Smart Pulmonary Drug Delivery Systems for the Management of Respiratory Disorders

Respiratory illnesses such as asthma, chronic obstructive pulmonary disease (COPD), tuberculosis, and cystic fibrosis remain major health burdens worldwide, with their prevalence steadily increasing. Traditional treatment methods often fall short due to limited drug bioavailability and systemic side effects. Consequently, the pulmonary route has emerged as a highly effective method for delivering medications directly to the lungs, where the disease is localized. The lungs offer a vast surface area—approximately 100 square meters—alongside an exceptionally thin alveolar membrane and an extensive capillary network, making them ideal for both local and systemic drug administration [1]

The concept of inhalation therapy is not new; it has historical roots in ancient practices involving herbal vapors. However, recent advancements in drug formulation and delivery technologies—such as dry powder inhalers (DPIs), metered dose inhalers (MDIs), and nebulizers—have significantly improved the precision, efficiency, and patient compliance of pulmonary treatments [2]These innovations have enabled effective targeting of therapeutic agents to the respiratory tract, minimizing systemic exposure and enhancing therapeutic outcomes.

Moreover, the pulmonary route is now being explored for the delivery of biologics and systemic therapies, including peptides, proteins, and vaccines. Technological progress in particle engineering, liposomal encapsulation, and nanocarriers has further broadened the scope of pulmonary drug delivery, making it a versatile platform for treating not only respiratory but also systemic conditions [3]

This review focuses on the fundamental principles, recent innovations, and clinical relevance of pulmonary drug delivery systems, especially in the context of managing respiratory disorders.

ANATOMY & PHYSIOLOGY OF LUNGS IN RELATION TO DRUG DELIVERY :

The lungs serve as an ideal route for drug administration due to their unique structure and physiological attributes. With a vast surface area of around 100 m², thin alveolar membranes (0.1–0.2 µm), and extensive vascularization, the pulmonary system facilitates efficient and rapid absorption of both small molecules and macromolecular drugs. Figure .1 . absorption of both

Fig1.Anatomy and physiology of lungs

The respiratory system is divided into two functional zones: the conducting airways, which include the trachea and bronchi, and the respiratory zone, composed of alveolar sacs where gas exchange occurs. The latter is particularly important for drug delivery, as deposition in the alveolar region allows drugs to cross into the bloodstream with minimal enzymatic degradation and bypasses hepatic first-pass metabolism

An additional advantage lies in the low enzymatic activity within the lung’s extracellular environment, making it suitable for the administration of labile biological drugs, including peptides, proteins, and nucleic acids, which would otherwise be degraded in the gastrointestinal tract

Furthermore, the presence of alveolar macrophages and a functioning mucociliary clearance mechanism presents both an opportunity and a challenge. While these features help protect the lungs from pathogens and particulates, they can also hinder drug absorption by removing inhaled particles before therapeutic action occurs. Therefore, aerodynamic particle size (generally 1–5 µm) becomes a critical design parameter for effective deposition and retention.(4)

Advantages:

1. Rapid onset of action.
2. It requires a low fraction of oral dose.
3. Pulmonary drug delivery has negligible side effects since the rest of the body is not exposed to the drug.
4. The onset of action is very quick with pulmonary drug delivery.
5. Degradation of the drug by the liver is avoided in pulmonary drug delivery.

Disadvantages:

1. Dose Inaccuracy
2. Device Complexity
3. Drug Formulation Challenges
4. Limited Drug Types
5. Environmental and Storage Sensitivity
6. Local Irritation or Allergic Reactions
7. High Cost of Devices and Formulations

MECHANISMS OF DRUG DEPOSITION IN LUNG:

Diffusion

It is the deposition of small particles(less than 0.5 microns) from high concentration to low concentration as a result of Brownian-motion. Diffusional deposition happens mainly in nasopharynx and smaller airways.

