Pulmonary route of administration is instrumental in developing therapeutic interventions against respiratory diseases.

Pulmonary route of drug delivery has drawn significant attention due to the limitations associated with conventional routes and available treatment options. Drugs administered through pulmonary route has been an important research area that focuses on to developing effective therapeutic interventions for asthma, chronic obstructive pulmonary disease, tuberculosis, lung cancer etc. The intravenous route has been a natural route of delivery of proteins and peptides but associated with several issues including high cost, needle-phobia, pain, sterility issues etc. These issues might be addressed by the pulmonary administration of macromolecules to achieving an effective delivery and efficacious therapeutic impact. Efforts have been made to develop novel drug delivery systems (NDDS) such as nanoparticles, microparticles, liposomes and their engineered versions, polymerosomes, micelles etc to achieving targeted and sustained delivery of drug(s) through pulmonary route. Further, novel approaches such as polymer-drug conjugates, mucoadhesive particles and mucus penetrating particles have attracted significant attention due to their unique features for an effective delivery of drugs. Also, use of semi flourinated alkanes is in use for improvising the pulmonary delivery of lipophilic drugs. Present review focuses on to unravel the mechanism of pulmonary absorption of drugs for major pulmonary diseases. It summarizes the development of interventional approaches using various particulate and vesicular drug delivery systems. In essence, the orchestrated attempt presents an inflammatory narrative on the advancements in the field of pulmonary drug delivery.

Introduction

The oral, parenteral and topical are the preferred routes of administration in practice. Nowadays, researchers are exploring other routes to address the existing limitations of route of administration. The non-invasive routes such as pulmonary, nose to brain delivery, colon targeting, buccal and transdermal delivery are being explored. Lung targeted drug delivery showed an enormous potential and attracted significant attention for the treatment of pulmonary diseases (Patil et al., 2012). Advantages of rapid absorption of drugs due to border surface area of respiratory endothelium, elimination of the first pass metabolism and small dosages resulting in the reduced adverse effects (Chandel, et al., 2019). The inhaler therapy is advantageous over the oral route based therapy due to rapid absorption of drug molecules because of large surface area of respiratory endothelium, elimination of first pass metabolism of drug, dose reduction and minimal side effects as compared to the oral route of administration (Anderson, 2001, Bryson and Laskin, 1944, Rau, 2005). Severe side effects observed by the intravenous delivery of drugs in the lungs were overcome by inhalation (Mastrandrea, 2010). The intravenous administration is highly expensive and requires trained personnel. On the contrary, inhaler therapy is cost-effective and easily administered. Therefore, pulmonary route has been considered important for the local and systemic delivery of biomolecules including proteins and peptides (Flume and Klepser, 2002, Groneberg et al., 2003, Rubin and Fink, 2001, Wigley Fw Fau et al., 1971). In essence, this article reviews and comprises orchestrated attempts to show the pulmonary route as an alternative to the existing conventional routes of administration.

Lung anatomy and physiology

Lungs are rudimentary respiratory organs playing a crucial role in gaseous exchange. Inhalation of O2 via lungs, breakdown of sugar macromolecules and release of CO2 out of the human body are important functions of lungs. Human lungs weigh approximately one kilogram (Kg) and constitute 40–50% of blood (Wagner, 2015). The vicinity of pleural membranes around the lungs can extensively divide both left and right into different lobes namely upper, middle and lower, and middle lobe is absent in the left side (Effros, 2006, Scadding, 1955)..The cardiac notch is the lateral deflection of anterior border of the left lung wherein heart is located. The air we breath in goes from nose and oral cavity into pharynx, larynx, and trachea, a rigid structure surrounded by cartilage. This trachea further splits up into two tubes known as bronchi. The point where no cartilage is present around the bronchi is the point where it splits into small tubes called “bronchioles”, and terminal ends of every super small bronchiole are equipped with little air sacs. These air sacs are the alveoli which are approximately 200–300 µm in diameter with respect to the normal human cell which is nearly 10 µM in size. These alveoli have super thin membrane around them and is one cell thick (Deffebach et al., 1987, Reckord, 1918). O2 molecules diffuse through alveoli into pulmonary arteries for gaseous exchange. Consequently, oxygenated blood is carried forwarded to heart via pulmonary vein. The internal surface area of alveoli where exchange of gases takes place is roughly 75 m2 and provides enough space for transporting O2 across alveoli membrane into the blood stream (Aoun et al., 2004, Griscom and Wohl, 1983, RC, 1958).

Cells lining the respiratory tract

Respiratory tract is hollow tube like structure lined by the numerous epithelial cells ranging from columnar to flat cells. The respiratory airways are lined with various types of cells such as goblet cells, basal cells, ciliary cells, alveolar pneumocytes and other epithelial cells. The alveoli are covered by epithelial cells known as alveolar pneumocytes divided into two categories; types-I & II. The type I cells are flat, squamous and cover approximately 90% alveolar surface. Whereas the second one is irregular in shape, contains the lamellar bodies and covers a small fraction of the alveolar surface area. The gross anatomy of the human lungs has been shown in Fig. 1 (Grassino et al., 1997, Mills, 2001, Nunn, 1993).

