(Chest. 2005;128:4036-4040.)
© 2005
American College of Chest Physicians
Heat Decreases Formoterol Delivery*
Richard A. Robbins, MD;
Allen R. Thomas, MD;
Lynda M. Proctor, PharmD;
Jeffrey C. Hoyt, PhD and
John M. Hayden, PhD
* From Pulmonary and Critical Care Medicine, Pharmacy Department, and Research Service, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ.
Correspondence to: Richard A. Robbins, MD, Pulmonary and Critical Care Medicine, Carl T. Hayden VA Medical Center, 650 East Indian School Rd, Phoenix, AZ 85012; e-mail: Richard.Robbins2{at}med.va.gov
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Abstract
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Study objectives: Based on anecdotal reports of formoterol aggregating in mailboxes in the summer in Arizona, we examined the effect of heat on formoterol as well as on drug delivery.
Design: Formoterol capsules in original blister packaging were heated to 40 to 70°C (104 to 158°F) for 3 h and at 70°C (158°F) for 15 to 180 min. Capsules were removed from packaging, and a vacuum setup was used to dispense the formoterol into a filter using the device provided by the manufacturer. The weights of the capsule predispensation and postdispensation were measured to calculate drug delivery. Measurements were compared to those of capsules not exposed to heat. For comparison, tiotropium and a combination of fluticasone propionate and salmeterol (Advair; GlaxoSmithKline; Research Triangle Park, NC) were similarly tested.
Results: Visual inspection of the heated capsules revealed gross distortion as well as visible clumping of formoterol at the higher temperatures. The mean (± SEM) change in the weights of capsules that underwent heating were significantly less than those obtained from capsules that had not been heated (mean change after heating for 3 h at 70°C, 2.3 ± 0.7 vs 24.7 ± 0.6 mg, respectively; p < 0.001), indicating decreased formoterol delivery. Heat produced a dose-responsive and time-responsive decrease in formoterol delivery. One of six capsules that were subjected to temperatures as low as 40°C (104°F) for 3 h had decreased delivery, and three of six capsules subjected to a temperature of 70°C (158°F) for times as short as 30 min decreased delivery. In contrast, neither tiotropium nor fluticasone propionate/salmeterol delivery was decreased by heating for up to 3 h at 70°C (158°F). Thermometers placed in mailboxes or in car windows in mid-summer in Arizona (approximate outside temperature, 110°F [43°C]) exceeded 70°C (158°F).
Conclusions: These data demonstrate that the exposure of formoterol to heat decreases drug delivery and that caution should be used when mailing, transporting or storing formoterol.
Key Words: bronchodilator • capsule • drug delivery • formoterol • heat • powder
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Introduction
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The delivery of inhaled bronchodilators for the treatment of asthma and COPD has been frequently studied, and involves correct patient use, factors such as inspiratory flow rate and time, as well as the physicochemical properties of the drug such as particle size and solubility.1 Studies of drug delivery are usually performed under optimal study conditions. However, studies examining physicochemical alteration of the drug such as extremes of temperature, humidity, and sunlight are usually performed initially in the laboratory. From these studies, recommendations for shipment and storage are made.
The use of mail-order pharmacies appears to be increasing both in the private sector as well as in the Veterans Healthcare Administration.2 It is usually assumed that the conditions of mail shipment approximate room temperature and humidity. However, it seems likely that shipped medications might be subjected to extremes in temperature such as those during the time spent in a mailbox prior to patient pick up. In addition, medications already in the patient’s possession might be subjected to environmental extremes such as being left in an automobile for an extended time on a hot day.
The environment in Arizona, where outside temperatures routinely exceed 40°C (104°F) during the summer months, can be at the extremes of temperature. One of us (LMP) received several reports from patients that formoterol capsules, a bronchodilator that is delivered by inhalation, appeared distorted after they arrived by mail. For this reason, we developed a simple method to study inhaled bronchodilators such as formoterol in the laboratory. The results suggest that the exposure of formoterol to heat decreased drug delivery under simulated conditions.
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Materials and Methods
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Heat Exposure
Formoterol fumarate inhalation powder (Foradil; Novartis Pharma AG; Basel, Switzerland) was stored in the hospital pharmacy prior to testing under conditions of heat and humidity recommended by the manufacturer.3 After visually inspecting at least one capsule, capsules in their blister packaging were placed in a laboratory dry heat oven at various temperatures for various lengths of time. The capsules were removed from the blister packaging and after a brief period of cooling (approximately 5 min) were subjected to delivery testing. For comparison purposes, tiotropium (Spiriva; Boehringer Ingelheim; Ridgefield, CT) and fluticasone/salmeterol (Advair 100/50; GlaxoSmithKline; Research Triangle Park, NC) were similarly heated.
