163

# Mechanism and Ways of Pulmonary Drug Administration

Authored by: Ahmed S. Fahad , Sai HS. Boddu , Jerry Nesamony

# Handbook of Lung Targeted Drug Delivery Systems

Print publication date:  October  2021
Online publication date:  October  2021

Print ISBN: 9780367490676
eBook ISBN: 9781003046547

10.1201/9781003046547-3

#### Abstract

Since the marketing of the first metered dose inhaler in 1956, pulmonary drug delivery has been extensively studied and developed. The lungs offer excellent permeability for a variety of lipophilic and hydrophilic molecules, including macromolecules such as proteins and peptides. The lungs have only a fraction of the enzymatic and efflux transporter activity of the gastrointestinal tract. Currently, researchers are investigating and testing more sophisticated devices and aerosolized particles. Several approaches have to be adopted to optimize pulmonary drug delivery, minimize clearance, and improve drug targeting within the lungs. This chapter mainly highlights the mechanisms of drug permeation into the lungs, and deposition and clearance of aerosol particles in the respiratory airways. In addition, the latest developments in the methods and devices used in pulmonary drug administration are included.

#### 3.1  Introduction

Medications and other substances have been administered through the pulmonary route for hundreds, if not thousands of years. An excellent historical overview of the development and use of inhalation therapies written by Mark Sanders in 2007 provides details about the origins of delivery of drugs and other active ingredients into the respiratory tract (1). The author has created a digital repository of media compilation at www.inhalatorium.com that shows examples of historical articles, advertisements, devices, patents, and other resources related to the history of inhalation formulations and devices. The inhalation method for delivering materials into the respiratory tract has been in use since ancient times and the earliest historical and archeological evidence for therapeutic inhalation was obtained from Egypt and dates back to 1554 BC (1). Similarly, the accounts of recreational and therapeutic inhalations of opium, tobacco, and herbal materials/medicines can be found in ancient China, India, Rome, Greece, and the Middle East. A more modern predecessor of a new era of the inhalation route of drug delivery is the inhalation device designed and developed in 1654 by the English physician Christopher Bennet. The historic evidence suggests that the earliest methods mostly used smoke from burned or burning material to deliver substances into the lungs. Over 100 years after Christopher Bennet’s inhaler, in the late 1700s devices that generated mists referred to as vapors were introduced (2). In the mid to late 1800s devices that generated nebulized mists were used. This time period also saw the invention of the first dry powder inhaler. The first metered dose inhaler that used chlorofluorohydrocarbons (freons) as the propellant was launched in 1956. Since then the three primary categories of inhalation therapies, namely mist-based nebulized dosage forms, aerosol-particles-based metered dose inhalations, and dry powder inhalations have undergone several advancements with respect to devices and formulations including excipients (3).

Currently, the market size of global inhalable drugs is valued over US$25.0 billion and is estimated to reach US$41.5 billion by 2026 (4,5). Approximately 1.21% of marketed pharmaceutical products are delivered via the inhalation route (3). The pulmonary route of drug administration allows a quick onset of action, high drug concentration at the site with a low dose (10–20% of the amount given orally), improves local drug release at the disease site, and bypasses hepatic first-pass metabolism (6). For many years inhaled drugs have been used for treatment of common respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Certain drugs such as corticosteroids are preferred via the pulmonary route for treating lung diseases due to their systemic side effects. The pulmonary route offers greatest bioavailability when compared to all other routes of non-invasive drug delivery. Additionally the inhalation route offers the fastest onset of biological action when compared to all other non-invasive routes for a wide range of drugs and molecules. The advantages of inhaled drugs for treatment of respiratory and systemic diseases are highlighted in Table 3.1 (7).

### Table 3.1   Advantages of Pulmonary Drug Delivery for Treatment of Respiratory and Systemic Diseases

Respiratory Diseases

Systemic Diseases

Reduce risk of systemic side-effects

A non-invasive ‘needle-free system

Rapid onset of action

Compatibility with a wide range of substances ranging from small to very large molecules (8,9)

Avoid harsh gastrointestinal environment and hepatic first-pass metabolism

Enormous absorptive surface area for absorption and highly preamble membrane in the alveolar area (10)

Ability to deliver a high drug concentration to the site of disease

Less harsh environment, low enzymatic activity, and bypass of hepatic first-pass metabolism

Achieve therapeutic effect at a fraction of the systemic dose

Prolong the residence time due to slow mucociliary clearance mechanism (11)

Sustained release effect

Reproducible absorption kinetic profile (9)

Considering these advantages, pulmonary administration of protein therapeutics and antibodies has gained a lot of popularity in recent times. Efforts to deliver such drugs as insulin, thyroid-stimulating hormone [TSH], calcitonin, follicle-stimulating hormone [FSH], growth hormones, immunoglobulins, cyclosporine A, recombinant-methionyl human granulocyte colony-stimulating factor, and pancreatic islet autoantigen are underway (12). When compared to various non-invasive routes of delivery, proteins and polypeptides are 10–200 times more bioavailable when administered through the pulmonary route. An inhaled form of insulin (Afrezza®) for systemic absorption of insulin is currently available in the market. In the future, inhalable medications may be available for gene therapy and to deliver various therapeutic proteins and polypeptides. In this chapter, our focus is mainly on the mechanisms of drug permeation in the lungs along with particle deposition and clearance from the lungs. In addition, the ways of pulmonary drug administration are also emphasized.

#### 3.2  Mechanisms of Drug Permeation into the Lungs

The respiratory system is divided into three major areas: the oropharynx, the nasopharynx, and tracheobronchial pulmonary region. The airway circulation starts with the nasal cavity and sinuses, and then proceeds to the nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles, alveolar ducts, and alveolar sacs (Figure 3.1). The rate and extent of drug absorption varies in different regions of the lung. For instance, the conducting airways offer ∼2 m2 for drug absorption, while alveolar surfaces offer ∼140 m2. In addition, the epithelial thickness and cell population are different in the airways and alveolar region (13). The absorptive area in the lung is mainly the alveolar epithelium, which basically includes type I pneumocytes.