Fig. 1

Gross anatomy of human lungs illustrating the mechanism of pulmonary absorption of drugs.

The primary step of pharmacokinetics in the pulmonary absorption is the interaction of drug with the surfactants followed by its deposition into the tracheo-bronchial or in the alveolar region. The lung surfactant may lead to aggregation, and compromising dissolution and enhancing engulfment by macrophages for macromolecular drugs such as proteins and peptides (Patton, 1996). A thick lining fluid lying beneath the surfactant layer which is more or less of 0.01–10 µm by which drug gets diffused into the epithelium. Subsequently transport of absorbed drug across the epithelium takes place through para-cellular or trans-cellular mechanisms. The transport of hydrophilic substance through intracellular space between the cells is called “paracellular transport”, and lipophilic compounds travel by intercellular pores known by the phenomenon called “trans-cellular diffusion”. Rate of respective drug absorption predominantly depends upon its solubility at physiological pH. For instance, lipophilic drugs such as fluticasone propionate with a log P value of 5 showed rapid pulmonary absorption whereas hydrophilic compounds such as β2 agonist salbutamol with a log P value of −2 gets absorbed slowly (Farr et al., 1998, Kuzmov and Minko, 2015).

Later on, drug solute passes through a monolayer of columnar cells (60 µm thick) present in the bronchi to a monolayer of broad cells (0.2 µm thick) present in the alveoli. These epithelial cells are attached to a basement membrane and interstitium containing collagen, elastic fibres, cells, lymphatic vessels and interstitial fluid present underneath (Labiris and Dolovich, 2003). The final barrier for the drug solute after traversing all the layers including surfactant layer, lining fluid, epithelium, the basement membrane and the interstitium is the endothelium layer which is a monolayer that makes up the walls with micro-vessels of capillaries. In the end, drug traverses its pathway from air spaces to the blood capillaries.

Effective drug delivery through lungs

The therapeutic benefits of pulmonary drug delivery (PDD) have drawn significant attention as far as its role in translational nanotechnology is concerned. Larger surface area and extensive vascularization aid in effective and target-specific delivery of drug through lungs (Byron and Patton, 1994). In addition, the technological advancements made the pulmonary drug delivery more patient friendly and effective, and fate of drug is decided when drug gets deposited into the lungs; a) either it is cleared through mucociliary clearance (MCC), b) absorbed into the systemic circulation. Out of 50 different types of cells, 12 are present in the lungs airways. In the membrane of airways, ciliated columnar cells (Fig. 1) are present that consists of cilia, helps in the transport of mucus towards the mouth. This mechanism helps in the removal of foreign materials, including organisms residing on bronchial surfaces, and thus disrupted mechanism occurs in MCC resulting in the disease like immotile cilia syndrome, bronchiectasis and asthma (Gianola, 2012). The nature of active pharmaceutical ingredient (API) is an important factor that may affect pulmonary drug delivery. Further, particle size of respective active molecule is considered for pulmonary drug delivery. The sub-optimal penetration to the deeper tissues and/or exhalation of compounds is the main concern with large and small particles, respectively. The dry powder inhaler formulations with aerodynamic size range of 1–5 µm retain drugs into lungs. Wet polishing, spray drying, jet milling etc. are some of the techniques which help us achieving desired range of aerodynamic particle size (Lopez-Rodriguez and Pérez-Gil, 2014). On the contrary, very small size particles possess the strong adhesive and cohesive forces leading to agglomerate formation. Therefore, such formulations required carriers such as lactose, mannitol, trehalose etc. for an effective delivery of drug(s). The metered dose inhalers (MDI) formulated drugs are either in solutions or suspensions in a single or mixture of propellants. Therefore, drug solubility is considered as one of the important factors in such formulations and factors important for pulmonary formulations are illustrated in Fig. 2.

Fig. 2

Factors playing a crucial role in effective delivery of drugs through pulmonary drug delivery systems.

