Date of Award

2-2010

Document type

Thesis

Degree Name

MSc by research (Master of Science by research)

First Supervisor

Zeibun Ramtoola

Funder/Sponsor

Entrtptise Ireland, SFI and The School of Pharmacy, RCSI

Keywords

Drug Compounding, Drug Delivery Systems

Abstract

Microencapsulation is a technique used in the pharmaceutical industry for many decades for stabilisation of a wide range of materials and therapeutic agents and to enhance drug delivery by controlled release, extended release, and targeted delivery of these materials.

Numerous microencapsulation techniques have been developed. One of the most commonly used techniques in the pharmaceutical and food industries is spray drying primarily because it is a one step continuous process which is easily scalable (Masters, 1991). Microencapsulation of actives using spray drying is a well established technology and the formulation and process parameters influencing microencapsulation varying activelpolymer combinations for oral, pulmonary and parenteral drug delivery have been studied extensively (Rattes & Oliveira, 2007b), (Learoyd, Burrows, French, & Seville, 2008) and (Mu, Teo, Ning, Tan, & Feng, 2005). In general, spray dried microparticles of drug and polymer tend to consist of a matrix structure where the drug is distributed within the polymer matrix giving rise to controlled release of the active by diffusion from the polymer matrix (Rattes & Oliveira, 2007a). While these matrix microparticles serve the purpose of controlled release and stabilisation, part of the active is usually available at the particle surface giving rise to a fast initial drug release or burst release andlor potential degradation of surface exposed labile molecules (He, Davis, & Illum, 1999) and (Freiberg & Zhu, 2004).

Traditionally, the spray drying process is carried out by spray drying a solution or suspension of the drug and polymer through a nozzle into heated air or nitrogen which dries the droplets formed resulting in the formation of drug/polymer matrix particles. In this research project, we examined the possibility of forming microparticles where the active would be coated or encapsulated by the coating polymer to give a 2 layered particle consisting of a core of the active and a polymer coat. The conventional nozzle was replaced with a novel nozzle configuration which allows the feeding of 2 separate streams of liquid, active and polymer solutions (Ramtoola, 2008). The microencapsulation of 3 model drugs; diclofenac sodium, omeprazole and simvastatin for oral delivery was examined using the polymers; ethylcellulose, hydroxypropylmethylcellulose (HPMC), poly (methyl methacrylate) (EudragitB L100) dissolved in either water or ethanol as the vehicle. Microparticles were prepared using the novel nozzle configuration and were compared with corresponding microparticles formulated using the conventional nozzle. The microencapsulation of Insulin, as a model protein by the biodegradable polymer, chitosan, was also studied using the novel nozzle configuration and was compared with corresponding microparticles formulated using the conventional nozzle.

The influence of process and formulation variables including the ratio of polymer to drug flow rates, the polymer to drug concentrations and percent total solid content of feed solutions on the properties of the microparticles were examined. The fluorescent markers; sodium fluorescein or rhodamine were added to the polymer (coat) and drug (core) feed solutions to allow visualisation of the internal morphology of the particles formulated. Microparticles formed were characterised for their morphology using various microscopy techniques. The size and size distribution, thermal properties, drug content and drug release properties of the micro particles were evaluated.

The results show that the novel double nozzle attachment successfully allowed the formation of microparticles which consisted of a defined core and coat as was shown by confocal and transmission electron microscopy. In contrast using the conventional nozzle, particles formed were shown to consist of a homogenous matrix with no defined drug/polymer regions.

Increasing the feed flow rates from 2ml to 8 ml per minute showed little increase in microparticle size for either the conventional or the novel nozzle configuration used. The particle size and size distribution of microparticles formulated using the novel double feed nozzle configuration were similar to corresponding microparticles spray dried using the single nozzle configuration. As the concentration of feed solutions increased to 10% wlv total solids, an increase in median particle size from 10-12 microns to >30 microns and a corresponding size distribution, Span value, was observed. As was expected, the effect of varying the feed flow rates of the polymer and drug solutions for similar polymer and drug concentrations was found to result in microparticles containing a drug to polymer ratio which was proportional to the feed flow ratio.

The internal morphology of the microparticles formulated using the novel nozzle configuration was markedly different to the internal morphology of the microparticles formulated using the conventional nozzle. Confocal microscopy and transmission electron microscopy showed a defined two layered structure analogous with a core and coat structure for particles spray dried using the novel nozzle. In contrast, a homogenous structure was observed for particles formulated using the conventional nozzle. Interestingly, scanning electron microscopy showed the outer morphology of the microparticles to be similar in most cases.

In general the drug content of microparticles were high with an encapsulation efficiency of >80% and were within expected levels for spray drying. Some deviations were observed as for chitosan and insulin microparticles where a low encapsulation efficiency of 20% was observed for the single nozzle microparticles. This was explained as a result of the poor extraction of the INS from the matrix structure microparticles during the analysis.

Drug release properties showed that while drug release was in general slower than for the pure drug, the rate of drug release from the microparticles was fast with release complete over 1-7 hours and were similar irrespective of the nozzle configuration used. This was probably related to the small particle size, hence large surface area of the microparticles formulated. At the lower drug loadings of 10% W/W, the initial burst release was lower and the subsequent release rate slower than at higher loadings as was expected.

While further work is required to better understand the impact of process and formulation variables on the particle characteristics and in particular drug release properties, the results from this research work show that this novel nozzle can be used to formulate drug and polymer microcapsules or reservoir type microparticles in comparison ta the matrix type of particles formulated when using the standard conventional nozzle configuration. The potential of this novel nozzle to formulate particles with enhanced stability, greater control of release of active and for targeted release and delivery of actives allows its application across a wide range of products including pharmaceutical, food, cosmetic and other consumer products.

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Comments

A thesis submitted to the Royal College of Surgeons for the degree of Master of Science, 2010.

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