Pulmonary drug delivery by dry powder inhalers (DPI) is undergoing rapid development realizing full potential of lungs for local and systematic treatment of diseases. Its propellant free nature, high patient compliance, high dose carrying capacity, drug stability and patent protection make it an option for local and systematic treatment of diseases. However, dry powder inhalers are complicated systems and their performance relies on many aspects, including the design of the inhaler, the powder formulation and the airflow generated by the patient.

DPI devices

Though the performance of the DPI system depends both on the powder formulation and the inhaler device, often devices are much less explored than the powder formulations. There is a wide range of passive (breathe driven) and active (power driven), single or multiple dose DPI devices in the market. Mostly all the marketed devices are passive devices, which rely on the inspiratory airflow of the patient for powder dispersion into individual particles. Each DPI device has a different air flow resistance that governs the required inspiratory effort by the patient. Even with active research on the development of newer DPI devices, the concept of powder interaction with device is not well understood. The relative effect of air turbulence and mechanical impaction (particle-particle and particle-device) for controlling powder dispersion in the device, the role of capsule and the influence of airflow are still unclear. However, recent application of computational fluid dynamics has been helpful in designing and developing DPI devices and understanding the effect of airflow changes and deagglomeration in the inhaler device.

Powder production methods

Conventionally, DPIs are developed by crystallizing the powder and milling it to micronize the drug particles. This process facilitates pulmonary delivery. However this method has a lot of limitations, including poor control over powder crystallanity, shape, size, and size distribution. The spray drying is promising alternative method for producing particles above 2 µm and has better control on particle formation. The other techniques for formulation of stable micron sized DPI products include milling, simple mixing of carrier with the drug, co-precipitation of drug and carrier by lyophilization and milling, specialized spray-drying, spray freeze drying, ultrasound assisted crystallization, flash crystallization, controlled precipitation and supercritical fluid technologies.

These methods may have the advantages of higher product yield, lower operating temperature, and higher powder crystallanity. However, all these techniques are costly and impurity can be considered as one of the major disadvantages.

Formulation

Drug delivery to the lung can be improved by using better devices and through more rationalized formulation. DPI consists of drug and carrier particles, either mixed or co-precipitated together into dry powder form. The size of drug / dry powder should be in the aerodynamic diameter range of 0.5 to 3 µm for alveolar region of lung for local effect and systemic absorption and 3 to 5 µm for local action.

The commonly used coarse carrier is inhalation grade lactose, mannitol, sucrose, maltose, glucose, trehalose, raffinose, melezitose, lactitol, maltitol and starch. Development of formulations in terms of particle size distribution, particle density, morphology, surface roughness, flow ability and surface that are suitable for maximizing drug delivery to lung is of paramount importance to therapeutic DPIs. Hence, a search for novel DPIs for inhalation therapy with excellent aerosolization property and higher respirable fractions, irrespective of the therapeutic agent is continued.

Attention has also been given to the manipulation of surface texture of dry powder aerosol, particularly to avoid the particle aggregation. The use of large particles apparently reduces the overall surface area of the powder preparation, resulting in improvements in flowability and respirable fraction. To advance aerosol powder technology, several strategies, including novel inhaler and novel particle design have been developed to improve flowability of dry powders. Also efforts are being made to break aerosol powder into individual particles.

Studies on influence of particle surface characteristics, environmental conditions, air flow rate inhaler resistance and excipients on aerosol generation are explored to improve the delivery efficiency of DPIs. The studies mainly focused on the particle engineering to lower powder cohesion and improved dispersibility. Coated particles, needle crystals, large porous particles, trojan particles, aerogel powders, spray-freeze dried particles, pulmosphere, corrugated particles, agglomerated particles and spray dried low density particles are the examples.

The DPI formulation aims at pulmonary drug delivery having uniform distribution, small dose variation, good flowability; adequate physical stability in the device before use, and good performance in terms of emitted dose and fine particle fraction. The performance of dry powder aerosol systems were improved significantly through blending and use of ternary mixtures, particle engineering through lowering the aerodynamic diameters of the particles & preparing less cohesive and adhesive particles.

Novel DPIs

While the conventional methods of DPIs production for inhalation products may have been sufficient in the past, they are not suitable to produce powders with the required flow and dispersion characteristics to meet the need of enhanced powder performance.

Many biologically active peptides have been discovered recently as new drugs. Because of transport and enzymatic barriers, clinical dosage forms of these peptides have been primarily parenteral forms. Development of sustained release forms of these peptide drugs are also being actively researched and the pulmonary route would seem to be a promising alternative for delivering them, because many drugs that are poorly absorbed from other mucosal sites are well absorbed from the lungs. There are more than 25 inhalation drugs on the market for treatment of lung diseases. These drugs are all absorbed to some extent into the body, most of them quickly, and with very high systemic bioavailabilities.

Pulmonary delivery of inhaled insulin for systemic absorption, pulmonary malarial vaccine for sustained release of antigens, as DNA, peptides and protein antigens, aerosol spray of polyene as amphotericin-B, pimaricin for pulmonary aspergillosis, leishmaniasis, schistosomiasis, lambliasis and trichomoniasisis, growth hormone for hormone deficiency or a non-growth hormone deficiency disorder treatable with human growth hormone (hGH), are few examples of peptides and macromolecules getting absorbed from lungs.

Future trends

The future will see stable DPIs with enhanced pulmonary drug delivery. These DPIs will be noted for easy process of manufacturing and improved devices by applying better particle engineering techniques and computational fluid dynamics to understand more about airflow and deagglomeration in inhaler devices and more rational formulations.

Pulmonary drug delivery offers the opportunity for local as well as systemic administration of therapeutic drugs and peptides and proteins. It is expected that the continued research interest in this route of administration will lead to more breakthroughs in several areas of formulation and device design. However, pulmonary drug administration research should be integrated and importance must be given to the safety and convenience of patients on a long-term basis.

(The author is with the faculty of technology and engineering, M. S. University of Baroda)