Low powder mass filling of dry powder inhalation formulations.

CONTEXT: The successful accurate dosing and filling of powders at fill masses of <10 mg is considered to be challenging for the pharmaceutical industry. This is mainly due to the limitations of current powder volumetric dosing technologies, which rely on formulations having 'good' flow properties. This is especially true for dry powder inhaler (DPI) applications where, together with good manufacturability, powders must also exhibit properties that allow acceptable product performance. OBJECTIVE: In this study, the OMNIDOSE® filling technology was investigated for its capability to accurately fill powders suitable for DPI applications, to masses as low as 1 mg. RESULTS: Several lactose monohydrate-based powders were successfully dosed at target fill masses of 1 and 5 mg using the current technology at laboratory scale. The filling behavior of the excipients could be related to various aspects of their physical properties. DPI formulations were dosed at masses of 4 and 25 mg at pilot scale to produce capsules that exhibited aerosolization fine particle fractions of ∼30% based on label claim. CONCLUSIONS: Initial studies suggest that the OMNIDOSE((®)) technology is readily adaptable for the dosing of low masses of DPI excipients and formulations and demonstrate the value of thoroughly evaluating powder performance at laboratory scale prior to pilot scale.

Developing therapeutics for the treatment of pediatric asthma.

The main goals for developing effective treatments for pediatric asthma are to improve the quality of life of children with asthma by reducing symptoms and the frequency of exacerbations, to allow undisturbed sleep and performance of daily activities, and to ensure a more healthy adult future. Despite advances in modern medical care and the introduction of effective therapies, such as inhaled corticosteroids, poor asthma control exists in clinical practice. This lack of control can be attributed to two primary factors: (i) poor compliance and adherence to treatment; and (ii) poor efficiency of inhalation drug delivery, resulting from the inability of young children to correctly use inhalers that were designed for adults. Both the FDA and EMEA have mandated pediatric testing regulations for drugs indicated for pediatric use and established incentives for the development of such agents; however, there are no inhalers on the market that have been specifically designed to meet the unique needs of children because most inhalers were developed for adults and then used for the treatment of children following minor modifications. Significant effort needs to be invested in the area of pediatric asthma to increase the availability of high-quality, patient-centric medication and delivery systems.

Factors affecting aerosol performance during nebulization with jet and ultrasonic nebulizers.

Nebulization of aqueous solutions is a convenient delivery system to deliver drugs to the lungs because it can produce droplets small enough to reach the alveolar region. However, the droplet size might be affected by the changes in the temperature and the concentration of the nebulizing solution in the reservoir during nebulization. In this study, the changes in the droplet size over the nebulization time using a PariBoy air-jet and a Multisonic ultrasonic nebulizer have been studied. The findings were related to changes in the temperature, concentration, surface tension, viscosity and saturated vapour pressure of the nebulizing solution. By using the jet nebulizer, an increase in the droplet size followed by a decrease has been observed. This observation could be attributed to the approx. 7 degrees C reduction of the temperature during the first 2 min in the jet nebulizer reservoir which increased the viscosity of the nebulizing solution. After this initial period of time, the increasing drug concentration induced a reduction of the surface tension and, consequently, a decrease in the droplet size. However, with the ultrasonic nebulizer a temperature increase of approx. 20 degrees C during the first 6 min in the nebulizing solution was observed leading to a decrease in droplet size, viscosity and surface tension and an increasing saturated vapour pressure. This again led to smaller average droplet sizes.

Effect of cryoprotectants on the stability and aerosol performance of nebulized aviscumine, a 57-kDa protein.