Understanding the role of liquid crystalline structures in the lung surfactant for local retention of drugs

The composition of lung lining fluid is very dense and complex. The fluid of airway contains plenty of mucus without phospholipids whereas the alveolar lining consists of more than 90% of phospholipids. Presence of phospholipids in the alveoli play a crucial role in the target specific delivery of drugs as these lipids form the liquid crystals under normal physiological conditions. During the accumulation of phospholipids into the bilayers, at certain melting temperature they lose their stability and transition will occur from an ordered state (gel phase) to a disordered one and resulting liquid crystalline phase gain the considerable mobility (Bernardino de la Serna et al., 2004, de La Serna et al., 2009, de la Serna et al., 2013, Schief et al., 2003). These liquid crystals serve as a depot for local retention of drugs into the lungs. The unsaturated and saturated phospholipids with mixed C16:0-C14:0 chains transit to liquid crystals at 37 °C. Palmitoyl-palmiteloyl-phosphatidyl choline and palmitoyl-oleolyl-phosphatidyl choline are two major unsaturated phospholipids play important role in local retention of drugs. Several studies have revealed the formation of smectic liquid–crystal phases due to the collapse of monolayers which is the combination of cholesterol (also present in the alveoli and the of mixtures of dipalmitoyl-phosphatidylcholine) (Baoukina et al., 2008, Das and Stewart, 2016, Harishchandra et al., 2010). Consistent to what was reported earlier, this structure shall enhance the release of drugs for the treatment of several local diseases (Bastacky et al., 1995, Bender et al., 2005, Biswas et al., 2007, Blanco and Pérez-Gil, 2007). The saturated and unsaturated phospholipids present in the alveolar lining fluid are summarized in Table 1

Table 1

Phospholipids present in the alveolar lining fluid.

Phospholipids	Fatty acids present
Dipalmitoyl-PC	C16:0-C16:0
Palmitoyl –oleyl-PC	C16:0-C18:1
Palmitoyl-palmiteloyl-PC	C16:0-C16:1
Dioleoyl-PC	C18:1-C18:1
Palmitoleoyl-oleoyl-PC	C16:1-C18:1
Myristoyl-palmitoleoyl-PC	C14:0-C16:1

Polar hydrophilic moiety and non-polar hydrophobic chains present into the phospholipids create the nature of amphiphilicity and make them more reliable for the depot of dual kind of drug molecules.

Challenges of inhaler therapy

The bioavailability of drugs is one of the major challenges faced during inhalation which mainly depends on inhalation technique and size of formulated particles (Jitendra et al., 2011, Ruge et al., 2013). The delivery of drugs to develop therapeutic interventional approaches against diseases such as tuberculosis, salmonellosis, brucellosis and leishmaniosis in which pathogen resides within the phagocytic cells of monocyte-macrophage lineage has been debated for a while. The enzymatic degradation of inhaled drugs by numerous cytochrome P 450 iso-forms present in the lungs is another challenge. The peptidase and protease enzymes are reportedly known to degrade peptide and protein drugs, one of the glaring example is insulin (El-Sherbiny et al., 2015). There has been an emergence of the development of Novel Drug Delivery Systems (NDDS) to address, understand and develop therapeutic interventions against various diseases (Gordon and Taylor, 2005, Mosser and Edwards, 2008, Pei and Yeo, 2016, Wynn et al., 2013).

Major pulmonary diseases

Infectious diseases

Tuberculosis

Tuberculosis is a disease caused by ‘Mycobacterium tuberculosis’ (Mtb). The bacterium enters the alveoli and engulfed by alveolar macrophages. These bacteria survive in the macrophages due to releasing ammonia, sulphatides and proteins/antioxidants such as catalase and superoxide dismutase which protects pathogen from being destroyed by macrophages (Campbell and Bah-Sow, 2006).

Pneumonia

The bacterium leads to a lot of secretion and mucus during pneumonia infection. When air sacs filled up with the fluid, exchanges of both gases O2 & CO2 across the air sacs is hindered, which in turn leads the reduction of O2 & increased level of CO2.‘Legionella pneumophila’. Later is responsible for the entry of pneumonia enters in alveolar macrophages by the deposition of complement C3b on alveolar surface and utilizes the host’s protein as a ligand for binding to the macrophage surface. Bacteria reside inside the vacuoles but do not fuse with the lysosomes and remain intact. Streptococcus pneumoniae’ surrounded by the polysaccharide capsules that serves as an anti-phagocytic substance for extended survival within the macrophages (Prina et al., 2015).

Lung anatomy related diseases

Chronic obstructive pulmonary diseases (COPD)

COPDs are the ailment in which patients encounter problems during expiration. The airways collapse and get stuck due to the loss of wall elasticity. COPD is a group of two diseases: emphysema and chronic bronchitis. Emphysema refers to the loss of elastic properties of lungs and chronic bronchitis refers to severe inflammation in lungs which leads to the excessive secretion of mucus (Balkissoon et al., 2011).

Lungs in some pathologic conditions do not expand properly for inhalation and thus resulting in the deficit of O2. Eventually, lungs get stiff and very hard to blow up, and lungs smaller in size lead to a lot of wastage of space which could have been utilized by O2.

Asthma

Asthma is a chronic lung disease with the symptoms of chest tightness, shortness of breath, inflammation in airways and coughing. The airways get infiltrated with inflammatory cells, leading to the release of tissue damage mediators (Byron, 1989). The immuno-histopathological features of asthma include inflammatory cell infiltration of neutorphils, eosinophils, lymphocytes etc. The other features are inflammation of airways, persistent changes in the structure of airways, injury to epithelial cells, hypertrophy, angiogenesis etc (Akbari et al., 2006, Kraft et al., 1996).

