Category: Formulation and Quality
Purpose: Lung transplantation serves as a therapeutic option for the treatment of a variety of end-stage lung diseases such as cystic fibrosis, interstitial pneumonia, chronic obstructive pulmonary disease, pulmonary hypertension, and sarcoidosis. Although the short-term outcome has improved significantly, the long-term survival after lung transplantation is still low. To improve the clinical outcome of immunosuppression therapy in lung transplant, direct delivery to the target site of local lung disease has been proposed. Direct delivery may also limit the potential for systemic side effects. Thin film freezing (TFF) is a particle engineering technique that is a continuous, scalable cryogenic process. With rapid freezing rate, the crystallization and aggregation can be minimized, forming brittle-matrix particles which are composed of nanostructured aggregate particles. In our study, we aim to develop a high potency tacrolimus dry powder for inhalation, and investigate the effect of processing parameters on the properties of the TFF powder.
Methods: Formulations of tacrolimus dry powder for inhalation were composed of tacrolimus and lactose. The drug loading of formulations was evaluated from 50% to 100%. Tacrolimus and lactose were dissolved in acetonitrile/water mixture, and frozen by thin film freezing. The frozen disks were collected and solvent removed by lyophilization. The effect of drug loading on the physical properties of TFF powder was investigated. Aerodynamic particle size distribution was determined by a next-generation cascade impactor. Specific surface area was analyzed by Brunauer−Emmett−Teller method. X-ray diffractometer (XRD) and modulated differential scanning calorimeter (mDSC) were used to analyze the physical state of the formulations. Moisture sorption was evaluated by dynamic vapor sorption. Dissolution of low and high potency tacrolimus formulations was compared in phosphate buffer saline (pH 7.4, 0.2% Tween 80). To increase throughput, the TFF processing parameters were also optimized. Moreover, different types of device (e.g. high-resistance RS01® inhaler, low-resistance RS01® inhaler) were evaluated.
Results: We found that drug loading did not affect aerosol performance of formulations. Aerodynamic diameter of TFF tacrolimus/lactose (50/50) and TFF tacrolimus/lactose (95/5) were 2.41±0.19 microns and 2.61±0.20 microns, respectively. Fine particle fractions (of delivered dose) of 50/50 and 95/5 formulations were 65.94±5.68 % and 72.97±3.23%, respectively. Specific surface area of 50/50 and 95/5 powders were 143.13±0.60 m2/g and 73.58±1.86 m2/g, respectively. Although specific surface area decreased as the drug loading increased, it did not affect the aerosol performance of the formulations. XRD patterns and mDSC thermograms show both tacrolimus and lactose were amorphous after TFF processing. Moisture sorption thermograms indicate that a higher content of lactose in the formulations increases hygroscopicity, and only TFF tacrolimus/lactose (50/50) exhibits recrystallization of formulation at 25°C/60%RH. This agrees with the results of XRD, which indicate that lactose in TFF tacrolimus/lactose (50/50) composition recrystallized after 24-hours exposure to 25°C/75%RH and 40°C/75%RH, while high potency tacrolimus formulation remained amorphous. Additionally, the dissolution profile for either TFF tacrolimus/lactose composition was similar. Moreover, solids content of formulation, solvent mixture composition and processing temperatures did not affect aerosol performance of the high potency formulation. For device evaluation, the high-resistance RS01® inhaler was more suitable for brittle-matrix particles, compared to low resistance RS01® inhaler. Fine particle fractions (of delivered dose) of TFF tacrolimus/lactose (95/5) evaluated by high-resistance RS01® inhaler at 1 kPa (30 L/min) and 4 kPa (60 L/min) were 65.11±0.98% and 72.97±3.23%, respectively. Fine particle fractions (of delivered dose) of TFF tacrolimus/lactose (95/5) evaluated by low-resistance RS01® inhaler at 1 kPa (52 L/min) and 4 kPa (90 L/min) were 56.95±2.99% and 67.24±0.02%, respectively.
Conclusion: Thin film freezing is a suitable method to prepare high potency tacrolimus powders that exhibit high aerosol performance and improvement of dissolution. Thin film freezing is a robust process with a broad processing window for producing aerosolized tacrolimus/lactose powder. The high-resistance RS01® inhaler is more suitable for dispersing brittle matrix of nanostructured aggregates due to lower flow rate dependence, as compared to low-resistance RS01® inhaler.