Pulmonary drug delivery

Pulmonary drug delivery is mainly utilized for topical applications in the lungs, such as the use of inhaled beta-agonists, corticosteroids and anticholinergic agents for the treatment of asthma and COPD, the use of inhaled mucolytics and antibiotics for the treatment of cystic fibrosis (CT) and respiratory viral infections,[1] and the use of inhaled prostacyclin analogs for the treatment of pulmonary arterial hypertension (PAH).[2]

In addition, this technique is employed for systemic application, for example the use of inhaled insulin for diabetes management,[3] the use of inhaled loxapine for treatment of psychiatric disorders. Vaccines, such as the measles-rubella vaccines, can also be delivered via inhalation.

To achieve successful pulmonary drug delivery, a fraction of the inhaled particles should not deposit on the upper respiratory tract since they will be swallowed or expectorated without reaching the lungs, leading to the loss of pharmacological effect or provoking unwanted systemic side effects. Factors affecting the deposition of drug particles in lungs include drug particle properties, breathing patterns and respiratory tract geometry.[17]

Several advantages are associated with the pulmonary route of administration. For respiratory diseases, drug can be delivered directly to the disease site to perform topical relief, thus rapid onset of action can be achieved and there is less systemic side effects.[21] Less dosage of drug can also achieve similar therapeutic effect compared to other routes of administration. For drugs designed to exert systemic effect through the lung as a drug target, the drug can reach the circulation bypassing poor gastrointestinal absorption and hepatic first pass metabolism which improve drug bioavailability.[21] The large absorptive surface area, highly permeable membrane with rich blood supply also enable rapid onset of action and increase bioavailability of the drug.[21]

Despite a number of advantages in the pulmonary route compared to other routes of administration, numerous disadvantages are associated with the pulmonary route. As the drug needs to be delivered through the respiratory tract to the lungs, drug formulation can be challenging due to the defense mechanisms which intend to remove or inactivate the exogenous chemicals. Airway constriction and mucus secretion with ciliary movement prevent drugs from reaching the lungs, while enzymes, macrophages and surfactant in the lungs may also inactivate the drugs leading to less drug being absorbed.[2] Studies show that only around 20% of drug reaches the lung for each inhalation and drug loss is mainly due to the accumulation in the oropharynx in terms of pMDIs and DPIs and drug retention in the device for nebulisers.[2]

Some irritating drug particles may also cause local side effects at the respiratory tract, for example inhaled corticosteroid accumulating in the oropharynx can result in dysphonia and oral thrush. Besides, drug dosing may be inaccurate due to the variations of breathing patterns between individuals and the presence of numerous factors affecting the deposition and absorption of drug particles in the lungs.[20] In particular, elder patients may not have enough strength to generate sufficient inspiratory flow, resulting in less drug inhalation and hence low drug bioavailability. Finally, inhalers, especially nebulizers, require regular maintenance and cleaning. The inhaler devices are relatively expensive compared to oral tablets,[22] which may not be affordable to low income patients.

The effectiveness of drug delivery highly depends on the patient's compliance and proper inhaler technique with no significant error in using the inhalers. Poor compliance may lead to uncontrolled or poorly controlled disease status.[23] For instance, a patient may feel recovered and discontinue the treatment, or a patient may forget to take the medication, resulting in suboptimal disease management. Reducing the amount of puffs by combination inhalers delivering two or more drugs in one breath or the use of electronic data loggers can improve compliance.[23]

Incorrect inhaler techniques, such as poor coordination, no exhalation before inhaling the drug aerosol or not holding breath for a few seconds after inhalation may lead to medication depositing inside the respiratory tract instead of the lungs, resulting in inefficient and inadequate treatment.[23][24] Practical demonstration instead of verbal instruction, education and rechecking on the inhaler technique after a period of time can reduce error and enhance true compliance.

The use of the pulmonary route as an entry into the systemic circulation is constantly developing due to the additional benefits of bypassing the hepatic first pass metabolism, rapid systemic absorption, higher patients compliance and its non-invasive nature. Potent drugs with the ability to penetrate the lung mucosa into the blood circulation may be available for treating diseases requiring systemic drug delivery.[25] The ongoing researches include the use of inhaled nicotine for smoking cessation,[26] the use of inhaled levodopa for the treatment of Parkinson's disease,[27] and the pulmonary delivery of various biologics.[28]

In addition to the development of new pulmonary drugs, the drug formulation and particle engineering technology is advancing, such as the use of Ultrasound Mediated Amorphous to Crystalline transition (UMAX) process to micronize drug into inhalable drug particles with better performance,[29] the use of drug nanoparticles to minimize unwanted drug adverse effects and increase drug bioavailability at the target site,[30] and the use of porous drug particles to improve pulmonary delivery efficacy.[31]

• Route of administration
• Inhaler
• Metered-dose inhaler
• Dry powder inhaler
• Nebulizer
• Respiratory tract
• Respiratory system
• Lung