Powder Delivery
After heating, the capsule was weighed. The capsule was placed in the well of the inhaler (Aerolizer; Schering-Plough; Kenilworth, NJ) supplied with the capsules, and the capsule was pierced by pressing and releasing the buttons on the side of the device. A plastic tubing adapter was connected to the inhalation port of the inhaler, which contained a loosely packed glass wool filter to trap the inhaled powder. The plastic tubing adapter was connected to a vacuum pump producing a flow of 10 to 12 L/min. This produced a whirring noise from the capsule spinning in the inhaler. After 15 s, the vacuum pump was removed, the capsule was inspected, and the amount of formoterol removed was visually assessed. The capsule was weighed again, and the amount of drug delivered calculated by subtracting the amount of weight of the capsule from the prevacuuming weight.
Tiotropium was similarly compared to formoterol with incubation of the capsules at room temperature, and at 70°C (158°F) for 0.5, 1, 2, and 3 h. The tiotropium capsules were placed in an inhalation device (HandiHaler; Boehringer Ingelheim; Ridgefield, CT), and the capsule was punctured by two large barbs and subsequently subjected to 15 s of suctioning.
The fluticasone propionate/salmeterol (Advair; GlaxoSmithKline) comes in a sealed inhaler (Discus; GlaxoSmithKline). For this reason, the entire inhaler was weighed. The lever on the inhaler that advances a rotating strip within it to dispense the powder was advanced, and the powder was suctioned five to six, as described above. The entire inhaler was weighed after each inhalation, and the decrease in weight was calculated. The entire inhaler was heated, and the powder was suctioned five to six times after 0.5, 1, 2, and 3 h at 70°C (158°F). After removing the inhaler for weighing after heating, the it was returned to the dry heat oven for additional heating.
Statistical Analysis
Results were expressed as the mean ± SEM and were compared using the two-tailed Student t test. Significance was defined as p < 0.05.
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Results
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Visual Inspection
Visual inspection of the formoterol capsules revealed some capsules with powder that was partially or completely retained in the capsule. This occurred even at lower temperatures with one capsule having no powder removed at 40°C (104°F), and increasing amounts of powder were retained in capsules that were subjected to higher temperatures (Fig 1
).
To ensure that the powder was not removed due to weak suction by our system, in several instances (including the single capsule in which powder did not appear to be removed at 40°C [104°F]); the capsule was replaced in the inhaler (Aerolizer). One of us (RAR) inhaled through the inhaler according to the instructions of the manufacturer. No additional powder was removed as assessed by visual inspection and repeat weighing.
At higher temperatures, the capsules became increasingly distorted and shortened. When capsules were particularly shortened, they were replaced in the Aerolizer with the cover open and the barbs pressed. In each instance, the barbs appeared to contact the capsule, although in some instances the barbs could not be seen to pierce the capsule nor was the sound that occurs with puncture of a capsule heard.
Increasing the time at which capsules were heated at 70°C (158°F) also decreased powder removal (Fig 2
). Exposure to 70°C (158°F) for 15 min had no apparent effect, while capsules exposed for 
30 min produced retained powder and increasing capsule distortion.
In contrast, none of the tiotropium capsules appeared to be distorted. However, the tiotropium capsules are opaque, and for this reason several of the capsules were opened. No retained clumped powder was observed. Visual inspection was not performed on the inhaler (Advair Discus) due to it being sealed.
Powder Delivery
Capsules exposed to temperatures of 40 to 70°C (104 to 158°F) for 3 h had increasing weights after vacuuming that was associated with the visual confirmation of retained powder (Fig 3
). In some instances, this appeared to be an all-or-none phenomenon, with some capsules having nearly all their powder retained while others had none retained. At temperatures of 40°C (104°F), 50°C (122°F), 60°C (140°F), and 70°C (158°F), respectively, one of six, two of six, four of six, and six of six capsules had weight changes of < 3 mg.
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Figure 3. Change in capsule weight with increasing temperature for 3 h. Temperature is indicated on the horizontal axis. After heating, the capsule was punctured in the inhaler device (Aerolizer) and the contents of the capsule were removed by vacuum suction trapping. The difference in weight of the capsule before and after vacuuming is on the vertical axis. Control consisted of capsules stored in a refrigerator and left at room temperature (25°C, 77°F) for approximately 5 min prior to vacuuming. n = 6 for each time point. * = p < 0.05 compared to the control.
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Increases of time at 70°C (158°F) also resulted in increased capsule weights after vacuuming (Fig 4
). No effect was observed after 15 min compared to the control. After 30 min, three of six capsules had weight decreases of < 3 mg. Increasing time produced increasing capsule weights after vacuuming.
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Figure 4. Change in capsule weight with increasing time at 70°C (158°F). Time exposed to 70°C (158°F) is on the horizontal axis. After heating, the capsule was punctured in the device (Aerolizer) and the contents of the capsule were removed by vacuum suctioning the capsule that was weighed. The difference in weight of the capsule from prevacuuming is on the vertical axis. The control (0 time) was not exposed to 70°C (158°F) temperature. n = 6 for each temperature. * = p < 0.05 compared to the control.