Figure 3.1   Anatomy of Human Respiratory System. Modified from https://en.wikipedia.org/wiki/Lung#/media/File:Illu_conducting_passages.svg

The pulmonary epithelium acts as a barrier to systemic absorption of drugs delivered via inhalation. However, its permeability is not uniform throughout the respiratory tract. The thickness of the epithelium is about 66 μm in the bronchi, and about 13 μm in the terminal bronchioles (14, 15). As one goes deeper into the lungs and into the alveoli where gas exchange occurs, the epithelium is extremely thin and is about 0.1–0.2 μm. The total area through which absorption can occur also undergoes drastic changes from the airways to the alveoli. The total airways surface area is about a few square meters; however, the alveolar surface area is very high and varies with respiration state. The alveolar surface area is reported to be about 35 m2 after a deep expiration and 100 m2 after a deep inspiration (14). Although good conclusions regarding the aerosol size beneficial for pulmonary drug delivery has been established, the ideal deposition site where optimal drug absorption occurs upon pulmonary delivery is not known. High permeability to water, gases, and to lipophilic materials is a characteristic feature of both alveolar epithelium and capillary endothelium.

Generally, inhaled drugs are absorbed either via paracellular or transcellular pathways (Figure 3.2). In the paracellular pathway, drugs pass through the tight junctions (integral proteins of claudins and occludins) present between the lung epithelial cells. The epithelial electrical resistance is highest in the upper airways, decreases to a minimum in the distal airways, and again becomes a maximum in the alveoli. This implies that the paracellular absorption occurs in the distal bronchioles. For example, small molecular weight hydrophilic drugs such as insulin (Mol wt: 5808 Da) was reported to undergo absorption via paracellular transport in the lungs. Furthermore, the alveolar type I cells limit the entry of molecules of size less than 1.2 nm diameter due to the presence of tight junctions, while endothelial junctions have larger gaps ranging from 4 to 6 nm (16). The rate of diffusion of drug molecules through the intercellular pores is found to be inversely proportional to the molecular radius (17). The use of permeation enhancers to modulate the tight junctions is considered to be a promising strategy as it enhances the delivery of hydrophilic compounds and protein drugs. Paracellular transport of drugs can be increased by using chitosan, hypertonic saline, sodium caprate (sodium salt of medium chain fatty acid), and oleic acid (fatty acid), which decreases the tightness between the paracellular junctions in a reversible manner (18, 19). In a recent study, sodium decanoate was shown to significantly increase the permeation of Flu-Na (paracellular marker) and PXS25 (anti-fibrotic compound) through the reversible opening of tight junction modulator in Calu-3 lung epithelial cells (20).

Figure 3.2   Transport Mechanisms across Pulmonary Epithelium

Low molecular weight hydrophobic drugs are absorbed through the lungs via transcellular pathways, wherein drugs passively diffuse through the cell membrane. Studies have also demonstrated that lipophilic molecules (log P > 0) are readily absorbed in about 1 minute and absorption of hydrophilic molecules (log P < 0) takes about 1 hour. A study conducted by Schanker et al. concluded that the compounds administered to lungs absorbed by passive diffusion had a rate of absorption that increased with lipophilicity of compounds (partition coefficients, chloroform/buffer pH 7.4, ranging from –3 to 2) (21). However, in the case of hydrophilic compounds, the absorption rate was inversely related to the molecular weight within the range 60–75000 Da (17). Large intracellular gaps within microvascular epithelium are more permeable and they allow proteins and all molecular sizes to enter systemic circulation. Apart from passive diffusion, transcellular pathway also occurs via transporter molecules expressed on the surface of cell membranes. In comparison to the passive diffusion, drug transport via transporters and receptors is very limited.

Two classes of transporters are expressed in lung cells, namely the solute carrier (SLC) and ATP binding cassette (ABC) transporters. The SLC family includes both organic cationic transporters (OCT) and organic anionic transports (OAT) such as OCT1, OCT2, OCTN1, OAT2, OAT3, OAT4, PEPT2, OATP1A2, OATP1B3, OATP2B1, and PGT/OATP2A1 as confirmed through QTAP LCMS/MS analysis in human lung tissue. The expression of ABC transporters such as MDR1, MRP1, MRP3, MRP4, MRP5, MRP6, MRP8, and BCRP are also reported. Of all these, the highest expression was observed in OCTN1, MRP1, BCRP, and PEPT2 proteins (22). For example, salbutamol (albuterol) undergoes absorption via OCT1, OCT3, OCTN1, and OCTN2 as it is positively charged at the physiologic pH in the lungs. An increased apical to the basolateral transport of albumin, transferrin, and immunoglobulin G was observed in rat alveolar monolayers via adsorptive endocytotic and/or receptor-mediated processes (23). Further details on drug transporters in the lungs and their impact on distribution of pulmonary administered drugs are highlighted in a recent proceedings of the workshop on Drug Transporters in the Lungs. (22)

Studies have also shown the presence of membrane vesicles within the epithelial type I cells and alveolar endothelial cells. These vesicles are non-coated or smooth-coated vesicles recognized as caveolae (24). The number of caveolae-like structures were found to be more in the endothelium compared with the alveolar type I epithelium. Membrane vesicles were shown to be involved in the transcytosis or the vesicular movement of macromolecules across endothelial cells (25). For example, caveolae-mediated transport of albumin was observed in the rat pulmonary endothelium. It has also been scientifically established that regular smoking and the presence of pulmonary disease increases lung permeability (16).

#### 3.3.1  Mechanisms of Particle Deposition in the Respiratory Airways

Three major mechanisms are responsible for particle deposition in the lungs: inertial impaction, sedimentation, and Brownian diffusion (16). The deposition mechanism directly correlates with the particle diameter and determines the deposition of the particles in a particular area of the respiratory airways (26).

