Many inhaled medications currently on the market for asthma and COPD are formulated as dry powders and delivered by dry powder inhalers (DPIs). DPI drug delivery is considerably more convenient than wet aerosol administration, as devices are portable, do not require external power, have short administration times, and do not require refrigeration, rigorous cleaning, or disinfection. Pharmaceutical powders are hygroscopic, requiring manufacturing and packaging under conditions that exclude water. Traditional powders are formed by milling the drug into small particles that have large relative surface areas and strong cohesive forces between particles. This requires the addition of large carrier particles such as lactose to improve disaggregation of the powder into a respirable aerosol, a modification that severely limits the quantity of active drug that can be packed into a dose. Typical DPIs deliver between 18 and 550 μg of active drug per dose, several orders of magnitude less than the quantity of tobramycin delivered by TIS to persons with CF. For this reason, traditional DPI technologies have not been suitable for the delivery of tobramycin to the lungs in the past.
Recently, an alternative method for the manufacture of a dry powder tobramycin formulation, termed PulmoSpheres®
(Novartis AG, Basel, Switzerland), has been developed.76
PulmoSpheres of tobramycin inhalation powder (TIP) are produced by an emulsion-based spray-drying process that yields light porous tobramycin particles with improved flow and dispersion properties and more uniform particle size distributions when compared with traditional milled powders.76
With improved flow and dispersion, TIP can be delivered using modest inspiratory efforts from capsules with the portable breath-actuated T-326 Dry Powder Inhaler Device (Novartis AG). When compared to TIS delivery, the T-326 inhaler/TIP combination offers faster tobramycin delivery77
and improved intrapulmonary deposition in a convenient, portable format.76
The chemistry and manufacture of TIP PulmoSpheres are complex and have been extensively reviewed.76
Briefly, submicron oil-in-water emulsion droplets are created by homogenization of perfluorooctyl bromide (perflubron) in water. The dispersed oil droplets are then stabilized with a monolayer of the long-chain phospholipid distearoylphosphatidylcholine (DSPC). Tobramycin sulfate and CaCl2
are then added to the water phase of this feedstock, which is atomized into a hot air stream, with each atomized droplet containing a large number of submicron emulsion droplets. As water evaporates from atomized droplets in the hot air stream, tobramycin diffuses to the center of the droplet while the submicron oil droplets migrate to the periphery of the droplets. Eventually, shells consisting primarily of DSPC, CaCl2
, and perflubron are formed on the exterior of the droplets. Further drying causes perflubron evaporation, leaving dry particles with a porous exterior shell of DSPC and CaCl2
and amorphous solid tobramycin within that are collected from the airstream by cyclone separators. The process of conversion of atomized feedstock droplets to dried particles of TIP occurs within milliseconds. The final TIP formulation contains tobramycin sulfate as the active ingredient and DSPC and CaCl2
as excipients, with only trace levels of perflubron remaining. TIP is chemically very stable, with a long shelf life and no need for refrigeration. As with all powders, TIP is extremely hygroscopic and must be packaged in unit-dose blister packs to avoid hydration and retain flow and dispersion properties.
The physical characteristics of TIP PulmoSpheres are quite different from those of traditional dry powders that are created by the milling of crystallized compounds ( ).76
PulmoSphere size distributions are considerably more uniform, and their spheroidal shape and DSPC surface composition result in much lower interparticle cohesive forces (), meaning that PulmoSpheres are substantially less prone to agglomeration than milled powders and the amount of force necessary to suspend them as dry aerosols is lower, allowing the facilitating of their use in younger patients or those with low levels of pulmonary function.76
For instance, it has been estimated that a patient could essentially empty a TIP capsule in a T-326 inhaler with a single 1.0 L inhalation at a 40 L/min flow rate or with two 0.6 L inhalations using a 30 L/min flow rate.78
These volumes and rates are well within the capabilities of most (but perhaps not all) persons with CF aged ≥6 years.79
Low agglomeration and easy dispersal of PulmoSpheres obviates the need for carrier particles such as lactose, allowing a much higher payload of active drug per capsule.
Figure 2 TIP PulmoSpheres® (Novartis AG, Basel, Switzerland) and the T-326 Dry Powder Inhaler Device (Novartis AG). (A) Electron micrograph of PulmoSpheres, which are light, hollow, porous, particles that are less dense than milled powders, and travel (more ...)
The T-326 inhaler is pictured in . A hypromel-lose capsule containing tobramycin PulmoSpheres is loaded into the device by removing the mouthpiece and inserting the capsule into the chamber. The mouthpiece is screwed back onto the body, the button is depressed to pierce the capsule, and the patient inhales through the mouthpiece. During inspiration, the capsule rotates rapidly in the T-326 chamber, which causes TIP to be emptied from the capsule. The T-326 has relatively low airflow resistance to allow patients to generate high airflow rates and produce reliable dose delivery.76
Although most CF patients, including those as young as 6 years of age, can empty more than 90% of the contents of a capsule in a single inhalation,78
treatment instructions call for a second inhalation from the T-326 inhaler to ensure that capsules are completely emptied. The lowest values for respiratory parameters used to test capsule emptying in the lab were a 0.6 L inspiratory volume and a 30 L/min peak inspiratory flow.78
It is likely that some patients with very severe limitation in lung function may not be able to empty the capsules to achieve lung deposition. Patients can confirm that the entire capsule dose has been delivered by inspecting the capsule after inhalation.