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In contrast, heating at 70°C (158°F) for 0.5 to 3 h did not decrease the change in weight of either the tiotropium or the inhaler (Advair Discus) compared to baseline values. The mean (± SEM) change in weight of the tiotropium capsules was 4.9 ± 0.1 mg at room temperature and 4.6 ± 0.1 mg after 3 h of heating at 70°C (158°F) [p > 0.05]. The change in weight of the tiotropium capsules incubated for 0.5, 1, and 2 h also did not differ compared to capsules maintained at room temperature (p > 0.05 for all comparisons). Similarly, the mean change in weight of the inhaler (Advair Discus) was 11.5 ± 2.0 mg at room temperature and 9.1 ± 2.6 mg after 3 h at 70°C (158°F) [p > 0.05]. The change in weight of the inhaler incubated for 0.5, 1, and 2 h also did not differ compared to capsules that were maintained at room temperature (p > 0.05 for all comparisons).
Temperature Extremes in Arizona
To confirm that temperatures could exceed 70°C (158°F), a standard laboratory thermometer was placed in a mailbox and on a car dash. Both the mailbox and the dash were in direct sunlight, and the outside ambient temperature was approximately 110°F (43°C) at the time of testing. In both instances, the temperatures exceeded 70°C (158°F).
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Discussion
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The present study demonstrates that heating formoterol to temperatures that might be encountered during an Arizona summer lowers powder delivery. Combined with the reports from patients who received deformed formoterol capsules in mailboxes during summer months, it seems likely that temperature led to the decrease in powder delivery.
The decrease in the production of ozone-depleting chlorofluorocarbons has led many pharmaceutical companies to prioritize the development of dry powder inhalers (DPIs) above that of metered-dose inhalers pressurized with chlorofluorocarbons.4 Regulatory guidelines from the US Food and Drug Administration demand consistent dose delivery.1 Multiple studies5 have reviewed drug delivery with these DPIs, which appear to be comparable to metered-dose inhalers. However, these studies are almost always tested under clinical research conditions and not field conditions. Although the manufacturer recommends storage and transport conditions that would obviate the decrease in powder delivery seen in the present studies, the clinical observation that patients returned capsules that appear similar to those heated in the laboratory again demonstrates that actual clinical conditions and use may differ from clinical trial conditions and use.
Arizona during the summer is a particularly harsh climate with temperatures that are often as high as 115°F (46°C). Temperatures in parked cars have been reported as high as 70°C (158°F). At this temperature, we observed powder clumping and capsule distortion with formoterol.6 Not surprisingly, we found similar high temperatures in mailboxes. This may be a peculiarity of environments with extremes in temperature such as Arizona. In support of this concept, we could find no reports in PubMed using a search strategy of DPI and temperature that reported a decrease in drug delivery with extremes in environmental temperature. On the other hand, it is possible that the lack of reports is due to a lack of consideration of the physical alteration of DPIs as a cause for worsening for asthma or COPD. In support of the concept that environmental temperature can affect medications, heat has been reported7 to affect some medications used in prehospital emergency situations.
Formoterol, like most DPIs, is composed of a small amount of active drug (12 µg with formoterol) in milligram quantities of an inert powder such as lactose.3 Although deformity of the formoterol capsules occurred after heating, all appear to have contacted the barbs in the inhaler (Aerolizer) and were likely punctured. It seems likely that this capsule deformity might contribute to the decrease in powder delivery. However, the tiotropium capsules were not deformed and had a large hole punctured in each end.
Based on the above results, we recommend caution in the mailing or transport of drugs that might be heat-sensitive. In this context, the Carl T. Hayden Veterans Affairs Medical Center in Phoenix no longer mails formoterol to patients but requires patients to pick up medications at the pharmacy during the summer months. An alternative strategy would be for mail-order pharmacies to pack the drug in dry ice to avoid this problem. Moreover, physicians should counsel patients to read the storage instructions on medicines. If there are cautions about heat exposure, patients should make sure the mail-order pharmacy ships the drugs in a way that avoids this problem. Furthermore, patients are warned not to leave medications in the car. With the creation of these guidelines, it seems that problems with altered delivery of formoterol from heat are unlikely, and we have not had any further reports of distorted capsules.
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Acknowledgements
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The authors thank our patients who brought the altered capsules to our attention, and Robert Egan, PhD, from the Schering-Plough Corporation.
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Footnotes
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Abbreviation: DPI = dry powder inhaler
Received for publication August 5, 2005.
Accepted for publication September 22, 2005.
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References
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- Olson, BM Approaches to pharmacy benefit management and the impact of consumer cost sharing. Clin Ther 2003;25,250-272[Medline]
- Foradil Aerolizer [package insert]. Kenilworth, NJ: Schering-Plough, 2002
- Dolovich, M New delivery systems and propellants. Can Respir J 1999;6,290-295[Medline]
- Dolovich, MB, Ahrens, RC, Hess, DR, et al Device selection and outcomes of aerosol therapy: evidence-based guidelines; American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest 2005;127,335-371[Abstract/Free Full Text]
- Surpure, JS Heat-related illness and the automobile. Ann Emerg Med 1982;11,263-265[CrossRef][ISI][Medline]
- Valenzuela, TD, Criss, EA, Hammargren, WM, et al Thermal stability of prehospital medications. Ann Emerg Med 1989;18,173-176[Medline]
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Abstract
Introduction
