Sagar Pardeshi

Combined Microfluidic and Drying Process for Continuous Fabrication of Mannosylated Dry Powder Inhalation Formulation for Effective Therapy of Tuberculosis

Tuberculosis, affecting one-third of the world's population, is a deadly and highly contagious disease caused by Mycobacterium tuberculosis (M. TB), an intracellular pathogen. While oral administration is a common route for anti-TB drug delivery, issues such as limited drug availability, short biological half-life, and enzymatic barriers hinder their efficacy. Thus, enhancing TB treatment through drug delivery strategies is imperative. Direct lung delivery presents a promising alternative to address these limitations.

This study aims to develop Mannose-anchored mucoadhesive dry powder inhalation formulations (DPIs) containing anti-tubercular (Anti-TB) drugs. Leveraging the affinity of the mannose receptor for M. tuberculosis, the mannosylated formulation targets alveolar macrophages for effective TB therapy. Traditional methods of creating respirable drug particles involve crystallization followed by milling, necessitating further processing for stability. Our research innovatively utilizes a microfluidic approach combined with thin film freezing (TFF) technology to prepare mannose-anchored fine drug particles. By bypassing the need for additional homogenization or stabilization, this approach offers enhanced formulation stability. We believe that the TFF technology will enable many of these medications to be formed into the convenient, direct-to-lung dry powder inhaler, allowing drug delivery directly to the target site for the first time.

The TFF technology produces particles that are ideal for DPI delivery. The process produces a "Brittle Matrix Particle," which has a low bulk density, a large surface area, and an amorphous morphology, enabling the particles to supersaturate once they come into contact with the target, such as lung tissue. According to lab experiments, the aerodynamic attributes of the particles allow for up to 75% of the drug to be deposited in the deep lung. The TFF process entails dissolving therapeutics in a solvent, which may include agents meant to enhance dispersion and avert clumping, as well as excipients to enhance adhesion to the target site.

Using a T or Y junction microfluidic reactor feeding directly into the freezing chamber, particulate suspension is obtained, followed by lyophilization. When combined with lactose and dispersed in an inhaler, the resulting DPIs exhibit fine particles with an aerodynamic diameter of 1-5 µm, ensuring good aerosol efficiency. We hypothesize that the low-density brittle matrix obtained can be aerosolized by inhaler shear force, eliminating the need for additional additives in DPI formulations. Furthermore, mannosylated drug delivery vehicles may enhance macrophage uptake, leading to improved activity and reduced side effects, thereby offering a more efficient treatment strategy for tuberculosis.

My research on dry powder inhalations for pulmonary drug delivery systems has significantly broadened my personal and professional horizons as a pharmaceutical solid-state and formulation scientist. Throughout my career, I have actively pursued opportunities to explore various pathways, with a particular interest in respiratory medication delivery research. Currently, I am pursuing my Ph.D. (submitted Ph.D thesis) under the guidance of Dr. Jitendra Naik at the Research Group of the University Institute of Chemical Technology (KBC North Maharashtra University). My research focuses on the formulation and development of dry powder inhalations and ophthalmic formulations.

Recently, I took on the role of Assistant Professor at St. John Institute of Pharmacy and Research, Palghar, where my responsibilities include academic lecturing, student mentoring, and overall class management to provide undergraduate and postgraduate students with a deeper understanding of research methodologies.

I have authored two research articles in the area of respiratory research: "Mannose-anchored N,N,N-trimethyl chitosan nanoparticles for pulmonary administration of etofylline," published in the International Journal of Biological Macromolecules by Elsevier, and "Preparation and characterization of sustained-release pirfenidone-loaded microparticles for pulmonary drug delivery: Spray drying approach," published in Drying Technology by Taylor & Francis. Additionally, I have contributed to several research papers, review articles, and book chapters in the field of microreactor and drying technology. In total, I have published more than 30 research papers, reviews, and book chapters in reputable journals like ACS, Elsevier, Springer, Taylor & Francis, and Wiley, focusing on pulmonary and ophthalmic formulations. My Google Scholar citations are 384, with an H-index of 12 and an i10-index of 15.

The next stage of my research aims to assess the suitability of a combined microfluidic and drying process for the continuous fabrication of mannosylated mucoadhesive dry powder inhalation formulations targeting macrophages for effective tuberculosis therapy. Utilizing mannose-conjugated mucoadhesive carriers such as chitosan and N,N,N-trimethyl chitosan, I will load anti-TB active pharmaceutical ingredients (APIs) into the carrier using microreactor technology in conjunction with thin-film freezing (TFF) to evaluate their impact on dry powder inhalation (DPI) performance. This study will employ APIs like rifampicin and rifabutin to assess the functionality and drug delivery properties of TFF-assisted dry powder inhalations and measure output and aerosol properties. Manufacturing techniques based on microreactors and TFF can address persistent issues in inhalation drug delivery due to engineered particle shapes. Although still in its early stages, recent advancements have enhanced the utility and applicability of these techniques. However, access to appropriate manufacturing technology for complex designs in high resolution remains a significant challenge.

Financial and technical support is crucial for the development of this research. A DDL Career Development Grant would mark a significant turning point in my interdisciplinary career as a scientist specializing in lung drug delivery. My long-term objective is to compile a comprehensive scientific report detailing the preliminary investigations of intricate dry powder inhalations. I envision continued research in academic and institutional settings, as this topic remains substantially unexplored. My ultimate goal is to contribute to the advancement of this emerging field of study and present my research to an international audience of aerosol scientists. The research outcomes will be published in reputable peer-reviewed journals. If successful, this proposed research will establish a method for consistently producing inhalable particles of drugs at a larger scale, demonstrating sufficient storage stability and performance efficiency.

This work will enhance our understanding of API processing techniques in DPI-based formulations, particularly for drugs with poor aqueous solubility. It may also enable the production of drug-polymer mixtures suitable for pulmonary delivery, with the potential for technology transfer from lab to industry. Pulmonary drug delivery systems have always intrigued me, and I am eager to delve deeper into this field as a formulation scientist. This research will also provide valuable insights into dry powder inhaler systems.