Amorphous drug-polyelectrolyte nanoparticle complex with controlled release functionality, enhanced amorphous stability, and its continuous production platform

• Main Author: Dong, Bingxue
• Other Authors: Kunn Hadinoto Ong
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Engineering
• Online Access: https://hdl.handle.net/10356/138167
• Institution: Nanyang Technological University

In spite of various contemporary medicinal approaches developed, there are still more than 40% of drugs in the pharmaceutic market and more than 70% of the drug candidates are insoluble in water, resulting in low oral bioavailability and low therapeutic effectivity of the drugs or drug candidates. Solubility enhancement remains a significant challenge in drug formulation technology development. Various methods have been applied to increase the solubility of poorly soluble drugs. Rendering of drugs into their amorphous form is a promising strategy to enhance the rate and extent of the dissolution of poorly soluble drugs. Nanoization has been used as an effective method to prepare the drug formulations aimed at increasing drug solubility as well. However, most of the existing formulations of poorly soluble drugs are not able to provide fast dissolution or not able to provide the high drug loading required to decrease the pill burden. Amorphous drug-polysaccharide nanoplex with high drug loading (above 80 %) were prepared by the self-assembly electrostatic driven complexation between ionized drug molecules and oppositely charged polysaccharide. The prepared nanoplex was proven to exhibit fast drug dissolution, prolonged supersaturation. The electrostatic driven drug-polysaccharide complexation method is a simple yet effective method without thermal or mechanical stress during manufacture. To increase the drug-polysaccharide nanoplex production consistency and develop a continuous production platform, a milli-fluidic platform was designed. Millifluidic production mode and the bulk mixing production mode were directly compared for the first time on the physical characteristics, preparation efficiency, amorphous stability of the resultant nanoplex, the dissolution/superstation generation and the production consistency. The millifluidic platform showed its superiority in production consistency, continuous production ability, and scalability. The drug-polysaccharide nanoplex exhibited fast dissolution, prolonged supersaturation and suggested improved bioavailability. Nevertheless, sustained release with the enhanced extent of dissolution and high apparent solubility is still desired to meet the different requirements in different physiological environments. The bioavailability of the broad-spectrum antibiotic Ciprofloxacin (CIP) was limited because of its narrow absorption in the stomach. In Chapter 6, a ternary nanoparticle complex (nanoplex) was designed via co-complexation with polyanions and an anionic amphiphile (sodium dodecyl sulfate (SDS)) to modify the release of CIP in the stomach as well as to prolong the gastric residence time of CIP. The effect of the charge ratio of DXT to SDS on the size, zeta potential, CIP utilization rate, payload of the CIP-DXT-SDS nanoplex and the dissolution characteristics in the simulated gastrointestinal fluids were studied. The CIP-DXT-SDS nanoplex prepared with a lower charger ratio (i.e. below 80:20) were proved to exhibit sustained CIP release compared to the native CIP and the binary CIP-DXT nanoplex in SGJ. Though the amorphous solid drug formation represents an attractive approach to enhance the solubility of poorly soluble drugs, they have a trait that the amorphous solid drug tends to become crystalline during storage due to the inherent thermodynamic instability. The poor physical stability of many amorphous drug formulations has limited their application in marketing. To address this issue, in my research, different methods were explored to increase the stability of the amorphous of the drugs. Crystallization inhibiting agents, i.e. hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were incorporated into the nanoplex formulation to improve the amorphous state stability of CIP. With the addition of HPMC or PVP, the nanoparticle formed (i.e. CIP-DXT-HPMC nanoplex and CIP-DXT-PVP nanoplex) has increased nanoparticle size (from 300 nm to 500 nm) and increased CIP utilization rate (increased from 65 % to 90 %, w/w) without decreasing the CIP payload. Both CIP-DXT-PVP and CIP-DXT-HPMC exhibited solubility enhancement and increased amorphous stability. In Chapter 8, another method was used to increase the amorphous stability. Carboxymethyl cellulose (CMC) was used to substitute DXT because it has the crystallization inhibiting ability. CIP-CMC nanoplex with the size at around 200 nm, zeta potential at around -49 mV, and high payload at approximately 76% were successfully prepared. The CIP-CMC nanoplex exhibited superiority over CIP-DXT nanoplex on not only the significantly improved amorphous stability but also on the higher CIP payload and production yield. Overall, amorphous drug-polyelectrolytes nanoplex has emerged as an appealing drug formulation to address the problem of the poorly soluble drug due to its fast release, prolonged supersaturation, and simple yet highly efficient preparation. Millifluidic reactors were designed as continuous platforms to produce nanoplex with increased product consistency. The dissolutions of the nanoplexes were tunable to achieve sustained release in the stomach by designing the ternary nanoparticle complex prepared via electrostatic interaction and hydrophobic interaction. The nanoplex with increased amorphous stability was designed. Nanoplex was equipped with an adjustable release functionality and enhanced amorphous stability and continuous production. The future work I would like to recommend are 1) comparison on the co-amorphous drug formulations with the amorphous nanoplex equipped with modifiable dissolution rate functionality and improved the amorphous stability. 2) design of a one-step synthesis and recovery of the nano-complex via a flocculation and filtration process based on the charge-driven flocculation as an intensified process for the nanoplex purification. 3) widened application of the nanoplex on selective release functionality.