Nebulization of aqueous drug solutions is a suitable delivery system for pulmonary application of proteins because it can easily produce droplets small enough to reach the alveolar region. However, proteins are sensitive to nebulization. Therefore, stabilizers need to be added which on the other hand influence the aerosol performance, such as average droplet size or mass output. This research presents the effect of various cryoprotectants such as Na-polyphosphate, CaCl(2) x 6H(2)O and MgSO(4) x 7H(2)O on the stability and aerosol performance of freeze-dried aviscumine after reconstitution and nebulization using three different nebulizers. Formulations containing Tris-buffer, polysorbate 80, Na(2)-EDTA and HES450 were lyophilized and reconstituted with a buffered isotonic solution containing 100 mmol/l Tricine-buffer pH 8, 0.03% (w/v) octanoyl-N-methylglucamide, 150 mmol/l NaCl and a cryoprotectant. The aviscumine activity was determined by a binding assay. The addition of 0.2% Na-polyphosphate to the reconstitution medium led to retention of approx. 73% of the aviscumine activity after 20 min nebulization with the Systam ultrasonic nebulizer. It has been observed that 84 and 72% of the activity were retained by the addition of 10 mmol/l CaCl(2) x 6H(2)O using PariBoy air-jet and Multisonic ultrasonic nebulizer, respectively. In addition, a decrease in the mean droplet size with increasing the cryoprotectant concentration has been observed. A relationship between the average droplet size, surface tension and viscosity depending on the used cryoprotectant type and concentration could be established.

The effect of formulation variables on the stability of nebulized aviscumine.

The pulmonary drug delivery of proteins present an alternative to parenteral and oral administration. Nebulization of aqueous protein solutions is an ideal method for pulmonary application of therapeutic proteins considering the difficulties of their formulation as MDIs or DPIs. This research presents the effect of variable excipients on the stability of freeze-dried aviscumine after reconstitution and nebulization. Formulations containing different lyoprotectants have been lyophilized and reconstituted with isotonic salt solution. The loss of aviscumine activity in the nebulizer reservoir and after nebulization with a PariBoy air-jet nebulizer, a Multisonic ultrasonic nebulizer and a Systam ultrasonic nebulizer was determined by a binding assay. The effect of variable lyoprotectants such as 8% (w/v) Dextran T1, HES130, HES450, HP-beta-CD and 6% (w/v) HES450 plus 2% (w/v) mannitol on the stability of aviscumine to air-jet and ultrasonic nebulization has been evaluated. Only 50% of aviscumine activity was retained after 20 min nebulization, where 8% (w/v) HES450 was shown to be the best stabilizer. Stabilization of aviscumine by the addition of variable surfactants as 0.01 and 0.1% (w/v) Poloxamer 188, 0.03 and 0.1% (w/v) PEG 8000, 0.03 and 0.1% (w/v) Solutol HS15 and 0.03 and 0.1% (w/v) octanoyl-N-methyl-glucamide to the reconstitution solution has also been studied. By the addition of 0.03% (w/v) octanoyl-N-methyl-glucamide, 70% of the activity was retained after 20 min nebulization.

Effect of excipients on the stability and aerosol performance of nebulized aviscumine.

Pulmonary delivery is an attractive alternative route to deliver protein drugs that are currently delivered by injection. Inhalation therapy via nebulizers is a well accepted way for pulmonary application of proteins considering the formulation difficulties of MDIs or DPIs. This research presents the effect of variable excipients on the stability and aerosol performance of freeze-dried aviscumine after reconstitution and nebulization. Aviscumine formulations containing 100 mmol/L Tris buffer, 0.1% (w/v) Polysorbate 80, 0.01% (w/v) Na(2)-EDTA and 8% (w/v) Hydroxyethyl starch have been lyophilized and reconstituted with a buffered isotonic solution pH 8. The aviscumine activity was determined by a binding assay directly after reconstitution and after nebulization with a PariBoy air-jet nebulizer, a Multisonic and a Systam ultrasonic nebulizer. The stabilization of aviscumine by the addition of variable buffer salts to the reconstitution medium, such as 50, 100, and 200 mmol/L Tris buffer, 20 and 100 mmol/L phosphate buffer, and 20 and 100 mmol/L Tricine buffer, was studied. About 50% of aviscumine activity was lost after 20 min nebulization time without any additives. Nevertheless, higher buffer concentrations confer greater stability. About 70% of the aviscumine activity could be retained by the addition 0.03% octanoyl-N-methylglucamide and 100 mmol/L Tricine to the reconstitution medium.