Aerosol Science and Technology

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In Vitro Testing of Dry Powder Inhalers Michiel Van Oort To cite this article: Michiel Van Oort (1995) In Vitro Testing of Dry Powder Inhalers, Aerosol Science and Technology, 22:4, 364-373, DOI: 10.1080/02786829408959754 To link to this article: http://dx.doi.org/10.1080/02786829408959754

Published online: 12 Jun 2007.

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In Vitro Testing of Dry Powder Inhalers Michiel Van Oort Glaxo Research Institute, Inhalation Product Development, 5 Moore Drive, Research Triungle Park, NC 27709 -

There is increasing focus on the development of dry powder inhalers (DPIs) for the delivery of therapeutic entities to the lungs. In vitro testing of metered-dose inhalers (MDIs) has evolved through the years and general tests and methods have been published through USP general chapter (601), monographs, and guidelines issued by the FDA. In contrast, very few guidelines have been established for the testing of dry powder inhaler systems. In fact, these systems may prove to

be more dimcult to propose general tests for because they are based on different principles leading to a greater diversity in the number of types of devices and formulations in comparison to the MDIs. To form absolute standards at this stage will be difficult and this paper will present a comparison of the in vitro test methods of MDIs to some of the DPIs that are commercially available and suggests some guidelines to follow.

There is increasing focus on the development of dry powder devices for the delivery of therapeutic entities to the lungs. While pressurized metered-dose inhalers (MDIs) continue to be the most frequently prescribed delivery system because of their proven history of safely and efficaciously delivering drugs to the lungs, there is a recognized need for alternatives for patients who have difficulty using MDIs (e.g., poor hand-to-inhalation coordination) as well as the uncertainties associated with alternative MDI propellants. In vitro test methods used by the pharmaceutical manufacturing companies are primarily intended for quality control where the focus is on the relative measures of product performance. In contrast, the researcher uses in vitro methods as a means to measure absolute differences between different products (formulations and/or devices) and as a simple way of approximating or predicting a therapeutic response. In vitro testing of MDIs has evolved through the years and general tests and methods for their evaluation have been published through USP general chapter

(601), monographs and guidelines issued by the FDA. In contrast, very few guidelines have been established for the testing of dry powder inhaler (DPI) systems. This may be because it is more difficult to propose general tests for DPIs because there are a variety of systems which are based on different aerosolization and metering principles. Thus there is a greater diversity in the number of types of DPI devices and formulations in comparison to the MDIs. Therefore, to form absolute standards at this stage will be difficult but it is important to present some of the issues that have arisen in the testing of DPIs. In order for any drug to be safe and efficacious, the therapeutic entity must reach the site of action in an appropriate concentration and have acceptable impurity levels. For inhalation dosage forms, the amount of drug delivered as well as the aerodynamic particle size must be tested. This aspect is determined by the mass of drug of a particular size range being delivered to the respiratory tract. Metered-dose inhalers and dry powder inhalers are the most common portable deAcrosol Science and Technology 22364-373 (1995) O 1995 American Association for Aerosol Research Published bv Elsevier Sc~enceInc.

365

In Vitro Testing of Dry Powder Inhalers

vices used to deliver drugs to the lung. The operating principles of the two delivery systems are very different and this needs to be reflected by the in vitro test methods employed to characterize these dosage forms. The design of the pressurized metered-dose inhaler used by a number of pharmaceutical companies is fundamentally the same; MDIs consist of a metering valve, container, actuator, micronized drug, propellant, and surfactant. The high vapor pressure propellant passing through the small exit orifice in the valve stem propels the drug to the patient in a deaggregated state, therefore the drug delivered to the patient is relatively independent of the patient's inhalation flow rate. In contrast, the majority of the DPIs currently available in many markets such ~~, as the DiskhalerTM,~ o t a h a l e rTurbuhalerTM (Figs. 1-3) and the SpinhalerTM devices rely on the patient's inspiratory power to deliver and deaggregate the drug for inhalation. Because the patient provides the driving force and device design differences exist, these must be considered and reflected in the in vitro test methods employed. All pharmaceutical dosage forms must ensure that the drug delivered is safe and efficacious. In addition, it is important that the in vitro tests should be designed to simulate the patient use as much as possible. In the case of some of the inhalation dosage forms, more testing is necessary due to the uniqueness of this dosage form in order to develop, critically assess and ensure product quality. Product safety testing ensures that the correct drug is present with an acceptable level of impurities. The tests typically performed as part of product safety are listed below: Appearance Identity (chromatography and spectroscopy) Microbial limits

Opening Bar (or Fin)

Rotacap Entry Port

Air Inlet Slots

FIGURE 1. Schematic of RotahalerTMdevice.

