Pulmonary Drug Delivery through Responsive Materials

Introduction

1.1. Pulmonary Delivery

The delivery of therapeutics and active compounds is critical in remedying a disease. There are many ways to deliver an active compound or drug to a specific area in the human body. The most common ways of providing a drug are (i) nasal, (ii) pulmonary, (iii) oral, (iv) transdermal, and (v) intravenous. Depending on the targeting of the specific disease, the drug’s mechanism of action, and the nature of the compound, the most suitable way of delivery is chosen. The delivery of drugs is currently systemic in most cases [1]. This technique has proven efficient depending on the specific targeted disease. However, it also has some drawbacks, such as not providing sufficient quantities of drugs at the desired location, especially for drugs with limited therapeutic windows, and, most importantly, the crossing of specific biological barriers [1,2]. In these terms, pulmonary delivery is exciting since it can deliver compounds for local and systemic use [1,2]. The lung offers a remarkable and demanding route for drug delivery with high absorption and surface area, ca. 100 m2 [3], and abundant vessels of lung tissues [4].

Moreover, lungs offer a highly vascularized surface area for drug absorption, an epithelial barrier of low thickness, and the absence of the first-pass effect that plagues oral delivery methods [1,2]. Delivery through this technique has resulted in improved biodistribution and reduced systemic toxicity compared to conventional formulations administered intravenously [5]. In local treatments of tuberculosis, asthma, lung cancer, or chronic obstructive pulmonary diseases, the inhalation of the drug goes directly to the site of action [1,2]. Pulmonary delivery would allow enhanced bioavailability, decrease side effects, and limit accumulation in the liver, spleen, and kidney [1,2]. Throughout the lung system, systemic delivery into circulation is also possible due to the lung’s natural permeability to small molecules, proteins, and peptides [1,2]. The approach of pulmonary delivery has been researched extensively in the last few years. It has been used positively for preparing formulations for inhalable carrier systems in addition to pure drug formulations. Inhalable carriers protect the drugs by avoiding early degradation and fast clearance [6]. Research has also been carried out on inhalers to improve their effectiveness and delivery of the therapeutic by using different types such as metered doses, nebulizers, and dry powder inhalers [4].

1.2. Finding the Way to the Lung

Aerosols are inhaled through the mouth and pass into the respiratory tract. The route in order is oropharynx, larynx, trachea, bronchi, bronchioles, and alveoli. Successful deposit in the airways and alveoli requires that carriers have a specific diameter. According to the literature, carriers must have a size of <5 mm. Particles of >5 mm diameter are deposited mainly in the oropharynx by inertial impaction and are then swallowed into the gastrointestinal tract [7]. Due to impaction, large particles (>10 μm) are deposited in the oropharyngeal and larynx region. Small particles (0.5–2 μm) are retained in the alveoli and smaller conducting airways, resulting from gravitational sedimentation. Very small particles (<0.5 μm) are generally not deposited and are expelled upon exhalation [8]. Drug-loaded nanoparticles are usually deposited in the pulmonary region by sedimentation after being released from the device due to lung agglomeration. These agglomerated nanoparticles can reside longer in the tracheobronchial region, thereby providing effective targeting and improved drug therapeutic efficacy. Even though pulmonary delivery has a favorable route to the target (lungs), pulmonary clearance exists to protect the patient from foreign bodies. Mucociliary clearance is the primary clearance mechanism for removing foreign particles in the airways. The epithelial cilia mechanically transport the particles along the mucous layer toward the oropharynx, where the particles are subsequently swallowed or expectorated. Coughing is the usual mechanism for removing large particles that deposit. In the alveolar region, macrophages may engulf and destroy particulate materials [7].