Sedimentation

Gravitational forces apply on the particle as they travel via air. Thus, they will settle to the lower exterior of the airway. This type of mechanism is more prevalent in the bronchioles and bronchi.

Fig.2 Mechanism of particle deposition

APPROACHES IN PULMONARY DRUG DELIVERY

The most crucial aspect of administering medication is using devices that send medications straight to the lungs. Because it targets the lungs directly, this approach allows medication to reach the proper spot in greater volumes. Compared to administering medication throughout the body, it can therefore function well with far smaller dosages. The amount of medication that actually enters the lungs, however, can vary from one medication to another based on the manufacturing process, particle size,

and administration method. The conventional belief that 10–20% of medications enter the lungs is therefore not true for all medications.In addition to reducing adverse effects in other areas of the body, this technique improves the medication’s effectiveness in the lungs.  In order to provide medication through the lungs, scientists have created novel methods.  Some employ lactose and medication mixes, for instance, in dry powder inhalers for rapid release.  Others employ controlled, gradual release using nanoparticles.  Moreover, liposomes, micelles, and microparticles—which are frequently composed of polymers—are used to regulate the release of the medication

1. Microspheres:-

Using tiny particles called microspheres through the lungs can help deliver medicine in a controlled way, which works for both diseases affecting the lungs and others. The way these microspheres look, how big they are, and how porous they are all play a big role in how they are made and how well they work. Even though many of these particles are small to prevent them from taking in moisture, how they react to moisture can change based on the type of medicine used and the conditions inside the lungs.(5)

2. Nanoparticles:-

The medication is either attached to the surface or trapped in the core of the polymer-based nanoparticles. This special structure improves bioavailability, protects against enzymatic breakdown, and makes controlled release of the drug easier. Recent developments in nanotechnology-based medication delivery have shown many benefits, including increased therapeutic effectiveness and a lower chance of systemic adverse effects. Researchers have addressed a number of issues in the field and achieved tremendous progress in medicine delivery by utilizing nanoparticles' ability to target lung ailments. This creative method has successfully increased the pharmacokinetics and bioavailability of drugs, opening the door for better treatment outcomes for patients with lung conditions.(6)

3. Liposomes:-

Liposomal formulations for aerosol delivery present numerous important advantages and uses, such as compatibility with water, prolonged release in the lungs, and enhanced delivery to specific alveolar cells, which helps mitigate local irritation and decrease toxicity. These liposomal formulations can be applied both locally and systemically, offering the unique benefit of enhanced effectiveness while minimizing harmful effects. Although liposomes represent a highly promising method for drug delivery with efficient drug entrapment, they are especially beneficial for lipophilic medications. In contrast, hydrophilic drugs are often poorly encapsulated within liposomes, which may lead to leakage and diminished efficacy.

4. Micelles:-

Micelles are spherical clusters created when amphiphilic surfactant molecules organize in solution, with hydrophilic heads directed outward and hydrophobic tails positioned inward. This arrangement enables micelles to enclose hydrophobic materials inside their center, promoting the solubilization and movement of poorly water-soluble medications. A hydrophilic coating encases nanoparticles, safeguarding the contained drug and possibly hindering identification by the reticuloendothelial system(7)

5. Cyclodexstrins:-

Cyclodextrins (CDs) are cyclic oligosaccharides that are produced when oligosaccharides interact.  Each of them has six, seven, or eight glucopyranose units, or α-, β-, or γ-CD.  They are very soluble in liquids because these cyclodextrins frequently form non-covalent bonds.  Pharmaceutical research often uses cyclodextrins due to their suitable size, good drug-molecule interactions, and low manufacturing costs.  Research has examined the potential of delivering drugs directly to the lungs via CDs.  Salbutamol and testosterone can both be encapsulated in CDs.  In particular, they improve the solubility and bioavailability of drugs that are poorly soluble in water. Through improved drug stability and regulated release, these formulations enhance the therapeutic effects of drugs for respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD)[6] According to clinical investigations, cyclodextrins effectively reduce the dosages of a number of medications while minimizing side effects, which enhances patient adherence and treatment outcomes in general.  Cyclodextrin formulations are also flexible options for targeted pulmonary therapy since they can encapsulate a range of medications, including proteins and peptides.