Water content Extractives Drug-related impurities The tests listed above would be appropriate for development stability testing. However, when stability trials are conducted to support a New Drug Application (NDA) to the FDA, a number of the tests may prove to be inappropriate or unnecessary since they may not be diagnostic or the test values do not significantly change during preliminary stability trials. For example, if no extractables are present in the component materials, testing in a final device would not be necessary. DOSE DELIVERY

Dose delivery is an important aspect since it is related to both the safety and efficacy of the dosage form. Since most devices rely on the inspiratory air flow to provide the energy to deliver and deaggregate the particles, it is important that the required air flow through the device for optimal performance be measured and be achievable by the patients. Spiro et al. (1992) measured the flow through the DiskhalerTM device at submaximal inhalation for a variety of pa-

M. Van Oort

Support wheel

Sliding tray

\ I

Cleaning brush

*

FIGURE 2. Schematic of D i ~ k h a l e r ' ~device.

Inhalation channel

iral channels for

One metered dose

otating dosing disc

FIGURE 3. Schematic of TurbuhalerTM device.

In Vitro Testing of Dry Powder Inhalers

tients with different severities of asthma as defined by FEV,% of predicted. The measured mean flow rate during submaxima1 inhalation was 126 L/min through the DiskhalerTM device with a range of values between 59 and 170 L/min and the flow rate appeared to be independent of the severity of asthma. Engel et al. (1990) performed a similar study with the TurbuhalerTMand the mean peak inspiratory flow rate was found to be 59 L/min with values between 25 and 93 L/min. In many cases, researchers compare devices using the same flow but data generated at single flow rates must be treated with caution. One should make comparisons at the equivalent inspiratory effort and not equivalent flow since the flow rates through different types of devices will depend on their internal resistances. Patient studies with devices should therefore be performed to establish appropriate flow rates. Clark et al. (1993) reported that a 50 L/min peak flow through the ~ o t a h a l e r ' device ~ is equivalent to 11 /min through the inhalatorTM device based on an equal pressure drop, therefore suggesting that device comparison studies performed at the same flow rate are incorrect. Particle sizing and delivery characteristics should be performed at flow rates appropriate to the device 6.e. achievable by the patient) and the flow rate varied for comparisons of devices to approximate the same inspiratory effort. If the drug delivery characteristics are dependent on the inhalation flow rate, then an appropriate inspiratory flow rate should be chosen for evaluation but how does one define the flow rate? Should the flow rate be based on a mean or a minimum? For example, Meakin et al. (1993a) determined the dose delivery as a function of flow rate for the TurbuhalerrM (Fig 4). The results of their studies indicate that at 60 L/min, the mean flow determined in patient studies, the dose delivery was 454 f 26 pg. When a similar

30

10

60

FLOW RATE(litres.min

FIGURE 4. Plot of emitted dosc versus flow ratc for the Bricanyl ~urbuhaler'" device (Meakin et al., 1993a).

study was performed at 30 L/min, the approximate minimum in the patient study, the dose delivered was 266 f 88 pg. This change in flow results in a 188 p g decrease in the dose delivered as well as a nearly threefold increase in the variability of delivery. Kim et al. (1993) investigated the delivery characteristics of the albuterol RotahalerTMdevice as a function of flow rate. They observed that the dose delivered varied widely from 30 to 146 p g in the range of 30-120 L/min and the delivery was consistent only with Aow rates greater than 60 L/min (Fig. 5). Patient studies using the RotahalerTMdevice (Timsina et al. 1993) measured mean peak inspiratory flows of 216.6 k 45.6 L/min for males and 160.1 f 43.7 L/min for females suggesting that the average patient could generate air flows through the ~ o t a h a l e r 'de~ vice, well above 60 L/min, where Kim et al. indicated that consistent performance

M . Van Oort

0 Undischarged Oropharnyx Larnyx Lower Airways

lnspiratory Flow Rate (Llrnin)

FIGURE 5. Plot o f emitted dose versus flow for Ventolin RotahalerTMdevice (adapted from Kim et al., 1993).

