Analysis on the Delivery and Formulations of Inhaled Drugs

Jiaying Yan

Department of Chemistry, University of California Davis, U.S.A.

Keywords: Inhaled Drugs, Aerosol Administration, Metered-Dose Inhalers (Mdis), Dry Powder Inhalers (Dpis),

Nebulizers.

Abstract: Inhalation or aerosol administration is an area that deserves more research. It is a helpful way to deliver the

drugs that are hard to administrated by other routes. It is also promising for delivering biomacromolecule

drugs such as insulin and peptide drugs. Aerosol administration is a multidisciplinary topic that includes

physics, chemistry, engineering, and physiology. The relationship between the respiratory system and aerosol

drugs is essential when studying aerosol administration. In order to get desirable effects, inhalation devices,

drug formulations, and the patient are three significant factors to consider. This paper includes three

commonly used delivery devices: metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers.

Research has found that most of the aerosol administration devices have low lung depositions, but nebulizers

can reach a relatively higher lung deposition than other devices. All of them have advantages and

disadvantages, but each of them possesses distinct characteristics. These three devices have different

mechanisms and require different formulations.

1 INTRODUCTION

Inhalation or aerosol administration is one of the

common drug administration routes and has been

widely used. It is mainly used to treat respiratory

diseases such as asthma, chronic obstructive

pulmonary disease (COPD), and lung fibrosis.

Research has shown that aerosol administration can

also be used to treat some systemic diseases such as

diabetes, anticoagulation, headache, and osteoporosis

(Groneberg et al., 2003). This paper mainly talks

about the drug delivery to the reparatory system, three

commonly used inhalation devices, and drug

formulations used in different devices.

The delivery pathway of aerosol administrated

drugs is the respiratory tract. There are two types of

respiratory epithelial cells that contribute to the

absorption of inhaled drugs: type I and type II

pneumocytes (Groneberg et al., 2003). In these two

types of cells, type I pneumocytes predominate in the

surface area of the lungs, so they play an important

role in inhaled drug absorption (Ehrhardt et al., 2002).

Through the epithelial cells, drugs can go to the

circulatory systems and exhibit target or systemic

effects. Besides, different devices are used by

different patients to treat various diseases. Three

common inhalation devices are MDIs, DPIs, and

nebulizers. Each of them has different but significant

functions. It is important to consider the patients’

conditions and drug formulations before choosing the

devices. Also, different devices require different drug

formulations to ensure their performances.

Compare to other common drug administration

routes, such as oral and intravenous administration,

aerosol administration shows significant advantages

over other administration routes. When a drug is

delivered by oral and intravenous routes, it circulates

throughout the whole body. In contrast, most aerosol

administrated drugs would directly have effects on

the target organ, the lungs. Only a small

concentration would go to the systemic circulation,

which can reduce the off-target effects (Rau, J. L.,

2005). Aerosol administration is also a promising

way to deliver the macromolecule drugs to human

bodies (Choy & Prausnitz, 2010).

2 CONSIDERATIONS OF

AEROSOL ADMINISTRATION

From the first use of inhalation of epinephrine in 1929

to the present day, problems and challenges of aerosol

administration have shown up (Rau, 2005). The

development of aerosol administrated drugs is a

1314

Yan, J.

Analysis on the Delivery and Formulations of Inhaled Drugs.

DOI: 10.5220/0011509100003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 1314-1319

ISBN: 978-989-758-595-1

multidisciplinary challenge—it needs considerations

from physics, physiology, engineering, and chemistry

aspects. Scientists need to consider the interactions

between the respiratory system and the drug particles.

In order to achieve successful delivery and absorption

of the drugs into our system, it is important for the

manufacturers to consider the drug products' particle

shape and size, humidity, hygroscopy, excipient, and

density (Groneberg et al., 2003). Individual

difference is also a critical factor to consider during

drug delivery. Gender, body weight, age, and tidal

volume might influence the dosing and efficacy of the

drugs.

Compare to oral and intravenous administration,

aerosol administration is more complicated. It needs

devices to help the administration. The three common

aerosol delivery devices are dry powder inhalers

(DPIs), metered-dose inhalers (MDIs), and

nebulizers (Rau, 2005). Not only the drugs, but also

the devices are costly for both the patients and

researchers (Milgrom et al., 2001).