#### 3.3.1.1  Inertial Impaction

This is the most important mechanism of aerosol particles deposition with Mass Medium Aerodynamic Diameter (MMAD) of more than 5 μm. When velocity and mass of particles lead to an impact on the airway track, as in the case of a bifurcation or further subdivision of the airway tube, the particles tend to settle in the upper respiratory airways. Partial blockade of the respiratory airways and changes in the direction of inspired air improve the chances for deposition through this mechanism. Thus, as the airflow changes direction when the airway tube branches out, the aerosols tend to retain their existing path due to the particle momentum (27). This will cause the aerosol to eventually collide with the respiratory airway walls and deposit at the site of impaction. The larger and denser the aerosol particle, the greater will be its momentum and the greater will be the probability for it to deposit through inertial impaction. The probability of aerosol particles to deposit through inertial impaction can be expressed as a function of the Stokes number (Stk). The Stokes number is defined as

$Stokes number = Stk = ρ p . d p 2 . u ) / ( 18 μ d )$

where $ρ p$ is the particle density, d p is the particle diameter, u is the mean velocity, μ is the dynamic viscosity of the carrier gas, and d is the airway tube diameter. Hyperventilation, a condition in which overbreathing patterns develop due to various reasons, may significantly affect particle deposition via impaction (16).

#### 3.3.1.2  Sedimentation

Sedimentation occurs in the peripheral airways and involves aerosols with an MMAD from 1 to 5 μm. This mechanism occurs due to the action of gravitational forces on particles and occurs primarily in small airways and alveolar cavities. Particle motion is not considered a factor that has an effect on this type of particle deposition because gravitational settling occurs predominantly when the distance for particle deposition is very small (28). However, breath holding has an impact on particle sedimentation and can improve deposition. The terminal settling velocity of aerosols Vs is determined using the equation

$V s = ρ p . d p 2 18 μ . g ,$
where g is the acceleration due to gravity.

#### 3.3.1.3  Brownian Diffusion

This is the predominant deposition mechanism for particles with an MMAD of less than or equal to approximately 0.5 μm. These particles move arbitrarily with gas molecules and collide against the airway walls. This is the mechanism through which respiratory gas exchange happens within the functional units, acini, of the lung. Hence, it is hypothesized that aerosol particles depositing via Brownian motion deposit in the acinus part of the human respiratory apparatus. A contrasting characteristic of Brownian deposition is that as particle size decreases, deposition increases. Particle deposition via Brownian diffusion is directly proportional to the diffusion constant DB

$DB = ( ckT ) / ( 3 π μ d p ) ,$
where c is the Cunningham constant that factors the influence of air resistance on the extreme small size of aerosols, k is the Boltzmann constant and T is the absolute temperature. Around 80% of particles with an MMAD of less than or equal to 0.5 μm are removed out of the respiratory tract during the exhalation process (29). The pattern of deposition of aerosol particles in the body is shown in Figure 3.3.

Figure 3.3   Pathway of Aerosolized Drug Particles in the Body (16)

#### 3.3.2  Factors Affecting Particle Deposition

Various physicochemical properties, physiological, and anatomical factors affect the deposition of aerosol particles in the bronchial tree. Among the physicochemical factors, aerodynamic characteristics such as particle size, particle shape, density, and aerosol velocity are perhaps the most important determinants of aerosol deposition. Lung physiology can also impact aerosol deposition and the depth of penetration into the respiratory tract. Pulmonary function tests (PFT) are used to evaluate the impact and progression of pulmonary diseases on lung physiology. PFTs are used to distinguish between asthma and COPD, and are also used to categorize/stage the severity of the condition. The severity of the pulmonary disease determines the therapies recommended to treat the condition and when it is necessary to adopt changes in treatment regimens. Four general parameters should be considered to evaluate the size and morphology of an aerosol particle:

1. Mass Median Diameter (MMD) is the diameter of the particles of which 50% w/w of particles have lower diameter and 50% w/w have a higher diameter.
2. Percentage of weight of particles with a geometrical diameter of less than 5 μm.
3. Geometric Standard Deviation (GSD) is the ratio of the diameters of particles from aerosols corresponding to 84% and 50% of the cumulative distribution curve of the weights of the particles.
4. Mass Medium Aerodynamic Diameter (MMAD) describes the size and morphology of the aerosol’s particles by considering their geometrical diameter, shape, and the density: MMAD = MMD x Density½ (16).

#### 3.3.3  Effect of Particle Size

The particle size of an aerosol has a crucial impact on its mechanism and site of deposition in the lung. Large-size particles with diameters of (>10 μm) that come in contact with the upper airway tract are removed by mucociliary clearance. Aerosols with a particle diameter range from 0.5 to 5 μm deposit through sedimentation mechanism (16). Aerosol particles that are intended to penetrate the lung were determined to be in the size range around 2–3 μm (30). Particles with very small diameter may be exhaled before depositing in the lung; however, holding the breath can prevent this. Extremely small diameter particles (<0.1 μm) are not easy to manufacture, though they efficiently settle by Brownian diffusion mechanism. Human studies performed using particles in the size range of between 0.005 and 15 μm demonstrated that minimum deposition was seen at a particle size of 0.5 μm. For particles greater than 0.5 μm the deposition increased due to an increase of inertial and gravitational deposition, whereas deposition increased as the particles were progressively smaller than 0.5 μm due to an increase in diffusion transport. It has also been observed that at a particular particle size, higher deposition is seen with an increase in tidal volume, a clear indication that lung physiology and depth of inhalation can have an impact on aerosol deposition. Nevertheless, researchers have not been able to confirm an exact geometrical diameter that results in deposition of inhaled particles because even large particles that have a porous internal structure can penetrate and deposit in the lungs (31).

#### 3.1  Respiratory Clearance of Inhaled Particles

Mucociliary clearance or a combination of mucociliary and alveolar clearance mechanisms are responsible for removing settled particles that have not entered the lung epithelium and other unwanted particles from entering the respiratory system (16). The clearance mechanisms offers an important challenge that has to be overcome when formulating aerosol products (28).

#### 3.4.1  Mucociliary Clearance

This is the respiratory system’s unique mechanism against materials that enter the respiratory tract from the outside environment during breathing. The mucociliary clearance is an efficient self-respiratory cleaning besides other clearance mechanisms such as cough and alveolar clearance (16). From the trachea to the terminal bronchioles, the ciliated epithelium is extended and covered by a double-layered mucus blanket: a low-viscosity periciliary sol layer covered by a high-viscosity gel layer. The mucus is secreted by airway epithelial goblet cells and submucosal glands. The upward movement of the mucus clears the trapped insoluble particles toward the pharynx from where it can go into the gastrointestinal tract (28). The efficiency of mucociliary clearance is significantly diminished in respiratory diseases like asthma and cystic fibrosis (32).