Lung cancer

Both epithelial and endothelial cells are present in the lungs. Cell damage let them divide in an uncontrolled manner resulting in the lung cancerous growth and proliferation. Air that we breathe in is a mixture of bacteria and flows through out lung airways. There are many types of lung cancer amongst which the non-small cell lung cancer is the most common type (80–85%) which grows and spreads slowly as compared to small cell lung cancer (10–15%) (von Dincklage et al., 2013).

Pulmonary route for proteins and peptides

The most common means of administering proteins and peptides are injectable (intravenous, intramuscular or subcutaneous) formulations. These routes, however, have their own limitations including poor patient compliance and short half-lives of drugs in bloodstream. Therefore delivery of drugs through parenteral routes is not preferred to address various lung pathologies. The parenteral route due to its limitations may be replaced by the pulmonary route for the delivery of macromolecules. A marked increase of 10% bioavailability of insulin has been shown through the pulmonary route compared to the subcutaneous administration (Jitendra et al., 2011, Mack, 2007). There were many attempts made to enhance pulmonary absorption of insulin, and a study was carried out (Yamamoto et al., 2001) in which absorption of pulmonary insulin was increased using various adjuvants including glycocholate, surfactin, nafamostat and span.

Formulations for pulmonary delivery

Drugs can be administered in the lungs via dry powder inhalers, metered dose inhalers and through nebulizers either in conventional or nanoparticles & microparticles form. Pulmonary infections are amongst the leading cause of deaths, especially in the developing countries. These infections are difficult to treat as infectious agents generally reside in the deeper parts of the lungs where only a fraction of drug reaches after the oral or parenteral administration. Thus, high doses are required to maintain the levels of drug above the minimum inhibitory concentration (MIC) to keep a check on the further growth of the microorganisms deeper inside the lungs. Unfortunately, high drug dose leads to severe side effects such as nephrotoxicity and neurotoxicity. The direct delivery of the drugs for the treatment of these pulmonary infections may serve as a promising solution. Moreover, research has been underway with particulate drug delivery systems for direct penetration and delivery of drugs into the lungs (Patil and Sarasija, 2012, Ghadiri et al., 2019). This paper gives an insight about pulmonary drug delivery formulations for the treatment of most common and severe pulmonary diseases like lung cancer, tuberculosis, asthma and COPD

Particulate drug delivery systems

Nanoparticles

The attributes such as small particle size, a large surface area and scope of modifications in their surface properties, of nanoparticles has drawn significant attention. The delivery of nanoparticles as aerosol is an exciting prospect as it evades the pre-systemic metabolism after the administration of drug through oral route (Babu et al., 2013, Pontes and Grenha, 2020). Many researchers have been using the formulated and characterized nanoparticles to address COPD. Fabricated gold nanoparticles (Geiser et al., 2013) were administered in Scnn1b-transgenic mice (COPD model) to study uptake and localization of macrophages, and compared to the wild type mice. The nanoparticles showed rapid binding to alveolar epithelium in both Wt and Scnn1b-transgenic mice. The delayed uptake of nanoparticles by surface macrophages was seen in Scnn1b-transgenic mice as compared to Wt mice. This delayed uptake promoted the in-depth translocation of nanoparticles in Scnn1b-transgenic mice. Results obtained with these transgenic mice advocate for gold nanoparticles as an effective approach for the management of COPD.

Curcumin, a well-known anti-inflammatory agent showing poor bioavailability was loaded on to solid-lipid nanoparticles (SLN) to assess its improved therapeutic efficacy in the experimentally induced allergic rat model (Wang et al., 2012). The formulated nanoparticles were shown to have an average particle size of 190 nm and entrapment efficiency of 75%. The pharmacokinetic results of SLN loaded curcumin showed the presence of higher concentrations of curcumin for extended period compared to the plain curcumin. This implies that curcumin loaded SLN may be a promising strategy for treating asthma. Plain budesonide (BD), a non-halogenated corticosteroid, is a potent anti-inflammatory agent used in the asthma therapy. BD-SLNs were prepared by Emami et al. (2015) using emulsification-solvent diffusion method. The size and entrapment efficiency of formulated nanoparticles were 218.2 ± 6.6 nm and 92.5 ± 0.52%, respectively. These nanoparticles were co-spray dried with lactose to make it a flow-able powder. The fine particle fraction achieved was 49.5% with a mass median aerodynamic diameter of 2.06 µm.