As shown in Figure 1, there are inseparable

relationships among patients, formulation, and

devices of inhaled drugs (Hou et al., 2015). Patients

need to take effective drug formulations by using

available inhalation devices. The drug formulation

needs to fit into the devices and must be delivered by

the devices. Meanwhile, the drug formulation needs

to achieve efficacy in patients. Also, the devices

should be compatible with the drugs and usable by

the patients. The development of pharmaceutical

engineering technologies of inhaled drugs is crucial

to obtain a desirable relationship among these three

considerations.

Figure 1: Considerations of aerosol administered drugs

(Hou et al., 2015).

3 DRUG DELIVERY TO THE

RESPIRATORY SYSTEM

The delivery and absorption of aerosol drugs are

mainly through the lower respiratory tract, including

small bronchioles and alveoli (Groneberg et al.,

2003). Between type I and type II pneumocytes, type

I pneumocytes are in charge of drug absorption

(Groneberg et al., 2003). In addition, type I

pneumocytes epithelial cells are the rate-limiting step

of absorption because they have smaller pore size and

tight junction depth compare to endothelial cells

(Wangensteen et al., 1969). In order to be absorbed

through the epithelial cells, particle size is a

significant characteristic to consider. Aerodynamic

diameter, dA, is used to describe the particle size of

inhaled drugs. Research has shown that particles with

dA smaller than 5 μm can reach small bronchioles

and alveoli to exhibit local effects (Chow et al.,

2007). Meanwhile, particles with dA that are between

1-2 μm can go to the systemic circulation, which

might lead to off-target effects (Chow et al., 2007).

Different excipients are used to manufacture different

drugs, and they might also influence the relationship

between particle size and absorption. For example,

research has shown that the aerodynamic diameter for

solution-based aerosol drugs are usually 2 μm, while

the one for suspension-based aerosol drugs are

usually 4 μm (Chow et al., 2007).

Hygroscopy is also a vital characteristic to

consider. The humidity of the environment might

influence the particle size of drugs. When the

environment reaches a humidity of about 44 μg/cm3,

hygroscopic growth of the drug particles can happen

(Groneberg et al., 2003). Therefore, the administrated

particle size might increase in the respiratory tract.

The hygroscopicity of excipients is one of the major

reasons that lead to an increase in particle size. Water

vapors in the human respiratory tract would bind with

the hygroscopic excipients to increase the size (Worth

Longest & Hindle, 2011). Thus, during drug delivery,

the final particle size after exposure to water vapor is

also an essential factor to consider.

Aerosol administration would have different

effects on different individuals because each patient

has different physiological conditions. Tidal volume,

breath pattern, and flow rates would all affect the

drug efficacy (Groneberg et al., 2003). Age and

gender would lead to individual differences in these

three parameters. Therefore, it is crucial to administer

aerosol drugs differently to different groups of people.

4 DEVICES

4.1

Metered-Dose Inhalers (MDIs)

MDIs are commonly used by asthma and chronic

obstructive pulmonary disease (COPD) patients for

treating bronchospasm (Hou et al., 2015). MDI

containers have three parts, which are metering valve,

Analysis on the Delivery and Formulations of Inhaled Drugs

1315

canister, and actuator. The metering valve controls

the volume of a single dose. The canister contains

pressurized drug formulation. Then the drug

formulation is decompressed and released by the

actuator (Lavorini, 2013). One of the advantages of

MDI devices is that a single device can contain

multiple doses, so that it can be used for a long time.

It has shown that one MDI device contains at least

two hundred doses (Lavorini, 2013). Since every dose

has an equal volume, there is no worry for overdose.

Comparably, MDI devices are also portable and low-

cost. However, MDI devices require good

coordination between patients and the devices.

Patients need to breathe while releasing the drug and

hold breath for a few seconds to increase lungs

deposition (Lavorini, 2013). In addition, the materials

of the metering valve, canister, and actuator would

affect the drug properties. The inner walls of the MDI

container are usually coated with polymers, such as

perfluoroalkoxy (PFA), fluorinated ethylene

propylene–polyether sulphone (FEP–PES), and

polytetrafluoroethylene (PTFE), to prevent changes

in drug properties (Traini et al., 2006).

Figure 2: Drug deposition for patients who use MDI

devices (Newman et al., 1981).