#### 3.4.2  Alveolar Clearance

Absorptive and non-absorptive clearance mechanisms clear deposited particles from the terminal airways (33). The absorptive mechanism involves either direct penetration into the epithelium cells or uptake and clearance by alveolar, interstitial, intravascular, and airway microphages. The alveolar epithelial surface where respiratory gas exchange occurs is populated by alveolar macrophages that engulf and remove undissolved particles that deposit in the alveoli. The uptake by macrophages can severely limit the systemic bioavailability of drugs contained in such particles due to enzymatic degradation inside the macrophages. The non-absorptive mechanism carries particles from the alveoli to the ciliated area from which the mucociliary clearance process further removes the particles from the conducting airways (16).

#### 3.5  Ways of Pulmonary Drug Administration

There are numerous devices and formulations that are commercially available to deliver drugs and pharmaceuticals into the respiratory tract. All of these methods and devices in the market can be placed under one of the three broad categories that includes: 1. pressurized metered dose inhalers that are also referred to as metered dose inhalers (pMDIs), 2. dry powder inhalers (DPIs), and 3. nebulizers (34). All three different types of pulmonary drug delivery methods utilize different techniques and technologies in formulations, product components, packaging and use. An important aspect that determines the efficacy of an inhalation product is the technique used when administering the product. Thus, each product is accompanied with detailed instructional material, virtual animated, and real instructional videos about proper methods of administration. Healthcare providers, including pharmacists play a very important role in delivering patient education related to proper use of inhalation devices.

#### 3.5.1  Pressurized Metered Dose Inhalers

The pMDI revolutionized pulmonary drug delivery. The pMDI consists of a pressurized canister that contains the drug in the form of a solution or suspension along with a suitable propellant. Initially chlorofluorocarbons (CFCs) were used as the propellant in pMDIs. But due to the deleterious impact on the ozone layer and its subsequent banning, CFCs are no longer used in pMDIs. Currently, hydrofluoroalkanes (HFA) are used as the propellant in marketed formulations. A dose metering valve is a part of the sealed end of the canister that inserts into the actuator. As the actuator is depressed, it presses the valve stem assembly down through an attached spring mechanism. As the valve stem moves down it disconnects the metering chamber, allowing the propellant and formulation to eventually emanate through the valve orifice. This releases the pressurized propellant along with the drug solution or suspension into the actuator. The unique design features of the actuator extend out as the mouthpiece delivers the high-velocity aerosol spray. The mouthpiece has a removable cover that prevents dust and particle contamination. The basic aspects of this system have not undergone considerable change; however, the methods that are used in formulating the drug suspension have undergone some changes. MDIs have to be primed before using, and when the formulation is a suspension, the system has to be shaken well prior to use (35).

Numerous studies have been done to evaluate how much of the emitted dose eventually deposits in the lungs. It has been established that the lung deposition of the emitted dose from a pMDI is between 10 and 20%. The low lung deposition is partly due to oropharyngeal deposition of about 50–80% of the emitted dose (28). Additionally, efficient delivery of the aerosol from the pMDI into the lungs significantly depends on the use of proper technique when self-administering the dose. Some common mistakes that were found among patients are errors related to the breathing pattern and inspiratory air flow. A considerable number of patients were found to hold their breath after emitting the dose from the device leading to loss of drug in the oropharyngeal region. When inspiring the emitted dose from a pMDI, the patient is expected to breathe in slowly and deeply. If the patient breathes in rapidly this alone will cause the aerosol particles to deposit mostly in the oropharyngeal region. After proper breathing in of the aerosol, most products require the patient to hold the breath for 10 seconds, which in itself may not be always possible due to the decline in respiratory anatomy and physiology in advanced disease states (36). Numerous patients have difficulty with the hand–mouth coordination that is necessary while using the product.

Accessories that can be attached to the pMDI mouthpiece, such as spacers and valved holding chambers, have helped to alleviate the problems associated with hand–mouth coordination. These devices function as an aerosol reservoir into which the dose is actuated and which then can be inhaled, reducing the problems related to hand–mouth coordination. Another innovation that was developed in pMDIs to address hand–mouth coordination is the breath actuated pMDI (BApMDI). BApMDIs use an inspiratory airflow triggered system that releases the dose when the patient inhales after the device mouthpiece is placed appropriately (37). The inhalation causes the firing of the device and no hand-based actuation is needed. Despite all these disadvantages, pMDIs are still the most popular method for pulmonary drug delivery due to the small size, convenience of handling, and its sheer presence and optimization in the pulmonary drug delivery realm for over 65 years.

Table 3.2 shows various pMDIs currently in the US market along with certain characteristics associated with each product. As is evident from the table, the two most commonly used propellants are HFA-134a and HFA-227. Most products have minimal amounts of other excipients when present in the formulation. All the products except ciclesonide (Alvesco®) are suspensions. Ciclesonide is a solution and the product does not have to be shaken prior to use. The Bevespi Aerosphere® product uses a co-suspension of the active ingredients in porous phospholipid particles prepared from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) stabilized by calcium chloride. The aerosphere technology coupled with the co-suspension delivery technique is a notable advancement among the pMDI product platforms. The aerosphere (also referred to as pulmosphere) technique is used to first manufacture highly porous phospholipid microparticles (17). An emulsion of DSPC in perfluorooctyl bromide (perflubron) and water stabilized by calcium chloride is atomized and sprayed into a dryer. As the drying proceeds, the perflubron evaporates, leaving behind nano- and micrometer sized pores on the dried DSPC microparticles. The DSPC microparticles can then be blended/mixed with one or more micronized active ingredients within a single product. The drug crystals interact strongly with the DSPC particles allowing for formulating a combination product with no drug–drug interactions that may destabilize the product. This technique also allows for delivering a higher than conventionally possible dose of the active ingredients due to the unique particulate microstructure, physicochemical stability, and suspension uniformity. The aerosphere-co-suspension technology has at least partially addressed some of the challenges traditionally attributed to pMDIs, such as low lung penetration, dose inconsistency, poor suspension stability, etc. The highly porous DSPC particles enter the lungs with ease through the inspiratory airflow where they absorb moisture and collapse into a mucinous mass that readily assimilates into the pulmonary membrane. This causes the active ingredient(s) to be released locally where it produces its biological action.

