and inhales through their nose when using Zicam, at most, an insignificant amount of each dose would be contained in droplets small enough to follow the minimal air-flow that might pass the olfactory region.
In my opinion, an unbroken stream of liquid would not be diverted significantly. Zinc Gluconicum is non-volatile, so almost none of the active ingredient will be molecularly dispersed in air and capable of reaching the olfactory region by diffusion alone. In conclusion, the combination of high viscosity and large droplet size of the sprayed formulation, characteristics of nasal anatomy and physiology, and the directions for use make it very unlikely in my opinion that a significant amount of Zicam will reach the olfactory region when the product is used as directed.
3. Based on existing data and experience with the delivery characteristics of other nasal products, what is the likelihood that Zicam gel, when used as directed, is deposited or distributed to the roof of the nasal cavity (i.e., the area at and above the upper portion of the superior turbinate) in any significant amount?
Research with other aqueous nasal sprays demonstrates that only droplets smaller than pm in diameter have a significant chance of reaching areas at and above the superior turbinate. Aside from nebulizer-derived aerosols, which typically produce droplets smaller than 10 ??m, commercially available aqueous nasal sprays do not deliver any significant amount of the formulation to the superior turbinate or olfactory region.
Zicam has even less potential to reach the roof of the nasal cavity in any significant amount compared to any other commercially available nasal sprays because of the comparatively large droplet size resulting from its higher viscosity. Due both to its viscosity and to the direction in which a user essentially directs the spray into the interior of the lateral nasal wall, it is highly unlikely that any significant amount of Zicam will reach the olfactory region when the product is used as directed. In many instances, most of the formulation will remain in the nasal opening. On rare occasions when Zicam passes the nasal valve, I expect Zicam to deposit mostly on the leading edge of the inferior turbinate and in the inferior airway (the meatus below the inferior turbinate and above the floor of the nasal cavity).
For these reasons, it is my opinion that no significant amount of the Zicam formulation is likely to come into contact with the superior regions of the nasal cavity when the product is used as directed.
I understand that some researchers have advocated the theory that the combined pump, actuator and formulation of Zicam are “over-powered” and that this would cause the normal protective function of the nose (described above) to be overwhelmed or in some way defeated and allow a significant fraction of the sprayed formulation to reach the olfactory region. This theory has no scientific basis and ignores the likelihood of inertial impaction enhanced by the large size of the droplets in combination with the anatomical obstacles. I am not aware of any scientific evidence that would support such a theory.
4. Are you aware of any scientific evidence that exit velocity significantly affects the location of deposition of an aqueous nasal spray?
No. Spray exit velocity from the tip of an aqueous nasal spray is not routinely measured. The potential for inertial impaction (mostly mediated through particle size) is considered the main predictor of location of deposition.
Only when particles entering the nose become much smaller than those typically emitted from aqueous nasal sprays (including Zicam) might particle velocity become the dominant source of their momentum and potentially influence their site of deposition. In fact, pressurized nasal sprays (those powered by propellants, not the patient's finger force) tend to deposit mostly in the front of the nose, and this is usually attributed to their higher exit velocity. Based on this observation, even if Zicam exited the spray nozzle faster than other aqueous nasal sprays, this should reduce rather than increase its chances of reaching the olfactory region.
5. Is it generally accepted in the scientific community that the olfactory epithelium is readily accessible for delivery of an aqueous nasal spray? Is it generally accepted that it is not readily accessible for delivery of such a spray?
As I discussed above, the characteristics of most aqueous nasal sprays, particularly their large droplet size combined with the fundamental anatomy of the nose and particularly the sheltered location of the olfactory region, make access to the olfactory region extremely limited. It is for this reason that olfactory drug targeting (and the related but controversial idea that drugs delivered to the olfactory region might enjoy preferential access to the brain) is primarily researched using nebulizers in humans. In my opinion, the olfactory epithelium is not considered readily accessible to aqueous nasal sprays by researchers in the field of nasal drug delivery, and this view is widely held within the scientific community.
6. Is it generally accepted in the scientific community that sniffing after use of aqueous nasal sprays would increase the probability of the sprayed formulation reaching the olfactory epithelium?
I am aware of very few studies that address the influence of sniffing on the location of nasal sprays. The Newman paper suggests that it has no significant impact on where a sprayed formulation deposits, so sniffing does not change my conclusions above. In as much as sniffing represents a transient increase in the flow-rate of air inhaled into the nose I would expect it to increase rather than decrease impaction on the turbinates if the sniff is concurrent with formulation release, and not to dislodge and redistribute formulation if the sniff occurs after the formulation is initially deposited. The Pittsburgh and Spanish studies are the only studies I know that address the influence of sniffing (confounded by other modes of misuse) on the location of Zicam deposition. Taken overall, these studies on human subjects suggest that sniffing does not significantly increase the possibility that Zicam would reach the olfactory region.