Newman et al. has measured drug depositions and

the data is shown in figure 2. When delivered by MDI,

most of the drugs, about 80.4%, would lost in the

oropharynx. Only 8.8% of the total amount would be

delivered to the lungs (Newman et al., 1981). There

are also other studies showed that the lung deposition

when using MDI with good techniques can reach to

11.2% (Newman et al., 1986).

4.2

Dry Powder Inhalers (DPIs)

Similar to MDI devices, DPI devices are portable and

convenient. A DPI device can have only one dose or

multiple doses. If one DPI device is single-dosed, it

is a disposable inhaler (Hou et al., 2015). Recent

research shows that disposable DPIs are suitable for

inhaled COVID-19 vaccines because they can

prevent reuse and contamination (Heida et al., 2021).

Furthermore, unlike MDIs, DPI devices do not

require coordination between patients and devices.

Drug delivery of DPIs only relies on patients’ breath

independently (Hou et al., 2015). However, this leads

to a drawback of this kind of device: DPIs require a

certain amount of inspiratory flow rate to get an

effective dosage (Lavorini, 2013). For example,

Newman et al. conducted an experiment that

measures the drug deposition in patients who use a

DPI device, SpinHaler.

Figure 3: Drug deposition for patients who use SpinHaler

with a high inspiratory flow rate (120 L/min) and with a

low inspiratory flow rate (60 L/min) (Newman et al., 1994).

As shown in Figure 3, the experiment illustrated

that drug deposition in lungs for patients with a higher

inspiratory flow rate and those with a lower

inspiratory flow rate are significantly different

(Newman et al., 1994). The drug deposition in the

lungs is doubled when the inspiratory flow rate is

doubled (Newman et al., 1994). Thus, some patients

might not use them correctly and efficiently.

Research has found that 94% of the patients do not

use the DPI devices correctly (Lavorini et al., 2008).

4.3

Nebulizers

Nebulizers are relatively larger and less portable than

MDIs and DPIs. They can provide continuous drug

delivery, which is especially useful for the delivery of

large-dosed drugs (Hou et al., 2015). This also leads

to a longer time duration of drug delivery, so some

nebulizers require outside energy sources to conduct

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

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drug delivery (Lavorini, 2013). However, nebulizers

are easier for patients to use. Nebulizers usually need

mouthpieces or facemasks to delivery drugs to

patients (Lavorini, 2013). Patients only need to

perform their normal breathing pattern to use

nebulizers, which is especially helpful for

incoordinate patients such as infants and elderly

patients (Lavorini, 2013). Tidal volume determines

the amount of drug delivered, so there might be

individual differences in terms of efficacy. On the

other hand, nebulizers are not disposable, so the drugs

need to be loaded into the devices. Thus, compare to

MDIs and DPIs, nebulizers have a higher chance of

causing drug contamination (Lavorini, 2013).

Figure 4: Drug deposition for patients who use Inspiron

Mini-Neb. O-P=oropharyngeal (Lewis & Fleming, 1985).

Experiment has found that nebulizers can reach a

lung deposition of 12.4%, which is higher than the

one for MDIs (Lewis & Fleming, 1985). In addition,

compare to MDIs and DPIs, most of the drugs, about

66.3%, would lost in nebulizer devices (Lewis &

Fleming, 1985).

5 FORMULATIONS

Different devices utilize different drug formulations.

MDIs and nebulizers are usually used to deliver

suspension or aqueous solution formulated drugs,

while DPIs, as the name indicates, are usually used to

deliver drug powders (Hou et al., 2015). Also, MDIs

contain propellants while DPIs and nebulizers do not

(Lavorini, 2013). Since different delivery devices

possess different mechanisms, different excipients

and formulations are needed to ensure the desired

performance of each kind of device.

5.1

Metered-Dose Inhalers (MDIs)

Drug particles are conserved with propellants in

MDIs and delivered together. Different propellants

were used since the first use of MDIs. One of the

previously used propellants is chlorofluorocarbons

(CFC), but it is no longer in use since the Montreal

Protocol in 1987 because of ozone-depleting effects

(Hou et al., 2015). The commonly used propellants

now are hydrofluoroalkane (HFA), which includes

HFA 134a and 227ca, which are less likely to cause

global warming than CFC (Lavorini, 2013). Except

for propellants, MDIs also need surfactants and

cosolvents (Lavorini, 2013). Some common

surfactants are sorbitan trioleate, lecithin, oleic acid,

and polyethylene glycol (PEG), which mainly serve

as valve lubricants and inhibit particle aggregation. It

is also shown that some surfactants contribute to the

taste (Lavorini, 2013). However, the solubility of

some surfactants is not ideal in HFA propellants

(Vervaet & Byron, 1999). Cosolvents such as ethanol

would help to improve the solubility of surfactants

(Hou et al., 2015).