### Table 3.2   Examples of pMDIs in the US Market

Active Ingredient

Product Name

Propellant

Other Excipients (if Applicable)

Albuterol

Ventolin® HFA

HFA-134a (1,1,1,2-tetrafluoroethane)

No excipients, microcrystalline albuterol sulfate in propellant

Proventil® HFA

HFA-134a

Ethanol, oleic acid

ProAir® HFA

HFA-134a

Ethanol

Levalbuterol

Xopenex® HFA

HFA-134a

Dehydrated alcohol, USP, Oleic acid

Beclomethasone

QVAR Redihaler (breath actuated)

HFA-134a

Ethanol

Mometasone

Asmanex® HFA

HFA-227 (1,1,1,2,3,3,3-heptafluoropropane)

Ethanol, oleic acid

Fluticasone

Flovent® HFA

HFA-134a

No other excipients

Ciclesonide

Alvesco®

HFA-134a

Ethanol

Salmeterol + Fluticasone

HFA-134a

No other excipients

Formoterol + budesonide

Symbicort®

HFA-227

Povidone K25, polyethylene glycol 1000

Formoterol + mometasone

Dulera®

HFA-227

Anhydrous alcohol, oleic acid

Ipratropium

Atrovent® HFA

HFA-134a

Sterile water, dehydrated alcohol, anhydrous citric acid

Formoterol + glycopyrrolate

Bevespi Aerosphere®

HFA-134a

Co-suspension of drug microcrystals in porous particles comprising of 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) and calcium chloride

#### 3.5.2  Dry Powder Inhalers (DPIs)

DPIs were first introduced in the market in the 1970s as single dose systems. The medication was present in gelatin capsules that were placed in the device and then inhaled. One important distinction between DPIs and pMDIs related to product usage is that the patient is expected to inhale forcefully and deeply when using the DPI. DPIs do not need any propellants and use inspiratory air to deliver the aerosol into the lungs. Thus, high-velocity inspiratory air will enable efficient entry of the particles into the lungs. Additionally, forceful inspiration will produce a turbulent stream of air that is capable of breaking down solid agglomerates propelling the aerosol into the lungs, thereby minimizing oropharyngeal deposition (38). Approximately 12–40% of the emitted dose from a DPI deposits in the lungs. A significant problem associated with DPIs is the loss of about 25% of the emitted dose within the device. Issues related to poor lung deposition from DPIs are partly due to the inability of the inspired air to de-aggregate large solid particulates in the formulation (39). The design of the device helps to address this issue to a certain extent, but the aerodynamics of the inspiratory air flow, humidity in the air flow, and temperature changes within the respiratory tract can determine how well large particulate agglomerates break down when a DPI is being used. The device itself can be an impediment to generating an optimal inspiratory air flow. Research on approaches such as the use of compressed air and powered propellers to disperse the aerosol powder have not yet lead to commercialization. The DPI products currently in the market are all inhalation driven and are available in different designs. Table 3.3 lists most of the currently available DPIs in the United States. One of the first modern DPIs approved in early 2000s was the Advair Diskus®. This product was one of the most significant innovations among pulmonary drug delivery systems to obtain widespread approval and market penetration since the first MDI was introduced in 1956.

### Table 3.3   Examples of DPIs in the US Market

Active Ingredient

Product Name

Product Type

Excipients

Albuterol

ProAir Respiclick®

Inhalation driven, multi-dose, non-reusable

Alpha-lactose monohydrate

Mometasone

Asmanex Twsithaler®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

Fluticasone

Flovent Diskus®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

Arnuity Ellipta®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

ArmonAir Respiclick®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

Salmeterol

Serevent Diskus®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

Salmeterol + fluticasone

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

Airduo Respiclick®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

Tiotropium

Spiriva Handihaler®

Inhalation driven, single-dose, reusable

Lactose monohydrate

Umeclidinium

Incruse Ellipta®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate, magnesium stearate

Aclidinium

Tudorza Pressair®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate

Glycopyrrolate

Seebri Neohaler®

Inhalation driven, single-dose, reusable

Lactose monohydrate, magnesium stearate

Indacaterol

Arcapta Neohaler®

Inhalation driven, single-dose, reusable

Lactose monohydrate

Vilanterol + fluticasone

Breo Ellipta®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate, magnesium stearate

Vilanterol + umeclidinium

Anoro Ellipta®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate, magnesium stearate

Indacaterol + glycopyrrolate

Utibron neohaler®

Inhalation driven, single-dose, reusable

Lactose monohydrate, magnesium stearate

Vilanterol + umeclidinium

Anoro Ellipta®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate, magnesium stearate

Umeclidinium + vilanterol + fluticasone

Trelegy Ellipta®

Inhalation driven, multi-dose, non-reusable

Lactose monohydrate, magnesium stearate

Insulin

Afrezza®

Inhalation driven, single-dose, reusable

Fumaryl diketopiperazine (FDKP) and polysorbate 80

Tobramycin

TOBI® podhaler

Inhalation driven, single-dose, reusable

Porous particles made from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride, and sulfuric acid

Zanamavir

Relenza Diskhaler®

Inhalation driven, multi-dose, reusable

Lactose

Soon after the Diskus® entered the market, the Turbuhaler® design, which was a reservoir-type multi-dose non-reusable device, became available. Additionally, one of the first inhalation driven, single-dose reusable types of DPI designs, the Handihaler® device, was introduced in the market at the same time. Based on the nature of the DPI devices and their design, the currently available products can be categorized as non-reusable or reusable types. And within the non-reusable type there are two categories: the ones that contain a premeasured dose of medications placed in blister strips and those that have a dry powder reservoir that can be metered to deliver the appropriate dose. The Diskus® device contains a blister strip of medication and the Turbuhaler® and Respiclick® designs are examples of the reservoir type. The reusable DPIs consist of a device into which a capsule or cartridge containing the dry aerosol powder is placed. The capsule is then pierced using needles connected to hand activated buttons on the device, after which the powder is inhaled (40).

