Development of inhalable antimicrobial nanoparticle complex

• Main Author: Yu, Hong
• Other Authors: Kunn Hadinoto Ong
• Format: Theses and Dissertations
• Language: English
• Published: 2018
• Subjects: DRNTU::Engineering::Chemical engineering::Biochemical engineering; DRNTU::Engineering::Nanotechnology
• Online Access: http://hdl.handle.net/10356/73467
• Institution: Nanyang Technological University

As a novel developed delivery method for treatment of lung infections, dry powder Inhaler (DPI) delivery attracts more and more attention in studies about inhalation therapy. Conventional dry powder inhaler delivery form is used for administration of nanoparticles (liposomes, polymeric nanoparticles, etc.). However, DPI form for these nanoparticles possesses some drawbacks such as lower payload, lack of long term storage stability. The emergence of nanoparticle complex (nanoplex) is able to improve this situation greatly considering its many merits like higher payload, better long term storage stability, better supersaturation generation ability and so on. Thus here we studied the feasibility of application of nanoplex in DPI form for inhalation therapy of lung infections. Firstly we investigated the effects of dextran chain length on characteristics of ciprofloxacin nanoplex. Characterization of nanoplex showed that chain length can only affect payload and yield of nanoplex in which longer dextran chain resulted in lower payload and higher yield. Afterwards we compared effects of different drying methods (spray drying and spray freeze drying) on aerosolization efficiency of ciprofloxacin nanoplex DPI form powders and effects of different adjuvants in mitigating adverse effects of drying process on supersaturation generation ability of ciprofloxacin nanoplex spray dried powders. In these studies, Carr’s Index, Fine Particle Fraction and other aerodynamic properties were tested and compared in 15 determining whether dried powders possessed capability to deliver nanoplex into infection sites in pulmonary system via inhalation. Supersaturation profiles and dissolution rates were determined to evaluate whether dried powders were able to generate supersaturated drug solution upon reaching the pulmonary system. Data proved the superiority of spray freeze dried powders of ciprofloxacin nanoplex in terms of aerosolization efficiency and importance of hydroxypropyl methylcellulose (HPMC) as adjuvant in maintaining higher level of supersaturated drug solution within longer time period. In this thesis, we also investigated feasibility in developing dual drug nanoplex by using ciprofloxacin and itraconazole as drug models. It was reported that a combination therapy with two antibiotics was able to effectively eradicate Pseudomonas aeruginosa [1] and this inspired us with the idea about developing dual drug nanoplex system. The potential of dual drug nanoplex system in inhalation therapy is promising especially when multi-drug application is needed. The dosage, administration frequency and patient’s compliance will be greatly improved. In this study, different preparation conditions such as acetic acid concentration and mass ratio of drugs were studied for condition optimization of dual drug nanoplex formulation. We can manipulate proportion of payload for each individual drug in dual drug nanoplex by simply changing the mass ratio of drugs during preparation process. 16 In the end, we studied the curcumin (CUR) nanoplex in DPI form and feasibility of curcumin nanoplex formation by complexation with bovine serum albumin (BSA). Curcumin solubility was improved in DPI form regardless of slower dissolution rate resulted from drying process. The superiority of curcumin nanoplex with BSA was proved in this thesis. As a type of protein, BSA has higher bioavailability and be able to render nanoplex better colloidal stability. Denaturation of BSA could affect nanoplex structure which resulted in influences on drug release. CUR-BSA nanoplex had superiority in terms of size, colloidal stability as well as supersaturation generation ability. More BSA in nanoplex meant higher susceptibility of CUR-BSA nanoplex to heat treatment which led to increase in release of curcumin from nanoplex