5.2

Dry Powder Inhalers (DPIs)

DPIs are used to deliver solid drug powders into

human body systems. The commonly used excipient

or carrier of DPI drugs is lactose. Micronized drugs

first blend with lactose particles with diameters of 30-

60 μm; they are granulated into micronized particles

using wet or dry granulation (Chow et al., 2007).

Meanwhile, particle size and shape are important

parameters to consider when formulating dry powder

inhaler drugs. Amorphous particles are less efficient

during delivery because of their high-energy surface

(Kawashima et al., 1998). Research has shown that

lung deposition is higher when the particles are

elongated and pollen-shaped (Fults et al., 1997).

Various techniques can be used in DPI drugs

formulation, such as spray drying, freeze-drying, and

roller drying (Hou et al., 2015). Among these

techniques, in vitro research has shown that

anhydrous β-lactose by using roller drying might be

more efficient and doable (Chow et al., 2007).

Trehalose, mannitol, and menthol could be other

excipient carriers that can replace lactose (Chow et

al., 2007).

5.3

Nebulizers

Nebulizers are usually used to deliver drugs with

suspension or aqueous solution formulations. A

common solvent of nebulizer drugs is sterile water,

Analysis on the Delivery and Formulations of Inhaled Drugs

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which is the same solvent for intravenous injection

(Hou et al., 2015). Similar to MDI drugs formulation,

ethanol can be the cosolvent for nebulizer drugs as

well (Hou et al., 2015). Furthermore, the physical

properties of drug formulations are essential because

they might lead to change in delivery efficiency and

result in side effects (Labiris & Dolovich, 2003). For

example, a low pH would lead to

bronchoconstriction, which might result in irritation

(Labiris & Dolovich, 2003). In this case, the pH can

be increased by adding sodium hydroxide, while

similarly, hydrochloric acid can be added if the pH is

too high (Hou et al., 2015). Besides, solution

viscosity can influence the size of particles—the

larger the viscosity, the smaller the particle size (Hou

et al., 2015). Therefore, physical properties are

crucial factors to consider in nebulizer drug

formulation. In addition, since nebulizers are not

disposable and have a higher chance of getting

contaminated, preservatives are needed.

Benzalkonium chloride can be an antimicrobial

preservative (Hou et al., 2015).

6 CONCLUSIONS

Aerosol administration is a promising area of drug

delivery and still needs more research. It is not as

common as other administration routes, such as oral

and intravenous administration, but it is a helpful way

of drug delivery. Aerosol administration has benefits

when the local administration is wanted. Meanwhile,

some aerosol drugs also have systemic effects.

Inhaled drugs are mainly absorbed by type I

pneumocytes to exhibit local or systemic effects.

There are three most commonly used inhalation

devices: metered-dose inhalers (MDIs), dry powder

inhalers (DPIs), and nebulizers. Each of them has

advantages and drawbacks compared to others. We

need to put drug formulation and patient conditions

into account when using these devices. Different

drugs and devices need different excipients and

formulations. The inhaled drugs and formulations

need to be compatible with specific devices. There

also might be individual differences in aerosol

administration because each patient has different

physiological conditions. Devices, formulations, and

patients together are three crucial factors to consider

for the development of aerosol administration (Hou

et al., 2015).

There are many approved inhalation devices. This

paper focuses on three common ones with different

formulation requirements. MDIs and nebulizers

require suspension or solution formulations, while

DPIs require drug powder formulations. There are

many aspects to consider in drug formulation, such as

propellant, excipients, and physical properties. More

studies on the specific effects of different

formulations and the optimal devices and

formulations for specific systems are still needed.

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to

Professor Axel Zeitler for delivering and sharing

knowledge about pharmaceutical engineering, which

laid a foundation of this paper. I was also grateful to

him for providing advice and suggestions. I would

also appreciate my peer tutor, Cheng Wei, for

providing not only advice, but also interesting

discussions.

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