An important improvement in DPI design was the introduction of the Ellipta® design. This device contains two blister strips delivering two or more different medications that cannot be combined in a single blend due to incompatibility or other technical difficulties. Another notable development among DPI products was the introduction of Diskhaler® technology (41, 42). This is a breath-actuated multi-dose reusable type product. An important and distinct characteristic is that the medication is placed in a disc shaped strip with each strip containing four blisters containing the antiviral medication zanamivir mixed with lactose. The disk is loaded into the device prior to use, punctured using the piercing mechanism in the device, and the patient inhales the powdered aerosol through the mouthpiece. Most DPIs use lactose monohydrate as the sole carrier excipient and some formulations contain magnesium stearate as a lubricant (43). The tobramycin Podhaler® uses DSPC microparticles as the carrier (44). A remarkable breakthrough among DPIs came through the introduction of fumaryl diketopiperazine (FDKP) microparticles. FDKP (bis-3,6(4-fumarylaminobutyl)-2,5-diketopiperazine) particles are manufactured using the patented Technosphere® technology that leads to the formation of highly porous and homogenous microparticles with an aerodynamic diameter between 2 and 2.5 μm. Over 90% of FDKP particles prepared in this manner are in the respirable size range (0.5–5.8 μm). FDKP, a fumaramide derivative of diketopiperazine at first self-assembles into planar nanocrystals in an acidic medium (pH < 5.2). A small amount of Tween 80 is also added in the liquid medium, and residual Tween 80 is present in the final product. The planar nanocrystals then further aggregate to form three-dimensional spherical aggregates with high porosity. The drug can be mixed into the initial excipient solution which gets adsorbed and incorporated in the final porous crystalline microparticles. The highly biocompatible preparation method led to the first successful inhaled insulin product, Afrezza® (an earlier inhaled insulin product, Exubera®, was withdrawn in 2007). Afrezza® is a tremendous technological achievement because of the non-invasive pulmonary method used to deliver a fast-acting insulin. The highly porous and homogenous FDKP particles containing insulin are capable of penetrating deep into the lungs where they readily dissolve at pH close to neutral, releasing the loaded insulin (45, 46).

DPIs are popular and very effective means of delivery inhaled therapeutics for systemic and local activity. Despite its unique advantages, there are several aspects related to the DPIs that have to be addressed. One particular issue is the loss of aerosol particles within the device. Because of the need for forceful inhalation during their use, DPIs are not recommended for children under 5 years of age. Even among older and adult patients significant errors related to proper use of DPIs have been reported. Some of the most commonly seen errors include incorrect breathing pattern during usage and wrong method of loading the inhaler. The DPIs also suffer from large inter-individual variabilities related to deposited dose, since the optimal delivery is mostly dependent on the patient’s respiratory pattern during product use.

#### 3.5.3  Nebulizers

Modern nebulizers use external energy to produce a fine mist that is inhaled by the patient. Most of the formulations for nebulization are sterile solutions, except for Pulmicort Respules®, which is a sterile suspension. Table 3.4 lists various nebulizer formulations currently available in the US. Traditionally nebulized formulations are administered using jet nebulizers or ultrasonic mist nebulizers (47). Jet nebulizers use compressed air that is passed using tubing into the nebulizing device chamber in which the solution or suspension formulation is placed. The gas is made to pass through a narrow opening, creating a huge pressure differential, increasing the air velocity. At the point where the high-velocity air exits the opening of an inner tube in the nebulizing chamber, a thin film of the liquid formulation is provided through a capillary effect operated feed. At the narrow orifice a negative pressure is produced, and the liquid film gets drawn into the path of the air where it collapses into fine mist droplets due to liquid surface tension. A significant portion of the mist developed consists of very large and non-respirable 15–50 μm droplets. A suitably placed baffle removes such large droplets, feeding the liquid back into the nebulizing chamber. Smaller respirable droplets are allowed to ensue out of the nebulizer into an appropriate mouthpiece or a mask that can be placed on a critically ill patient. This method of delivering inhalation mist is extensively used in institutional settings where compressed air outlets are standard fixtures by patient bedsides. Jet nebulizers are popular in home settings and are used in conjunction with a portable air compressor.

### Table 3.4   Examples of Nebulizers in the US Market

Active Ingredient

Product Name

Product Type

Excipients

Albuterol

Albuterol 0.5% nebulization solution

Solution in unit dose vials

Sulfuric acid to adjust pH, water for injection

Levalbuterol

Xopenex®

Solution in unit dose vials

Budesonide

Pulmicort Respules®

Micronized budesonide suspension

Disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate 80, water for injection

Ipratropium + albuterol

Combivent® Respimat®

Sterile solution and soft mist inhaler

Water for injection, benzalkonium chloride, edetate disodium, hydrochloric acid

Duoneb® (nebulized)

Solution in unit dose vials

Water for injection, sodium chloride, hydrochloric acid to adjust to pH 4, and edetate disodium

Tiotropium

Spiriva® Respimat®

Sterile solution and soft mist inhaler

Water for injection, edetate disodium, benzalkonium chloride, and hydrochloric acid

Glycopyrrolate

Lonhala Magnair®

Solution in unit dose vials

Water for injection, citric acid and sodium hydroxide

Revefenacin

Yupelri®

Solution in unit dose vials

Sodium chloride, citric acid, sodium citrate, and water for injection

Olodaterol

Striverdi® Respimat®

Sterile solution and soft mist inhaler

Water for injection, benzalkonium chloride, edetate disodium, and anhydrous citric acid

Formoterol

Perforomist®

Solution in unit dose vials

Sodium chloride, citric acid, sodium citrate, and water for injection

Arformoterol

Brovana®

Solution in unit dose vials

Sodium chloride, citric acid, sodium citrate, and water for injection

Olodaterol + tiotropium

Stiolto Respimat®

Sterile solution and soft mist inhaler

Water for injection, benzalkonium chloride, edetate disodium, and hydrochloric acid

Loxapine

Thermally generated mist

No excipients

Jet nebulizers are available in the reservoir, breath-enhanced, and breath-actuated types. The reservoir type employs continuous mist generation and cause over 80% of the aerosol to be lost to the environment. The breath-enhanced nebulizer uses two valves to minimize loss of the generated mist when the patient exhales. When in use, as the patient inhales, one valve opens on the vent through which air flows into the nebulizer and is carried through the mist and the mouthpiece. As the patient exhales, a valve present in the mouthpiece expels the exhaled air and mist out, but the vent valve closes, minimizing the loss of nebulized mist to the environment. Breath-actuated nebulizers have a valve that opens and aerosol generation is activated only when the patient inhales. Ultrasonic nebulizers use a piezo-electric plate that vibrates at ultrasonic frequency when electric current flows through it. The ultrasonic energy is transmitted to a mesh that vibrates when activated by the sound energy. The drug solution is in contact with the piezo-electric unit and the vibrating mesh. As the solution is vibrated, as well, cavitation causes water to break apart into small mist droplets as it extrudes out through the vibrating mesh. Some disadvantages related to nebulizers have been the need to clean the parts such as the reservoir regularly to prevent microbial contamination. Additionally, these devices also suffer from high loss of generated mist out into the environment (48).