was observed. In the same study, the measured peak inspiratory flows through the TurbuhalerTMwere 81.8 12.8 L/min for males and 55.6 13.0 L/min for females. This agrees quite well with the air flow resistance data recently reported by Clark et al. (19931, where, based on pressure drop curves, the pressure drop for the TurbuhalerTM at 60 L/min is equivalent to the pressure drop of the Rotahaler at 160 L/min. It is very difficult to absolutely define a minimum flow rate but by coincidence, the minimum flow in the above patient populations was approximately one-half of the mean. For example, the mean inspiratory flow for the ~ i s k h a l e rstudies ~ ~ was 126 L/min and one-half of that is 63 L/min which is close to the minimum of 59 L/min measured in the study. Similarly for the TurbuhalerTM studies, the mean value measured was 60 L/min and one-half of that is 30 L/min, which is close to the measured minimum of 26 L/min. Not only is the air flow resistance different for different devices, certain delivery tests necessary to characterize devices are also device specific. Independent of device delivery performance, comparisons should include lot-to-lot variability and device-to-device variability. In addition,

+

+

device operating characteristics or principles should be used to define other device characterization testing. For example, the ~ i s k h a l e r is ~ ~ based on factory-dispensed drug in a blister pack (Sumby 1993) and therefore the blisters can be individually assayed for drug content and their content is independent of the other doses. In contrast, the TurbuhalerTM has a reservoir of drug; each dose is dispensed by the patient when using the device; the individual doses cannot be accessed without either operating the device or disassembling the entire device. In addition, the reservoir device requires dose delivery through device use testing to ensure the labeled claim number of doses is delivered from the device, similar to the expectations regulatory agencies have for the metered-dose inhaler. Since the reservoir device has to be operated to acquire the dose to be assayed, a simulated patient-use flow rate needs to be defined. Meakin et al. (1993b) investigated dose delivery through simulated patient-use for the TurbuhalerTM using a flow rate of 60 L/min including omission of mouthpiece cleaning. Although no significant change was observed through simulated patient-use, the range of values obtained was quite large (169-523 pg) giving an average of 376 p g

369

In Vitro Testing of Dry Powder Inhalers

(75% of label claim). Occasional high Cascade impactors differ from impingers doses were observed (more than 750 pg) in that the collection substrate is a solid presumably associated with buildup of surface, whereas, impingers use a liquid to drug in the mouthpiece and body that collect the particles. One of the most were eventually entrained. An additional common inertial methods used in the consideration for the reservoir-type inpharmaceutical industry is the Andersen halation devices is the variability of dose cascade impactor. Its popularity is based metering by the patient. Ideally, the reserin part on the fact that it has 8 impaction stages with Effective Cut-Off Diameters voir device should be designed in such a way so as to minimize this variation due (ECDs) between 10 and 0.7 pm, thus proto patient handling or alternatively doses viding quantitation and resolution in the respirable aerodynamic particle size range. should be individually dispensed in the factory as is the case for the DiskhalerTM, Both the TI and MI do not provide any RotahalerTM and the SpinhalerTM. size distribution data and only give information on the mass of drug less than a particular aerodynamic particle size. For PARTICLE SIZING the TI, it is the mass of particles with As previously mentioned, the efficacy of ECDs less than 6.4 p m and for the MI it the drug product is determined by the is the mass of particles with ECDs less amount of drug with aerodynamic partithan 9.8 pm. A single cut-off technique cles sizes of a particular size range (i.e., may provide sufficient characterization of typically < 5 to 10 p m and is usually the dose because it may be consistent with referred to as the respirable dose). A varithe wide range of disease states and physiety of methods are available to characterological parameters observed in the paize the particle size of the drug. They can tient population. be broadly categorize into two areas: OpA key disadvantage of all of the comtical methods and inertial methods. A brief mercially available systems is that they are list of the optical methods includes: micalibrated at a fixed flow which may not croscopy, Time-of-Flight (API Aerosizer be representative of the flows typically and TSI APS-33B), Laser Diffraction achieved by the patient. For example, the (Malvern and Sympatec) and Laser Andersen cascade impactor is calibrated Doppler/Phase Doppler Anenometry at 28.3 L/min whereas the average pa(Aerometrics and Dantec). In general, the tient can achieve flows of 126 L/min in major weaknesses of these techniques are the DiskhalerTM and 60 L/min in the that they are not drug specific (is., unable TurbuhalerTM.Even if one sizes at the to discriminate between drug particles and minimum flow rate in the patient populacarrier particles if present) and in some tion, the Andersen would only be approcases, it is very difficult to characterize priate for the TurbuhalerTM.The advanthe delivered (ex-device) particle size in a tages of the impingers are they are easy to simulated patient use testing regime. use and are calibrated at 60 L/min, which The majority of particle sizing methods more closely approximates a patient's caacceptable to regulatory agencies are pabilities. Alternatively, it is possible to based on inertial impaction and the most operate the Andersen at 60 L/min and common systems are listed below: using a variation of the Stoke's equation, one can theoretically approximate the Twin impinger (TI) ECDs at the higher flow using the followMetal impinger (MI) ing equation: Multistage liquid irnpinger (MLI) Cascade impactor ECD,, = ECD (28.3/~2)",,