Anti-tubercular drugs (ATD), rifampicin (RFM), isoniazid (INH) and pyrazinamide (PZM) were encapsulated in poly (lactide-co glycolide) nanoparticles (Pandey et al., 2003). These nanoparticles showed an increase in drug bioavailability by 6.5 fold for RFM, 19.1 fold for INH and 13.4 fold for PZM. Lectin functionalized poly (lactide-co glycolide) nanoparticles (LFPN)/(PLG-NPs) used as a bio-adhesive drug carriers against tuberculosis were explored with an objective to reduce dosing frequency and improving patient compliance for ATDs (Sharma et al., 2004). In these studies, presence of RFM, INH and PZM were observed in plasma following administration of LFNP’s. It was observed that all three ATDs were present in liver, spleen and lungs for 15 days and in plasma for about 4–9 days. The bio-availability showed a remarkable increase in case of LFNPs compared to the oral administration of ATDs, and therefore these nanoparticles may serve as potential nanoscale drug carriers for ATDs. The chemotherapeutic potential of SLN of RFM, INH and PZM was evaluated. The bioavailability and the mean residence time saw an increase by manifold in the drug loaded SLN. In addition, SLN loaded drug when administered through nebulizer did not allow any bacilli to grow in the lungs and spleen of the guinea pigs (Pandey and Khuller, 2005). Preclinical studies of paclitaxel (PTX) loaded SLN has been carried out by Videira et al. (2012) in mammary carcinoma of mice. Nanoparticle formulation of PTX reduced the size and number of lung metastases more effectively in comparison to the intravenous administration of the same drug. The dual drug delivery through nanoparticles of Regorafenib (REGO) and Cisplatin (PT) exhibits a great anticancer potential, as REGO enhances the effect of PT treatment of human cells by conferring stability of the microenvironment (Zhou, 2020).

Microparticles

Microparticles are small particles in the size range of 1–1000 µM prepared from natural or synthetic polymers. They surmount several disadvantages of conventional drug delivery methods specifically the increase risk of adverse drug reactions. The steroid coated microparticles of ciprofloxacin hydrochloride (CH) and beclomethasone dipropionate (BCD) were developed by Lee SH et al (Lee et al., 2014) as an effective inhaler therapy for COPD. Microparticles were spray dried onto inhalable powder with a respirable particle size of 2.3 µm. The amalgamation of both the drugs together in microparticulate delivery system showed synergistic results with improved release and better fine particle fractions compared to single drug delivery system (Osman et al., 2018, Price et al., 2017). The delivery systems in combination of both drugs showed significantly strong activity against K. pneumoniae, P. aeruginosa, and S. aureusas compared to the single drug formulation.

The porous particles and microspheres of BCD using chitosan by spray drying technique were prepared (Naikwade et al., 2009) to improve the respirable fraction of drug. The mass median aerodynamic diameter of these particles was calculated to be 2.75 µm. Pharmacokinetic studies revealed the extended half-life of drug from 9.4 to 14 h as well as increased local and systemic bioavailability compared to the conventional formulation. In-vitro cytotoxicity was determined in A549 epithelial cells and the gamma scintigraphy studies were carried out to determine in vivo pulmonary deposition of the formulation, and 4 fold increase of BCD in the lungs was estimated. Solid lipid microparticles (SLM) of quercetin were prepared by Silva et al (Silva et al., 2013) from a mixture of glyceryl trimyristate and soy lecithin using hot solvent diffusion method. These microparticles exhibited desired mass median aerodynamic diameter. In-vitro lung deposition studies confirmed the deposition of drug very deep into the lungs (Sankhe et al., 2019).

RFM and rifabutin (RFB) loaded chitosan microparticles fabricated by Pai RV et al (Pai et al., 2016) were fabricated by spray drying and evaluated for in vitro lung deposition. In -vivo toxicity studies were carried out using Sprague Dawley rats. The fine particle fraction of RFM and RFB microparticles was found in the range of 21.46–29.97% with no adverse effects. Inhaled INH microparticles of poly-ɛ-caprolactone polymer were prepared by Parikh et al (Parikh and Dalwadi, 2014) via spray drying method. The mass median aerodynamic diameter of 1.9–4.0 µm confirmed the inhalation characteristics of microparticles essential for the deep lung deposition.

Poly lactic co glycolic acid (PLGA) microspheres containing PTX fabricated by Sinha VR et al (Sinha et al., 2004) for the treatment of lung tumor was investigated in the lewis lung carcinoma cells for the anti-cancer activity. These microspheres showed significant inhibition of lung tumor growth with no toxicity. Recently, chemically modified mesoporous microspheres with numerous surfaces molecules such as lipids, linkers, etc. sought attention in the micro-particulate formulation for lung targeting.

Therefore, nanoparticles and microparticles may serve as efficient tools for lung targeting treating systemic and local diseases. Further, SLNs have been predominantly prepared in the lung cancer studies to explore receptor mediated drug delivery (Uner and Yener, 2007) whereas the polymeric nanoparticles and microparticles were employed to reduce phagocytic uptake with minimal non-specific interaction with other proteins in the treatment of tuberculosis (Bocca et al., 1998).

