Lung Deposition and Inspiratory Flow Rate in Patients with Chronic Obstructive Pulmonary Disease Using Different Inhalation Devices: A Systematic Literature Review and Expert Opinion

Figures & data

Table 1 Main Characteristics of Pressurized Metered-Dose Inhalers

Formulation	Drug Suspended or Dissolved in Propellant (With Surfactant and Cosolvent)
Metering system	Metering valve and reservoir
Propellant	HFA or CFC
Dose counter	Sometimes
Priming	Variable priming requirements
Temperature dependence	Low
Humidity dependence	Low
Actuator orifice	The design and size of the actuator significantly influences the performance of pMDIs
Lung deposition	8%-53%
MMDA	1.22 μm-8 μm
Aerosol exit velocity	High (more than 3 m/s)
Lung distribution	Central and peripheral regions
Intrinsic resistance	Low
Inspiratory flow rate	~ 20 L/min
Advantages	Compact and portable, consistent dosing, and rapid delivery
Disadvantages	Not breath-actuated, require coordination

Abbreviations: pMDI, pressurized metered-dose inhaler; HFA, hydrofluoroalkane; CFC, chlorofluorocarbon; MMAD, mass median aerodynamic diameter; m/s, meter per second; μm, micrometer; L/min, liter per minute.

Table 2 Main Characteristics of Dry Powder Inhalers

Formulation	Drug/Lactose Blend, Drug Alone, Drug/Excipient Particles
Metering system	Capsules, blisters, multi-dose blister packs, reservoirs
Propellant	No
Dose counter	Yes
Priming	Variable priming requirements
Temperature dependence	Yes
Humidity dependence	Yes
Actuator orifice	Does not apply
Lung deposition	~ 20%
MMDA	1.8 µm–4.8 µm
Aerosol exit velocity	Depends on inspiratory flow rate
Lung distribution	Central and peripheral regions
Intrinsic resistance	Low/medium/high
Inspiratory flow rate	Minimum of 30 L/min to > 100 L/min
Advantages	Compact and portable Some are multi-dose devices. Do not require coordination of inhalation with activation or hand strength
Disadvantages	Require a minimum inspiratory flow Patients with cognitive or debilitating conditions might not generate sufficiently high inspiratory flows Most are moisture-sensitive

Abbreviations: DPI, dry powder inhaler; MMAD, mass median aerodynamic diameter; m/s, meter per second; μm, micrometer; L/min, liter per minute.

Table 3 Main Characteristics of the Soft Mist Inhaler

Formulation	Aqueous Solution or Suspension
Metering system	Reservoirs
Propellant	No
Dose counter	Yes
Priming	Actuate the inhaler toward the ground until an aerosol cloud is visible and then to repeat the process three more times
Temperature dependence	No
Humidity dependence	No
Actuator orifice	–
Lung deposition	39.2%–67%
MMDA	~ 3.7 μm
Aerosol exit velocity	0.72–0.84 m/s
Lung distribution	Central and peripheral regions
Intrinsic resistance	Low/none
Inspiratory flow rate	Independent
Advantages	Portable and compact. Multi-dose device. Reusable. Compared with dry powder inhalers, a considerably smaller dose of a combination bronchodilator results in the same level of efficacy and safety
Disadvantages	Needs to be primed if not in use for over 21 days

Abbreviations: SMI, soft mist inhaler; MMAD, mass median aerodynamic diameter; m/s, meter per second; μm, micrometer; L/min, liter per minute.

Table 4 Main Factors Associated to Inspiratory Flow Rate

Patient-related

Inspiratory capacity

Inspiratory effort

Comorbidities

Inhalation technique

COPD-related

Severity

Hyperinflation

Exacerbations

Respiratory muscle alterations

Inhalation device-related

Internal resistance

Disaggregation of the powdered drug dose (DPIs)

Abbreviations: COPD, chronic obstructive pulmonary disease; DPIs, dry powder inhalers.

Table 5 General Conclusions Regarding Lung Deposition and Inspiratory Flow Rate in Chronic Obstructive Pulmonary Disease

#	Conclusion
1	The lung deposition profile and required inspiratory flow rate are key factors to be considered when selecting an inhalation device
2	COPD is a progressive disease with specific pathophysiological features that impact patients’ lung deposition and inspiratory flow rate
3	In COPD patients, obstruction severity and especially hyperinflation are decisive pathophysiological factors
4	During the course of COPD, some situations, notably exacerbations, impact the inspiratory flow rate
5	An homogeneous drug distribution through the airways is essential, not only because of the COPD pathophysiology but also because of the different distribution of cholinergic and β2 receptors
6	COPD treatment requires inhalation devices capable of delivering particles with a MMAD comprised between 0.5 and 5 µm to achieve high lung deposition
7	The patients’ ability to perform a correct inhalation maneuver (inspiratory effort, coordination, etc.) is decisive to achieve an adequate inspiratory flow rate and lung deposition
8	Inhalation maneuvers that are similar to physiological/standard inspiratory flow are more likely associated with reduced oropharyngeal deposition and therefore increased lung deposition
9	Inhalation devices present different characteristics that define the required inspiratory flow rate and influence lung deposition
10	The inspiratory flow rate required for drug dispersion with a given DPI is inversely proportional to the intrinsic resistance of the DPI
11	The faster the exit speed of the drug delivered from the device (initial acceleration of the inhalation maneuver by the patient or directly by the device), the greater the risk of oropharyngeal deposition and the lesser the lung deposition
12	The SMI requires a low inspiratory flow rate. Therefore, compared with other inhaler devices, when performing a correct maneuver, oropharyngeal deposition is lower and lung deposition is higher

Abbreviations: COPD, chronic obstructive pulmonary disease; MMAD, mass median aerodynamic diameter; µm, micrometer; DPI, dry powder inhaler; SMI, soft mist inhaler.

Table 6 Experts’ Recommendations for the Selection of the Appropriate Inhalation Device in Chronic Obstructive Pulmonary Disease

#	It is Strongly Recommended to …
1	Consider COPD pathophysiological aspects as well as patients’ clinical status and disease severity/evolution when selecting an inhalation device
2	Take into account the specific characteristics of each inhalation device
3	Assess patients’ ability to perform a correct inhalation maneuver and the specific requirements for each inhalation device
4	Evaluate patients’ inspiratory flow rate or inspiratory capacity before selecting an inhalation device
5	Take into account patients’ history of exacerbations or other events that may affect their ability to perform adequate inhalation
6	Regularly review patients’ inhalation maneuver and check whether the inhalation device meets their needs
7	Use an active inhalation device, such as pMDI or SMI, in patients with reduced inspiratory capacity
8	Consider using a valved holding chamber with SMI or pMDI devices in fragile patients with inspiratory and/or coordination difficulties
9	Use inhalation devices that generate a low oropharyngeal and high lung deposition
10	Check patients’ inhalation maneuver during every visit and, where necessary, resolve errors or even change the inhaler

Abbreviations: COPD, chronic obstructive pulmonary disease; pMDI, pressurized metered-dose inhaler; SMI, soft mist inhaler.