Modification of nano- and micro-sized drug particles through individual enteric coatings

Ben Edwards

Research output: ThesisDoctoral Thesis

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Drug design and manufacture is a large industry that is continually changing as new research becomes available on new drug candidates, processing equipment and methodology, delivery systems and modification of existing moieties, among others. A lot of research, not just among drug development but elsewhere, is currently being performed on creating materials on the nanoscale and measuring their behaviour in relation to their more macroscopic counterparts. There is a widespread range of options for use of such nanomedicines ranging from oral dosage modifications, sustained release of drugs, targeting to specific sites, and imaging.

With regards to oral dosage forms, the majority of currently available drugs are present as a hard-packed tablet or granules within a capsule. Within these, there are several drugs, such as Non-Steroidal, Anti-Inflammatory Drugs (NSAIDs) which can cause irritation and other unwanted side effects when present in gastric environments. In order to offset these, enteric coatings comprised of pH dependant polymers are added to the outside of the tablet or granule. These polymers have very poor solubility within low pH conditions such as the stomach which prevents the enclosed drug from being released, yet under higher pH conditions such as are found in the intestines the polymer begins to swell and dissolve allowing the drug to be released and absorbed. Also noteworthy is that such coatings prevent breakup of the tablet to such a degree that if taken just before or after ingesting food, the tablet will remain in the stomach for several hours before being passed through, delaying the onset of the drugs actions considerably. This is one of the reasons that several tablets have a warning about taking the tablets several hours before or after eating.

Current methods for obtaining nanoparticles of drugs are varied and wide-spread. Some involve dissolving the drug into an organic solvent, before forcing it to nucleate in an aqueous solution undergoing mixing. Others use spray drying to force the drug to precipitate as the solvent in the droplets quickly evaporate. Researchers create polymer beads through some form of emulsification before incorporating the drug into these beads using a solvent. Other researchers use an organic solvent at some point in their processing. Applying a coating material adds additional processes, some depending on a pure drug particle, others with an encapsulated drug already formed.

Combing the use of drug nanoparticles with enteric coatings alleviates most of the inherent issues with taking drugs with food, which eliminate the strict conditions on its use making it more user-friendly for patients that may have memory issues. To this end nanoparticles of selected drugs (naproxen and progesterone) were produced via dry ball-milling and individually coated using a process intensification paradigm. Dry ball-milling involves the use of metal balls within a container, wherein the drug is added in powder form. This is shaken at high speed to induce particle reduction by high impact collisions. Simplistic acid/base precipitation methods were utilised to reduce the quantities of potentially harmful and difficult to remove organic solvents that are rife in the preparation of nanoparticles in the literature. The thin coats thus formed, provided significant protection from dissolution of the enclosed drug, while keeping the drug particles below 500 nm in diameter.

Research was also undertaken to explore the possibilities of using process intensification to create nanoparticles from a bottom-up approach and then synchronise it with the coating step to provide a one-pot process to create the coated drug nanoparticles. Another reason for this angle was to remove the use of large quantities of lactose that is part of the milling procedure, and thereby reduce the quantity of non-primary materials in the total manufacturing process. Through tests on three different process intensification equipment with multiple variables being tested, particles larger than those achieved through ball-milling were made; typical sizes of the drug particles varied from 800 nm to 5 μm. Nanoparticles were fabricated using low concentration drug solutions, but these proved to be a significant challenge when attempting to recover dry material for future tests. In addition, progesterone is not affected by the acid/base methodology in the same way and so could not be used for this stage of the research. Instead a solvent/anti-solvent approach was used with an ethanol/water system. This resulted in particle sizes comparable with milling, but simultaneous formation/coating proved to be elusive for the enteric polymers studied. A similar milling approach was used on curcumin to determine if the size reduction would improve bioavailability in oral dosages, as well as determining if these smaller particles would prove more effective that bulk curcumin in treating liver cancer. Although the size reduction did increase bioavailability, there was no distinction between its effects on cells, cancerous or otherwise. However the nanoparticles did affect the cells more than the bulk material. Finally turmeric was milled, leading to a significant decrease in particle size leading to increased bioavailability of curcumin under intestinal conditions.
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2013

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