1.3. Formulations and Materials in Pulmonary Delivery

Pulmonary delivery is an evolving field in therapeutics, but it is also quite challenging. The anatomy and physiology of the lung are demanding and challenging and must be taken care of before designing specific formulations for drug delivery. Carriers at the nanoscale can successfully load and deliver biological therapeutics, but they need to obtain sizes less than 300 nm for efficient cellular endocytosis and transport across the mucosal barrier [9]. One major problem is nanoparticles’ effectiveness in efficiently aerosolizing and depositing within the lung via inhalation, since particles of less than 1 μm are predominantly exhaled. Particles ideally need sizes between 1 and 5 μm for efficient deposition in the deep lung. At the same time, alveolar macrophages rapidly phagocytose particles with geometric diameters within the 1–5 μm range, making the therapeutic delivery difficult. Aerosolization of the formulations can lead to two groups of treatments: (i) those intended for lung administration and (ii) those that sustainedly release volatile compounds into the air for inhalation [10].
Much research has been carried out to find the proper nanocarrier to host specific therapeutics. Some of the most researched candidates are:

• Nanoparticles: Regarding pulmonary drug delivery, nanoparticles help target a specific site for delivering a therapeutic substance. This becomes a significant advantage, specifically with drastic reductions in the dose of the therapeutic substance required. In addition, the occurrence of side effects has been reduced relatively.
• Microparticles: These are prepared by encapsulating, entrapping, or dissolving the active drug within a polymer matrix. They can be employed for targeted delivery, sustained release, and controlled release of therapeutic agents in the pulmonary region.
• Liposomes: currently, they are used in sustained-release formulations for lung diseases and gene therapy.
• Powders: in pulmonary drug delivery, powders are used in different inhalational product preparations, like dry powder inhalers.
• Microemulsions: These are used for controlled drug release and specific tissue targeting. They are also used for reducing the rate of degradation of drugs [8].

Since the research is evolving, other types of formulations are being studied, such as phospholipids [5] and nanoscale metal-organic frameworks (NMOFs), which are a class of porous materials that have become promising candidates for drug encapsulation and delivery due to their high porosity, biodegradable structures, and controllable surface functionalities [11]. Specific mention must be made of liposomes, with excellent safety and biocompatibility, and drugs loaded with liposomes have prolonged lung residence time [12]. Liposomes can be prepared in different formulations, such as solid lipid nanoparticles, nanostructured lipid carriers, and liposomes [13].

Moreover, hydrogels, a unique class of materials, hold significant potential in pulmonary delivery. Their soft and low mechanical modulus properties, along with a size range of 0.5 to 5 mm, make them a promising option. These hydrogels can swell after deposition, reaching a larger size and avoiding macrophage uptake [2]. The added responsiveness to a stimulus further enhances their potential for medical applications. These formulations can change their shape or degrade controllably to deliver their payload. Currently, the major responsive characteristics for these formulations are based on pH, temperature, and enzymes [1]. Formulations such as hydrogels, complexes, liposomes, and composites with specific responsiveness (pH, temperature, magnetic, enzymatic, and others) have demonstrated successful delivery of therapeutics through the lungs, as depicted in Figure 1.

Another critical parameter to consider when designing the formulation is how to deliver the specific compound. The three significant ways of delivering are nebulizers, where droplets from a bulk liquid using either compressed air (jet nebulizers) or ultrasonic waves (ultrasonic nebulizers) generate continuous aerosol streams; metered dose inhalers (MDIs), in which the drug(s) are suspended or dissolved in a liquefied propellant system, which may also contain excipients such as co-solvents or surfactants (portability and simplicity); and dry powder inhalers (DPIs), which provide single- or multi-doses via oral inhalation, depending on the design of the powder reservoir and metering components [7]. Among these, DPIs are considered the most promising delivery systems since they maintain high physicochemical stability in a vast range of temperatures, provide better sterility, and are easy to operate and cost-effective [6]. The most used techniques for preparing inhalable powder formulations are spray drying (SD) or spray freeze drying (SFD). Spray drying involves atomizing the compounds of the desired products into droplets by spraying, followed by rapid evaporation into solid powder. Spray freeze drying also uses the atomization step and then solidification by cooling water and subsequently subliming them at low temperature and pressure interaction with the cryo liquid phase [14].

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Politakos, N.; Gregoriou, V.G.; Chochos, C.L. Pulmonary Drug Delivery through Responsive Materials. Macromol 2024, 4, 490-508. https://doi.org/10.3390/macromol4030029

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