The soft mist inhaler (SMI) Respimat® uses mechanical energy that is generated as a spring contained in the device is twisted and released to generate the mist. A cartridge containing the drug solution is loaded into the device. Following this step, the bottom of the device is twisted 180°, enabling the spring to be compressed to the desired tension. The twisting action also delivers an accurately metered volume of the drug solution into a pump cylinder. Next the patient presses the dose release button that causes the tension in the spring to be released and the energy from the spring forces the metered solution through one of the most crucial components in the system, called a uniblock (49). The uniblock is a precision engineered microchannel system comprising a silicon wafer bonded to a borosilicate glass plate. The silicon wafer has inlet, outlet, and filter channels etched on it using technology similar to that used to engineer microchips. Through rigorous and meticulous engineering, the channels have been produced to generate two fine jets of the drug solution that converge at a preset angle to generate a slow-moving cloud of mist (1/10th the speed of aerosol emitted from an MDI). The metered dose generated from a Respimat® device is expelled over ~1.2 s compared to the 0.1 s from an MDI. Although the breathing technique when using the Respimat® is similar to that of pMDIs, the lung deposition of various medications were found to be, in some instances, more than twice that obtained from pMDIs (50). The Loxapine (Adasuve®) oral inhalation product listed in Table 3.4 is unique in many respects. It is a single dose, breath-actuated, non-reusable mist system. After the device is properly activated by pulling and removing a tab, the device mouthpiece is placed in the mouth. The patient inhales through the device and the inspiratory air activates a drug-coated heat source that vaporizes the drug in less than 1 second. The drug vapor condenses into an aerosol mist with an MMAD between 1 and 3 μm (51).

#### 3.6  Conclusion

Although modern techniques and devices for pulmonary drug delivery were introduced in the mid–20th century, methods of administering medications into the lungs have been employed variously for over 2000 years. Devices used to deliver medications into the respiratory tract can be categorized into pMDIs, DPIs, and nebulizers. Over the past decade, numerous advancements in excipients, particle production, and device engineering have led to progress in terms of the diversity of active ingredients that can be formulated into an inhalation product. Additionally, the innovations and developments have addressed some of the challenges associated with delivering therapeutic aerosols into the lungs. The area of pulmonary drug delivery is going through a phase of renewed interest and rigorous research. The introduction of an inhaled rapid-acting insulin product has opened the possibilities for more biological macromolecules to enter the market in the near future.

