469699 The Effects of Formulation Factors on the Aerosolization Performance of Metered Dose Inhalers

Monday, November 14, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Denise S. Conti1, Jay Holt2,3, Poonam Sheth2, Dennis Sandell4, Anthony Hickey2,5 and Bhawana Saluja1,6, (1)Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, (2)Cirrus Pharmaceuticals, Inc., Morrisville, NC, (3)Present: Aurobindo Pharma USA, Inc., Raleigh, NC, (4)S5 Consulting, Blentarp, Sweden, (5)Present: RTI International, Research Triangle Park, NC, (6)Present: Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD


Introduction: Metered dose inhalers (MDIs) are complex drug-device combination products widely used as portable delivery systems to treat pulmonary disorders, such as asthma and chronic obstructive pulmonary disease (COPD). A typical MDI consists of a canister containing the formulation, a metering valve, and an actuator-mouthpiece.[1] The formulation can be either a solution [active pharmaceutical ingredient (API) dissolved in the liquid propellant] or a suspension (API particles dispersed in the liquid propellant) along with inactive ingredients (e.g., co-solvents and surfactants).[2] The product performance of MDIs depends on a multitude of factors including, but not limited to, the physicochemical properties of API, device geometry (e.g., valve metering chamber volume, actuator nozzle orifice diameter, actuator sump depth, and actuator orifice jet length), and nature and amount of inactive ingredient(s).[3] Under the Quality by Design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device and manufacturing process influence the product performance.[4] Although much is known about the effects of changes in device geometry on the aerosolization performance of MDIs,[5],[6] the effects of changes in formulation factors on MDI product performance are not clearly defined. Therefore, the purpose of this work is to provide a better understanding of the effects of different levels of inactive ingredients and API particle size distribution (PSD) on key aerosolization performance parameters of MDI products. The systematic approach applied in this work can be utilized as a QbD tool to develop mathematical models and design spaces, allowing the manufacture of formulations with desired in vitro product performance parameters through a proper combination of formulation factors.

Methods: Three commercial MDI products (albuterol sulfate and mometasone furoate suspension formulations, and beclomethasone dipropionate solution formulation) were chosen for this study. Reverse engineering was utilized to determine the qualitative and quantitative composition of the formulations. The aerosolization performance was characterized by measuring the delivered dose (DD) and aerodynamic particle size distribution (APSD) performance. MDI model systems were then developed and used as anchor point for developing a statistical experimental design to study the effects of formulation factors (inactive ingredients concentrations and API PSD) and simulate design spaces of product performance. The purpose of defining the MDI model systems was not to achieve in vitro bioequivalence to the commercial MDI products, but to develop systems similar to the commercial MDIs with respect to formulation composition and key aerosolization performance parameters. A reduced factorial statistical design of experiments (DoE) approach was then used to develop a MDI batch manufacturing plan to vary the levels of inactive ingredients (ethanol and oleic acid) and API PSD (D50, the value of the particle diameter at 50% in the cumulative distribution, that is, the median diameter of the PSD). The following ranges were studied:

API

D50 (μm)

Ethanol (% w/w)

Oleic Acid (% w/w)

Albuterol Sulfate

1.4 - 2.5

7 - 20

0.005 - 0.1

Mometasone Furoate

1.1 - 2.0

0.45 - 3.6

0.001 - 0.025

Beclomethasone Dipropionate

N/A

7 - 9

0 - 2

API D50 was varied for the suspension formulations only; micronized API was prepared from the same mother batch by sizing down to the desired API D50 using jet mill process. While the commercial solution MDI chosen for this work does not contain oleic acid, such an inactive ingredient was included in the DoE plan to study its effects in the solution formulation in comparison to the suspension formulations. The MDI batches were manufactured under non-GMP conditions, characterized and the data was statistically analyzed – a formulation factor (ethanol and oleic acid concentrations, or API D50) was considered to have a statistically significant effect on the aerosolization performance parameter if p value < 0.05. Multivariate mathematical models and design spaces were then developed to predict the MDI aerosolization performance with respect to DD and APSD according to the different levels of formulation factors. The potential effects of different propellants [hydrofluoroalkane (HFA)-134a in the albuterol sulfate and beclomethasone dipropionate MDIs, and HFA-227 in the mometasone furoate MDIs] were not studied in this work.

Results: For the albuterol sulfate suspension MDI formulations studied, the effect of ethanol on the DD was statistically significant – as the ethanol concentration increased from 7 to 20% w/w, the DD decreased by 17%. Both ethanol and API D50 showed statistically significant effects on the APSD – as the ethanol concentration and API D50 increased from, respectively, 7 to 20% w/w and 1.4 to 2.5 μm, the fine particle dose less than 5 μm (FPD<5) decreased by 40%. The effect of oleic acid on the DD and APSD was not statistically significant. For the beclomethasone dipropionate solution MDI formulations studied, the effect of ethanol on both DD and APSD was not statistically significant within the range studied. However, the effect of oleic acid on the DD and APSD was statistically significant – as the oleic acid concentration increased from 0 to 2% w/w, the DD decreased by 11% and the FPD<5 decreased by 65%. For the mometasone furoate suspension MDI formulations studied, the DD was significantly affected only by ethanol – as the ethanol concentration increased from 0.45 to 3.6% w/w, the DD increased by 7%. All three formulation factors (ethanol and oleic acid concentrations, and API D50) showed statistically significant effects on the APSD, but the strongest effects were provided by the ethanol and API D50 – for these, a change of approximately 40% in FPD<5 was obtained from the lowest to the highest factor level.

Conclusions: The changes in API PSD had statistically significant effects on the APSD performance of suspension MDI formulations studied, but not on DD. The changes in concentrations of inactive ingredients (ethanol and oleic acid) showed, in some cases, statistically significant effects on DD and APSD performance of suspension and solution MDI formulations studied. However, several cases without effects were also found, despite some large changes in concentrations of inactive ingredients studied. The possible effects of varying these must hence be studied on a case-by-case basis. The outcomes of this study allowed defining design spaces for DD and APSD performance according to the different levels of formulation factors (ethanol and oleic acid concentrations, and API D50). The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosolization performance of MDI products, helping to design MDI formulations with desired in vitro product performance parameters.

Keywords: Metered Dose Inhalers (MDIs); Quality by Design (QbD); Factorial Design of Experiments (DoE).

References:


[1] Stein, S.W., et al., Advances in metered dose inhaler technology: Hardware development. AAPS PharmSciTech, 2013. 15(2): p. 326-338.

[2] Bell, J. and S. Newman, The rejuvenated pressurised metered dose inhaler. Expert Opinion on Drug Delivery, 2007. 4(3): p. 215-234.

[3] Smyth, H.D.C., The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Advanced Drug Delivery Reviews, 2003. 55(7): p. 807-828.

[4] Lionberger, R.A., et al., Quality by design: Concepts for ANDAs. The AAPS Journal, 2008. 10(2): p. 268-276.

[5] Smyth, H., et al., Spray pattern analysis for metered dose inhalers I: Orifice size, particle size, and droplet motion correlations. Drug Development and Industrial Pharmacy, 2006. 32(9): p. 1033-1041.

[6] Smyth, H., et al., Spray pattern analysis for metered dose inhalers: Effect of actuator design. Pharmaceutical Research, 2006. 23(7): p. 1591-1596.


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