Lipid vesicular delivery systems

Liposomes and engineered versions

Liposomes are small vesicles prepared from cholesterol and natural phospholipids. The size and dual nature of hydrophilic and lipophilic are the characteristics accomplished them as promising novel drug delivery system (NDDS). Liposomes and their engineered versions render less toxicity and better compatibility with cells present on the lung surface during pulmonary drug delivery due to the presence of phospholipids as one of their core components. RFM loaded aerosolized liposomes coated with alveolar macrophage-specific ligands (maleylated bovine serum albumin and O-steroyl amylopectin) were prepared by Vyas SP et al (Vyas et al., 2004). The ligand coated liposomes showed 1.5–1.8 times greater penetration efficiency at lung bases than the plain drug solution. The percent viability of Mycobacterium smegmatis was reduced to 7–11% with ligand anchored liposomal aerosols in comparison to 45.7% and 31.6% viability with plain drug and plain liposomal solutions. Higher drug concentration in lungs was achieved with the ligand coated liposomes when compared to plain drug and liposomal solutions. Thus, results showed the potential of these ligand engineered liposomes in improved delivery of RFM to alveolar macrophages.

Several research investigations are on course for the pulmonary delivery of various anticancer drugs via liposomes. In vitro studies of transferrin- conjugated doxorubicin (DOX) loaded liposome as inhalation therapy for the treatment of lung cancer has been studied. The primary culture studies with the novel formulation showed increased cytotoxicity towards the cancerous cells when compared with non-cancerous AT1/ATII human cancerous cells (Anabousi et al., 2006). Also, pulmonary delivery of 9-nitrocamptothecin (9-NC) loaded liposomes (Zhang et al., 2008) advocated their potential to serve as a sustained release reservoir for local targeting.

Despite of stability issues of liposomal systems, their flexible nature allowing easy surface modification (conjugation, coating with ligands) proves them promising and versatile delivery systems.

Polymerosomes

Polymerosomes are self-assembled systems which represent a class of artificial vesicles which are made up of synthetic block copolymers and are of 50 nm to 5 µm in radius. They retain colloidal stability, capacity to incorporate a large number of drug molecules and also provide the tunable membrane properties (Zhao et al., 2014). The encapsulation of RFM within nano-polymerosomes was done employing di- and tri-block polyethylene glycol-poly ɛ caprolactone based copolymers. These derivatives showed the molecular weight range of 12.2–30.1 KDa and diameters ranging between 65.8 and 94 nm. Besides, RFM loaded polymerosomes reportedly showed to have accumulated greater quantity of RFM in macrophages, and thereby advocates its potential in tuberculosis therapy (Moretton et al., 2015).

Polymeric micelles

PTX loaded micelles fabricated from DSPE-PEG (5000) (1,2-distearoly-sn-glycerol-3-phosphoethanolamine-N-[folate(polyethylene glycol0-5000] showed an effective and sustained pulmonary drug delivery (Gill et al., 2011; Rawal, et al., 2019). PTX was successfully encapsulated in PEG-lipid micelles with 95% efficiency. The intratracheally delivered micelles showed higher concentrations of PTX in lungs for extended period than control group. AUC(0 −1 2) of intratracheally administered polymeric micelles of PTX was seen 45 fold greater than that with intravenous administration of pure drug. The mechanism of the formation of polymeric micelles is shown in Fig. 3.

Fig. 3

Mechanism of formation of polymeric micelles.

Niosomal drug delivery systems

Niosomes are the vesicular systems composed of non-ionic surfactant bilayers. The hydrophilic drugs get entrapped into the vesicular part whereas hydrophobic drugs get embedded into the bilayer. This characteristic of niosomes makes them a suitable carrier for both drug types. The niosomes were prepared by loading RFM and size achieved was 8–15 µm in diameter using span 85 and cholesterol (Jain and Vyas, 1995) and showed 65% localization of the drug during in vivo distribution. Also, niosomes of ethambutol hydrochloride were prepared by El-Ridy MS et al (El-Ridy et al., 2015) using film hydration method showing biphasic release. The prepared formulation showed the better biological activities.

Niosomes of DOX and 5-FU using surfactant synthesized from glucuronic acid were formulated and characterized (Tavano et al., 2014). Cholesterol content and chemical structure dependent prepared formulaion showed better entrapment efficiency. Also, hemolytic activity was dependent on the chemical structure of used surfactant monomers and dodecyl glucuronamide was reportedly seen to produce better results (Larson and Ghandehari, 2012). The investigated therapeutic carriers for targeting lung are summarized in Table 2 (see Table 3).

Table 2

Drug delivery systems with improved bioavailability of various drugs.