PULMONARY DRUG DELIVERY DEVICES:

Pulmonary drug delivery devices are specifically developed to deliver medications directly into the lungs for both respiratory and systemic treatment. These systems create aerosols with particle sizes suitable for deposition in different regions of the respiratory tract, ensuring effective therapy. The performance of these devices strongly influences drug delivery efficiency, patient usability, and overall clinical success.

The primary categories of pulmonary delivery devices include

1. Metered-dose inhalers (MDIs)
2. Dry powder inhalers (DPIs)
3. Nebulizers and
4. Soft mist inhalers (SMIs).

1) Metered-dose inhalers:-

A metered-dose inhaler is one of the most frequently utilized devices for administering medications directly to the lungs. Small and easy to carry, it houses medication in a pressurized canister that dispenses a specific quantity of aerosolized drug when triggered. MDIs are commonly prescribed for treating conditions like asthma and chronic obstructive pulmonary disease (COPD) due to their capacity to offer rapid relief and effective symptom management

Main Features:-

• Design: Made up of a canister containing the medication formulation, a metering valve, and a mouthpiece.
• Composition: The medication is typically suspended or dissolved in a propellant, usually hydrofluoroalkane (HFA).
• Mechanism: When the canister is pressed, the valve releases a precise dose of the medication as fine aerosol particles intended for inhalation.(8)

Here are some benefits of using MDIs:-

1. Precise Dosage: MDIs are engineered to provide an exact quantity of medication with every puff, which facilitates achieving the intended therapeutic outcome.
2. User-Friendly: MDIs are compact and straightforward to operate, making them a practical choice for patients who need to take their medication while out and about.
3. Rapid Relief: MDIs administer medicine directly to the lungs, promoting swift and effective alleviation of respiratory issues.
4. Fewer Side Effects: Since the medication is sent directly to the lungs, the required dosage is generally less than that of oral medications, thereby helping to minimize the chances of systemic side effects.
5. Economical: MDIs are frequently more affordable than other inhalation devices, positioning them as a more budget-friendly choice for patients.

2) Dry powder inhalers:-

This is a versatile system that requires a precise touch. The term itself suggests that the formulation exists in a solid state. It serves as a bolus drug delivery apparatus that holds the solid medication in a dry powder mixture that becomes aerosolized when the patient inhales. It may contain the active medication on its own or include a carrier powder mixed with the drug to enhance its flow characteristics. Dry powder inhalers offer improved stability, are easy to use, and are generally less expensive compared to metered dose inhalers. There’s no necessity for harmful propellants such as CFCs. They can be designed for either single or multiple doses.

3) Nebulizers:-

Nebulizers have been used for many years to treat asthma and other respiratory diseases. There are two basic types of nebulizers,

1. 1. Jet Nebulizer
   2. Ultrasonic Nebulizer

The jet nebulizer operates based on the Bernoulli principle, wherein compressed gas (either air or oxygen) flows through a narrow opening, creating a low-pressure area at the end of the nearby liquid feed tube. Consequently, this leads to the medication solution being pulled up from the liquid reservoir and broken into droplets within the gas stream.

The ultrasonic nebulizer operates using a piezoelectric crystal that vibrates at a high frequency (typically between 1-3 MHz) to create a spray of liquid within the nebulizer chamber; a higher frequency leads to the formation of smaller droplets. Although these disposable nebulizers are affordable, the air or oxygen compressors that power them are not. A significant portion of the prescribed medication fails to reach the lungs during nebulization. Most of the medication is either left behind in the nebulizer (known as dead volume) or expelled into the atmosphere during exhalation. On average, merely 10% of the medication placed in the nebulizer actually reaches the lungs(10)

Fig 3.Nebulizers