,,,,

M. Van Oort

where ECD,, = the ECD at the other flow rate; ECD,, is the ECD at the manufacturers flow rate (28.3 L/min) and F2 is the other flow rate in L/min. For example, at 28.3 L/min, the ECD for stage 0 of the Andersen is 9.0 pm, which corresponds to 6.2 p m at 60 L/min. We have performed a study in which the Andersen was operated at 60 L/min and 28.3 L/min using a metered-dose inhaler (MDI). An MDI was used for a number of reasons: (1) deaggregation is independent of the inhalation flow rate; (2) the particles are coated with sticky surfactant to minimize particle bounce; (3) the drug particles closely resemble the drug particles in the dry powder inhaler formulation; (4) the entire aerodynamic size distribution can be used to test the whole cascade impactor and one can perform a single experiment rather than generating numerous monodisperse systems. It was determined that Aerodynamic diameter L/min was not statistic measured at 60 L/min based the d ECDs at 60 L/min, suggeston ing t h a ~the approximation is valid. Even if there were not complete a theory, it is important to that the primary concern oduct performance rather ke measure since this testd to ensure that the uct that is marketed is similar to the uct that was tested in the clinic and for what regulatory approval was obtained.

,

Not only does one need to consi effect of flow rate on dose delivery, one also needs to consider the effect of flow rate on the in vitro measure of respirable dose. Jaegfeldt et al. (1987) showed that the respirable mass from the TurbuhalerTMdecreased from 250 p g at a flow

FIGURE 6. Plot of flow rate versus respirable dose for the Bricanyl T ~ r b u h a l c r ' ~devicc (Mcakin ct a]., 1993a).

rate of 60 L/min to 120 pg at a flow rate of 28 L/min, which is comparable to the nearly twofold decreased in lung deposition measured by Newman et al. (1991) when patients inspired at 57 and 28 L/rnin through the Turbuhaler rM. Meakin et al. (1993a) also determined the effect of inhalation flow rate on the respirable dose using the ~ u r b u h a l e r ~They ~ . invesrihe respirable dose at 28.3 and 60 for numerous batches of this produre 6 graphically shows the results of this study and the inset shows the mean f each of the batches at the different ow rates. The data demonstrate an apate four fold decrease in the resdose when the inhalation flow rate decreases from 60 to 28.3 L/min which would suggest that the efficacy and dose response could follow the same flowrate-dependent trend.

In the past, the pharmaceutical industry rirnarily focused on using cascade impaction to characterize metered-dose in-

371

In Vitro Testing of Dry Powder Inhalers

balers and the throat or induction port played a critical role in defining the amount of drug that entered the impactor (Van Oort et a]., 1994). The drug emitted from the actuator of a metered-dose inhaler exits at a high initial velocity (much faster than the velocity of air pulled by the cascade impactor) and rapidly decelerates. Therefore the amount of drug entering the impactor depends on the time that the particles are allowed to decelerate or the distance they travel before hitting their first impaction surface (typically the 90" bend). For most throats this is defined by the volume and unobstructed pathlength of the throat. Since most DPIs on the market are driven by the patient's inspiratory effort, the drug particles exiting the device should be traveling at approximately the same velocity as the air stream, therefore one may expect that the throat does not play as significant a role but it is important to bear in mind that the ECD of the throat will vary with the diameter of the throat and the flow rate used. TOTAL VOLUME THROUGH THE DEVICE

In the development of cascade impaction methodology for DPIs one must also consider the total volume of air passing through the DPI. For a given fixed flow rate, it can be based on time. If one assumes that the typical patient can inhale between 3 and 5 L of air (Mason, 1983), then at a fixed flow rate of 60 L/min, the DPI should be interfaced between 3 and 5 s. At lower or higher flows, the sampling time should be increased or decreased in order to have the same total volume passing through the DPI. There are a number of approaches to achieve a consistent volume such as positioning the DPI in the mouthpiece for a fixed amount of time, turning the pump on and off for a fixed amount of time or lastly connecting the pump to a timed flow diverter (Fig. 7).