Drug Candidate	Disease	Formulation	Remarks
Budesonide	Bronchial asthma	Microparticles	The concentration of BD showed 4 fold increase in lungs surfacingthe targeting potential of formulation.
Epirubicin	Lung cancer	Solid Lipid Nanoparticles	Pharmacokinetic studies revealed that higher drug concentration in lungs was achieved in case of EPI-SLN rather than EPI solutions.
5- fluorouracil	Lung cancer	Solid Lipid Nanoparticles	Effective local targeting and sustained efficacious concentrations at the tumor sites.
Telmisartan and Losartan	Lung cancer	Polystyrene Nanoparticles	A significant reduction in the weight of tumors in Nu/nu mice as compared to the control groups (vehicle treated groups).
Salidroside	Lung cancer	Lipid coated polymeric nanoparticles	Higher antitumor activities as compared to the free SAL in 4T1 and PANC-1 cells.
9-nitocamptothecin	Lung cancer	Liposomes	The mean residence time and AUC0-t of 9-NC liposomes were 3.4 and 2.2 folds higher than that of 9-NC solution.
Paclitaxel	Lung cancer	PEG (5000) micelles	The AUC (0−12) of intratracheally administered polymeric micelles of paclitaxel was 45 times greatercompared to intravenously administered drug.
Rifampicin, isoniazid and pyrazinamide	Tuberculosis	Poly lactide co glycolide nanoparticles	The drug bioavailability was seen increased by 6.5 fold for rifampicin, 19.1 fold for isoniazid &13.4 fold for pyrazinamide.
Rifampicin	Tuberculosis	Liposomes	In vitro penetration efficiency of liposomes reaching the base of the lungs was 1.5–1.8 times compared to plain drug solution aerosols.
Rifampicin	Tuberculosis	Polymerosomes	Polymerosomes exhibited increased rifampicin accumulation in macrophages and suggestive of promising results neededfor a potential tuberculosis therapeutic interventions.
Isoniazid and Rifampicin	Tuberculosis	Polymeric micelles	Nano-encapsulation of rifampicin into polymeric micelles reduced the degradation rate of the drug and showed 3.3 times increase in its bioavailability with respect to the free drug.
Curcumin	Asthma	Solid lipid nanoparticles	Higher concentrations of curcumin in plasma suspension were observed than plane curcumin.
Budesonide	Asthma	Chitosan microparticles	The concentration of budesonide showed 4 fold increase in the lungs indicating the targeting potential of the formulation.
Rifampicin	Tuberculosis	Niosomes	In vivo distribution studies of the niosomes showed about 65% localization of the drug.

Table 3

DPIs launched in the market.

Device	Category	Drug
NEXThaler® (Chiesi) (Kanniess et al., 2015)	Multi dose	Beclomethasone
Genuair® (AlmirallSofotec) (Chrystyn and Niederlaender, 2012)	Multi dose	Aclidinium
Handihaler (Boehringer-Ingelheim) (Islam and Gladki, 2008)	Single dose	Tiotropium
Spinhaler (Aventis) (Son and McConville, 2008)	Single dose	Sodium cromoglycolate
Clickhaler® (Recipharm) (Claus et al., 2014, Islam and Cleary, 2012)	Multi dose	Beclomethasone dipropionate, salbutamol sulphate

Advances in pulmonary drug delivery strategies

The polymer-drug conjugates have been gaining attention due to their several peculiar features; the most important one is their ability to bear both the therapeutic and diagnostic agents, which establishes them as a versatile carrier. The RFM loaded polymer drug conjugates were formulated in which RFM was conjugated by degradable ester bonds to make pro-drugs form hydrophobic drug (D’Addio et al., 2015). Further, these pro-drugs and non-conjugated RFM were encapsulated in nano-carrier systems for sustained drug release of RFM by undergoing hydrolysis. It also showed the potential for rapid delivery and knockdown of the intracellular Mycobacterium tuberculosis bacteria.

The muco-adhesive particles (MAP) have been reported to show the immense pulmonary delivery potential (Popov et al., 2016). However, their engulfment by luminal mucus layer and resulting elimination via expiratory clearance are the main stumbling blocks. Thus, the above-said limitation, mucus penetrating particles (MPP) were engineered in such a way that it gets diffused through mucus leading to the avoidance of mucociliary clearance, and showing extended persistence in the lungs. The encapsulated fluticasone propionate into poly-lactide based MPP and MAP were used to assess in vivo pulmonary residence of drug in the lungs of mice when administered through intratracheal route. The in vivo studies delineated the result of higher local exposure of MPP in the lungs around 60% against MAP, which declared the potential efficiency of the MPPs (Chen et al., 2013, Cu and Saltzman, 2009, Ensign et al., 2012, Kirch et al., 2012).

Another strategy to enhance the pulmonary delivery of lipophilic drugs is the use of a new class of excipients, semiflourinated alkanes (SFA). These are diblock molecules which contains fluorocarbon and hydrocarbon segments. Tsagogiorgas C. et al (Tsagogiorgas et al., 2010) compared the physicochemical properties of different SFA’s such as Perfluorobutylpentane (F4H5), Perfluorohexylhexane (F6H6), Perfluorohexyloctane (F6H8) and Perfluorohexyldodecane (F6H12) to test their effects in the lungs of rabbit after nebulization. Of four SFAs used, F6H8 and F4H5 revealed the potential aerosolization characteristics.