#### References

1
Sanders M . Inhalation therapy: An historical review. Primary Care RespIratory Journal. 2007; 16(2): 71–81.
2
Stein SW and Thiel CG. The history of therapeutic aerosols: A chronological review. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2017; 30(1): 20–41.
3
Zhong, H. , et al. A comprehensive map of FDA-approved pharmaceutical products. Pharmaceutics. 2018; 10(4): 263.
4
Yıldız-Peköz A and Ehrhardt C. Advances in Pulmonary Drug Delivery. Pharmaceutics.2020; 12(10): 911. doi:10.3390/pharmaceutics12100911.
5
Research GV . Inhalable Drugs Market Size, Share & Trends Analysis Report By Product (Aerosol, Dry Powder Formulation, Spray), By Application (Respiratory & Non-Respiratory Diseases), And Segment Forecasts, 2019–2026. 2019. Global Industry Report, Grand View Research, San Fransisco.
6
Zheng Y. , et al., Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans. International Journal of Pharmaceutics. 1999; 191(2): 131–140.
7
Byron PR . Drug delivery devices: issues in drug development. Proceedings of the American Thoracic Society. 2004; 1(4): 321–328.
8
Wolff R. , Safety of inhaled proteins for therapeutic use. Journal of Aerosol Medicine. 1998; 11(4): 197–219.
9
Byron PR and Patton JS . Drug delivery via the respiratory tract. Journal of Aerosol Medicine. 1994; 7(1): 49–75.
10
Patton JS . Mechanisms of macromolecule absorption by the lungs. Advanced Drug Delivery Reviews. 1996; 19(1): 3–36.
11
Barnes P. and Thomson N . Drug-induced asthma. Lippincott- Raven, Asthma. Philadelphia. 1997: 1245–1249.
12
Uchenna Agu R. , et al., The lung as a route for systemic delivery of therapeutic proteins and peptides. Respiratory Research. 2001; 2(4): 198.
13
Gonda I. , The ascent of pulmonary drug delivery. Journal of Pharmaceutical Sciences. 2000; 89(7): 940–945.
14
Ibrahim, M. and Garcia-Contreras L . Mechanisms of absorption and elimination of drugs administered by inhalation. Therapeutic Delivery. 2013. 4 (8): 1027–1045.
15
Fröhlich E. , et al., Measurements of deposition, lung surface area and lung fluid for simulation of inhaled compounds. Frontiers in Pharmacology. 2016; 7: 181.
16
Courrier H , Butz N , and Vandamme TF , Pulmonary drug delivery systems: Recent developments and prospects. Critical Reviews™ in Therapeutic Drug Carrier Systems. 2002; 19(4-5): 425–498.
17
Tronde A . Pulmonary drug absorption: In vitro and in vivo investigations of drug absorption across the lung barrier and its relation to drug physicochemical properties. Acta Universitatis Upsaliensis. 2002.
18
Verma, RK , Ibrahim M , and Garcia-Contreras L . Lung anatomy and physiology and their implications for pulmonary drug delivery. Pulmonary Drug Delivery. 2015: 1–18.
19
Ghadiri M. , et al. Modulating tight junctions on airway epithelial cells to enhance paracellular transport of antifibrotic drugs. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2016; 29(3): A11–A12.
20
Ghadiri M. , et al., The effect of non-specific tight junction modulators on the transepithelial transport of poorly permeable drugs across airway epithelial cells. Journal of Drug Targeting. 2017; 25(4): 342–349.
21
Brown R. and L. Schanker . Absorption of aerosolized drugs from the rat lung. Drug Metabolism and Disposition. 1983; 11(4): 355–360.
22
Ehrhardt C. , et al., Current progress toward a better understanding of drug disposition within the lungs: summary proceedings of the first workshop on drug transporters in the lungs. Journal of Pharmaceutical Sciences. 2017; 106(9): 2234–2244.
23
Matsukawa Y. , et al., Rates of protein transport across rat alveolar epithelial cell monolayers. Journal of Drug Targeting. 1999; 7(5): 335–342.
24
Gumbleton M. Caveolae as potential macromolecule trafficking compartments within alveolar epithelium. Advanced Drug Delivery Reviews. 2001; 49(3): 281–300.
25
Crandall, ED and Matthay MA . Alveolar epithelial transport: basic science to clinical medicine. American Journal of Respiratory and Critical Care Medicine. 2001; 163(4): 1021–1029.
26
Washington N , Washington C , and Wilson C. Physiological pharmaceutics: barriers to drug absorption, Taylor & Francis, United Kingdom.2000
27
Darquenne C . Aerosol deposition in the human lung in reduced gravity. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2014; 27(3): 170–177.
28
Labiris N. and Dolovich M . Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. British Journal of Clinical Pharmacology. 2003; 56(6): 588–599.
29
Tsuda A , Henry FS , and Butler JP . Particle transport and deposition: Basic physics of particle kinetics. Comprehensive Physiology. 2013; 3(4): 1437–1471.
30
Gonda I . A semi‐empirical model of aerosol deposition in the human respiratory tract for mouth inhalation. Journal of Pharmacy and Pharmacology. 1981; 33(1): 692–696.
31
Klas P . et al. Does lung retention of inhaled particles depend on their geometric diameter? Experimental Lung Research. 2000; 26(6): 437–455.
32
Houtmeyers E. , et al.. Regulation of mucociliary clearance in health and disease. European Respiratory Journal. 1999; 13(5): 1177–1188.
33
Pavia, D . Aerosols and the Lung: Clinical and Experimental Aspects. 2015. Elsevier Science, United Kingdom.
34
Ibrahim M , Verma R , and Garcia-Contreras L . Inhalation drug delivery devices: Technology update. Medical Devices (Auckland, NZ). 2015; 8: 131.
36
Marshik, P. , et al.. A novel breath actuated device (Autohaler™) consistently actuates during the early phase of inspiration. Journal of Aerosol Medicine. 1995; 8(2): 187–195.
35
Roche N. and Dekhuijzen PR . The evolution of pressurized metered-dose inhalers from early to modern devices. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2016; 29(4): 311–327.
37
Giraud V and Allaert F . Improved asthma control with breath-actuated pressurized metered dose inhaler (pMDI):The SYSTER survey. European Review for Medical and Pharmacological Sciences. 2009; 13(5): 323–330.
38
Islam N and Gladki E . Dry powder inhalers (DPIs)—A review of device reliability and innovation. International Journal of Pharmaceutics. 2008; 360(1-2): 1–11.
39
Labiris NR and Dolovich MB . Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. British Journal of Clinical Pharmacology. 2003; 56(6): 600–612.
40
Tarsin WY , et al. Emitted dose estimates from Seretide® Diskus® And Symbicort® Turbuhaler® following inhalation by severe asthmatics. International Journal of Pharmaceutics. 2006; 316(1-2): 131–137.
41
Jones TL , Neville DM , and Chauhan AJ . The Ellipta® in asthma and chronic obstructive pulmonary disease: Device characteristics and patient acceptability. Therapeutic Delivery. 2018; 9(3): 169–176.
42
Boulet L. , et al. Comparison of DiskusTM inhaler, a new multidose powder inhaler, with DiskhalerTM inhaler for the delivery of Salmeterol to asthmatic patients. Journal of Asthma. 1995; 32(6): 429–436.
43
Lee HJ , et al. The role of lactose carrier on the powder behavior and aerodynamic performance of bosentan microparticles for dry powder inhalation. European Journal of Pharmaceutical Sciences. 2018; 117: 279–289.
44
Buttini F. , et al.. Dose administration maneuvers and patient care in tobramycin dry powder inhalation therapy. International Journal of Pharmaceutics. 2018; 548(1): 182–191.
45
Gelber C and Rousseau K . Cell transport compositions and uses thereof. Google Patents. 2009.
46
Potocka E. , et al.. Pharmacokinetic characterization of the novel pulmonary delivery excipient fumaryl diketopiperazine. Journal of Diabetes Science and Technology. 2010; 4(5): 1164–1173.
47
Thorat S and Meshram S . Formulation and product development of pressurised metered dose inhaler: An overview. PharmaTutor. 2015; 3(9): 53–64.
48
Vecellio L , et al. Deposition of aerosols delivered by nasal route with jet and mesh nebulizers. International Journal of Pharmaceutics. 2011; 407(1-2): 87–94.
49
Mehri R , et al. Respimat soft mist inhaler (SMI) in-vitro aerosol delivery with the ODAPT adapter and facemask. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2019; 5: 1–10.
50
Lavorini F , Buttini F , and Usmani OS . 100 years of drug delivery to the lungs. Concepts and Principles of Pharmacology: 100 Years of the Handbook of Experimental Pharmacology. 2019; 260: 143–159.
51
Zeller S. , et al. Response to inhaled loxapine in patients with schizophrenia or bipolar I disorder: PANSS-EC responder analyses. BJPsych Open. 2017; 3(6): 285–290.

## Use of cookies on this website

We are using cookies to provide statistics that help us give you the best experience of our site. You can find out more in our Privacy Policy. By continuing to use the site you are agreeing to our use of cookies.