The flow diverter approach may be the preferred configuration since the pump is allowed to reach a steady state before the flow is diverted through the impactor, which should overcome differences in pumps to achieve steady state flow rates.7 ENVIRONMENTAL EFFECTS

Another aspect that needs to be considered in simulated patient testing is the effect of handling the dosage form in different environmental conditions. Meakin et al. (1993a) simulated the patient use of the ~ u r b u h a l e r * according ~ to the patient insert to determine the effect of a constant temperature and humidity environment on the dose delivery and respirable dose. The protective closures were removed four times daily, for 2 min each time, to simulate the dosing time. The results of this study are presented in Fig. 8 and although the emitted dose remained constant throughout the study when inhalation flow rates of 60 L/min were used but when operated at 28.3 L/min, a significant drop in both the emitted dose and respirable dose occurred with increasing exposure time. The results indicated that

3-Way Electric Valve /

Flow Diverted

Flow Through Timer

FIGURE 7. Schematic of the flow diverter setup for the Andersen cascade impactor.

M. Van Oort

DAYS

0 10 21 40

0 5.5 11 20 39

DAYS

0

5.5

11

20

39

FIGURE 8. Effect of relative humidity on the respirable dose for the Bricanyl ~ u r b u h a l e r ' device ~ (Meakin et al., 1993a).

simulated patient use at 30"C/72%RH would result in a 50% drop in the emitted dose and the respirable dose would decrease from 20% initially to 7% after 40 days of patient use. These data illustrate the need for an evaluation of the device simulating patient use in a simulated climate. In summary, Fig. 9 outlines some of the general guidelines for in vitro testing of dry powder inhalers. The most important aspects are safety and efficacy. If these aspects are significantly affected by the patient's physical attributes (inspiratory effect) and patient handling, then in vitro test methods must reflect this. Although it is practically impossible to make any device "idiot proof," device design must minimize patient factors such as flow rate effects, environmental effects, and complexity to operate so as to ensure that the majority of the patient population receive a safe and efficacious dose.

General Guidelines for In Vitro Testing of DPls Appearance Identity (chromatography and spectroscopy) Microbiai Limits Water Content Extractives Drug Related Impurities Drug Content Per Unit Dose/Dose Delivery Particle Size Analysis/Respirable dose Simulated Patient Use e Through Device Use Patient Parameters/Parallelisms Flow Rate Inhalation Volume Environmental Aspects (In the patient's hands) Reusable vs. Disposable Reiiability Testing

. . . ... . . .

.

.

.

FIGURE 9. General guidelines for in vitro testing of dry powder inhalers.

REFERENCES Clark, A. R., Hollingworth, A. M. (1993). J. Aerosol Med. 699-110. Engel, T., Heinig, J. H., Madsen, F., Nikander, K. (1990). Eur. Respir. J. 3:1037-1041.

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In Vitro Testing of Dry Powder Inhalers

Jaegfeldt, H., Anderson, J. A. R., Trofast, E., Wetterlin, K. I. L. (1987). In: Newman S. P., Moren F., Crompton G. K., eds. A New Concept in Inhalation Therapy. London: Medicom. 90-9, 116. Kim, C. S., Garcia, L. (1993). J. AerosolMed. 6:199-211. Mason, E. B. (1983). Human Physiology. Banjamin/ Cummings, California, p. 385. Meakin, B. J., Cainey, J. M., Woodcock, P. M. (1993a). ALA/ATA International Conference, San Francisco, USA. Meakin, B. J., Cainey, J. M., Woodcock, P. M. (1993b). Am. Rev. Respir. Dis. 147:(4, Pt 2kA997. Newman, S. P., Moren, F., Trofast, E., Talaee, N., Clarke, S. W. (1991). Int. J. Pharm. 74:209-213.

Sumby, B. S., Cooper, S. M., Smith, I. J. (1992). Br. J. Clin. Res. 3:117-123. Sumby, B. S., Churcher, K. M., Smith, I. J., Grant, A. C., Truman, K. G., Marriott, R. J., Booth, S. J. (1993). Pharm. Tech. Znt. 2-7 (June). Spiro, S. G., Biddiscombe, M., Marriott, R. J., Short, M., Taylor, A. J. (1992). Br. J. Clin. Res. 3:115-116. Timsing, M., Martin, G. P., Marriott, C., Ganderton, D., Lee, K. C., Suen, K. O., Yianneskis, M. (1993). J . Aerosol Med. 6 (Suppl): p 41. Van Oort, M., Gollmar, R., Bohinski, R. (1994). Pharm. Res. 11:604-607. Received May 3, 1994; revised October 14, 1994.