Development of Inhalable Nano-lipid Carriers for the Treatment of Pulmonary Aspergillosis using Hot Melt Extrusion Technology

Overview: I am Gauri Shadambikar, second year PhD. student in department of Pharmaceutics and Drug Delivery. Pulmonary Aspergillosis is an infection caused by a type of mold and can have serious effects on patients with a weak immune system or with underlying lung disease1. Itraconazole, a triazole is a compound with a broad antifungal spectrum. 2. An inhalation-based drug delivery system has the advantage of rapid onset of action directly at the site of infection along with controlled and prolonged delivery. 3. Hence the aim of my project was to prepare inhalable nano-lipid carriers (NLC) which would be a viable and efficient alternative to traditional routes such as oral administration. Intellectual Merit: Pulmonary Aspergillosis, is a mycotic disease caused by Aspergillus fumigatus, a saprophytic and ubiquitous airborne fungus. Fungal infections such as Aspergillosis can be life threatening for immunocompromised patients. 4. The lung as a major port of entry into the body and site of infection plays an important role in this disease. Itraconazole, a broad-spectrum antifungal compound helps in inhibiting the fungal cell membrane. 5. The treatment for pulmonary aspergillosis includes several weeks of administration of antifungal medicines given orally. The above-mentioned delivery mode for treatment depends on systemic absorption resulting in undesirable side effects of itraconazole such as nausea, abdominal pain and hepatotoxicity. To overcome aforementioned issues, there is a need to have products that are able to achieve an instant therapeutic level and able to maintain its level in the body for longer periods of time. Inhalation drug delivery represents a potential delivery route for the treatment of pulmonary diseases. It has several advantages as it can directly reach the lung epithelium resulting in faster onset of action. 6. Also, the dosing and dose can be reduced compared to the traditional oral route as it can avoid first pass metabolism and systemic toxicity. Biodegradable nano-lipid carriers (NLC) of lipophilic compounds have the potential advantage in protecting the compound from degradation and releasing the drug in a controlled manner for a prolonged period. These NLCs can be immediately released into the pulmonary epithelium by nebulization and control the release of itraconazole for prolonged periods. Utilizing hot melt extrusion technology for preparation of nanoparticles over the conventional method will be energy efficient, as well as environmentally and industry friendly External Opportunity: We will use the preliminary data to write a pre-doctoral grant proposal to FDA, Broad Agency Announcement of 2020 (FDABAA-20-00123). New delivery systems for mycotic diseases is applicable to this announcement. The potential funding amount, in a collaboration could be $250K/year which is due in April of 2020. This accomplishment would propel my academic career and will provide a promising job offer

Vacuum compression molding as a screening tool to investigate carrier suitability for hot-melt extrusion formulations

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Hot-melt extrusion (HME) is the most preferred and effective method for manufacturing amorphous solid dispersions at production scale, but it consumes large amounts of samples when used for formulation development. Herein, we show a novel approach to screen the polymers by overcoming the disadvantage of conventional HME screening by using a minimum quantity of active pharmaceutical ingredient (API). Vacuum Compression Molding (VCM) is a fusion-based method to form solid specimens starting from powders. This study aimed to investigate the processability of VCM for the creation of amorphous formulations and to compare its results with HME-processed formulations. Mixtures of indomethacin (IND) with drug carriers (Parteck® MXP, Soluplus®, Kollidon® VA 64, Eudragit® EPO) were processed using VCM and extrusion technology. Thermal characterization was performed using differential scanning calorimetry, and the solid-state was analyzed via X-ray powder diffraction. Dissolution studies in the simulated gastric fluid were performed to evaluate the drug release. Both technologies showed similar results proving the effectiveness of VCM as a screening tool for HME-based formulations

APPLICATIONS OF HOT-MELT EXTRUSION (HME) TECHNOLOGY AND INVESTIGATION OF A SCREENING TOOL FOR HME

Hot-melt extrusion (HME), an adaptable technology, has established its position in manufacturing operations like amorphous solid dispersions, immediate and controlled oral formulations, implants and taste masked products. In recent years the industrial focus has shifted towards continuous manufacturing, thus HME is being explored for new applications. The aim of this research was to investigate the novel applications of HME by carrying out an in-depth study to understand the interaction between the process and product and to investigate a screening tool for its small-scale formulation and development.As HME consumes large amount of samples during the developmental phase, we investigated a screening tool by using minimum quantity of active pharmaceutical ingredient. Vacuum Compression Molding (VCM) is a fusion based method to form solid specimens starting from powders. Mixtures of indomethacin with drug carriers were processed using VCM and HME. Thermal characterization such as differential scanning calorimetry and powder x-ray diffraction along with dissolution studies were performed to prove the effectiveness of VCM as a screening tool for HME based formulations at small scale. The conventional techniques used for the preparation of nanostructured lipid carriers (NLC) are multi-step and time-consuming batch processes with low productivity. Hence, the continuous manufacturing advantage of HME was investigated for the preparation of NLC along with its process variation impact on the formulation composition. After optimization of screw configuration and process parameters, these formulations were successfully prepared using HME in a continuous manner. In addition, the itraconazole NLCs were explored for the pulmonary drug delivery by characterizing its aerodynamic properties thereby showing promising results for pulmonary aspergillosis treatment. To overcome the disadvantages associated with conventional liquid self-micro emulsifying drug delivery systems (SMEDDS), solid SMEDDS were formulated using HME. Solid surfactants were used to emulsify the lipids in the formulation. The prepared solid SMEDDS were characterized for globule size, PDI, zeta potential, dissolution test and differential scanning calorimetry. HME has gained attention in the pharmaceutical industry but its potential in preparing solid SMEDDS is still unexplored. Hence, solid SMEDDS were manufactured using HME for the first time