Drug delivery devices for inhalation

For the delivery of any therapeutic agent through pulmonary route, respective agent should be in the aerosol formulation is a necessity. Aerosols are basically colloids of solid or liquid either suspended or dispersed in gas or air. The particles get deposited in the airways by the following mechanisms: gravitational sedimentation, inertial impaction and diffusion. The particles of size 5–9 µm undergo impaction in the large airways, 1–5 µm particles undergo sedimentation in smaller airways and the respiratory bronchioles and the particles of size less than 0.5 µm undergo Brownian diffusion in the alveoli. The movement of the particle in lungs has been shown in Fig. 4 (Gerrity et al., 1981, Newman, 1985). The efficacy of aerosol therapy depends on the amount of drug which deposits deep into the lungs, and entire deposition pattern is regulated by the formulation and the delivery device. The devices used for the delivery of therapeutic agents are nebulizers (Ibrahim et al., 2015), pressurized metered dose inhalers (MDI) (Goel et al., 2013), and dry powder inhalers (DPI) (Anderson, 2001, Rees et al., 1982).

Fig. 4

The schematics of the movement of particles in the respiratory tract.

Nebulizers

Nebulizers were the first devices which were developed for the inhalation wherein compressed air or ultrasonic power is required to split a formulation into aerosol droplets. The jet nebulizers utilize compressed air which works on Venturi’s principle. The high velocity air carrying droplets impact on the baffles which break these large droplets into small size. In case of ultrasonic nebulizers, the vibration of piezoelectric crystals produces sound waves which break liquid droplets into smaller one, and the patient inhales the mist through the mouth and the nose using nebulizers. This delivery system has several demerits such as longer administration time, less delivery efficiency and is bulkier. Hence, this necessitated the development of other delivery devices for inhalation. The nebulizers available in the market can be categorized into breath actuated, breath enhanced and vibrating mesh nebulizers. AeroEclipse® II is a breath actuated nebulizer release droplets whenever the patient inhales. Examples of breath enhanced are PARI LC® Plus and SideStream Plus which allows air entrapment during inspiration. Vibrating mesh nebulizers like PARI eFlow®, I-neb AAD System contain a mesh plate which vibrates through piezoelectric elements and breaks the large droplets into small droplets (O'callaghan and Barry, 1997, Rau et al., 2004).

Pressurized metered dose inhaler (MDI)

The active substance is dissolved in a propellant system containing liquefied gas in a pressurized container in MDI. The container is sealed with a metering valve which confers various attributes such as portability, uniform dosing. However, proper breathing coordination and limited dose per actuation are some obvious limitations which advocated for the modifications in delivery devices. MDIs are of two types: breath actuated and breathe coordinated devices. Example of breath actuated is Easibreath® which gets activated when the patient breathes and in response to this, the device delivers the dose. In breath coordinated devices, the flow rate is controlled via actuator. MDI is available with several inhalation aids such as spacers and holding chambers which lead to increased efficiency of the aerosol delivery (Coady et al., 1976).

Dry powder inhalers (DPI)

DPI is very simple and easy to use. These are portable, inexpensive, propellant free systems with good stability. The powder formulation is first entrapped into hard capsules which are further loaded into the device for the delivery. However, strong adhesive forces between the drug particles and moisture can lead to stability issues in the drug delivery via DPI. Some of the DPI’s launched in the market are given in Table 2. DPI’s are classified as the single dose, multi-unit dose and multi dose reservoirs. Single dose inhalers can be disposable or reusable. Multi-unit dose inhalers hold multiple doses at the same time without reloading. In multi dose inhalers, the formulation is dispensed into the dosing chamber via back and forth action. The outline diagram of nebulizer, MDI and DPI has been shown in Fig. 5 (Bell et al., 1971, Dolovich et al., 1981, Lourenço and Cotromanes, 1982, Rawal et al., 2017).

Fig. 5

Outline diagram of nebulizer, metered dose inhaler and dry powder inhaler.

Conclusion and future perspectives

The pulmonary drug administration may play an important role in the treatment of various respiratory and systemic diseases. This route has been explored for the delivery of wide range of drugs, especially proteins and peptides. There are many applications of pulmonary drug administration in biotechnology companies to develop translational products useful for human life. Further, the pulmonary drug administration has been explored for the delivery of several biotherapeutics in nanoparticles, microparticles, polymerosomes, micelles, mucus penetrating particles etc. These formulations seem to have great potential in the translation of commercial market. Lastly, the inhalable forms of several antibiotics to treat diseases like tuberculosis with local minimal dosages has been another potent application.

Funding

This study was funded by First hospital of Jilin university, China