Investigations of nano and microparticles for drug and protein delivery produced by atomisation of biopolymer solutions

Dewi Melani Hariyadi (2011). Investigations of nano and microparticles for drug and protein delivery produced by atomisation of biopolymer solutions PhD Thesis, School of Pharmacy, The University of Queensland.

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Author Dewi Melani Hariyadi
Thesis Title Investigations of nano and microparticles for drug and protein delivery produced by atomisation of biopolymer solutions
School, Centre or Institute School of Pharmacy
Institution The University of Queensland
Publication date 2011-12
Thesis type PhD Thesis
Supervisor Associate Professor Allan Coombes
Professor Bhesh Bhandari
Total pages 182
Total black and white pages 182
Language eng
Subjects 111504 Pharmaceutical Sciences
Abstract/Summary Encapsulation of small molecule drugs and proteins has been investigated extensively to improve bioactive formulation, release behaviour, drug stability and drug absorption. Encapsulation of small molecule therapeutics, macromolecular entities and vaccine antigens into biopolymer micro- and nano- particle systems has been widely investigated as a promising strategy to overcome the challenges of oral administration. The work described in this thesis is a contribution to this important field of research. Gelatin nanoparticles have raised much interest for oral formulations to improve the bioavailability of immunosuppressants, to achieve gene delivery and transfection in specific regions of the gastrointestinal (GI) tract and to encapsulate fragile macromolecules such as protein and peptide drugs. Aerosolisation and solvent extraction techniques were used to study the production of gelatin nanoparticles using air brush techniques and a nozzle spray system (Chapter 2). Spherical nanoparticles with discrete sizes in range of 50-155 nm were produced. The ability to control the nanoparticle size within tight limits and stabilisation of the nanoparticles by treatment with glycerol offers advantages for oral delivery of biopharmaceuticals. Microencapsulation of small molecule drugs (gentamicin sulphate antibiotic, ibuprofen NSAID (Chapter 3), propranolol HCl antihypertensive (Chapter 4)) and macromolecular actives (lysozyme and insulin (Chapter 5)) was accomplished using a novel impinging aerosols technique. Alginate displays impressive physicochemical properties and ‘clean and green’ credentials and has been investigated extensively for many years in the pharmaceutical and biomedical sciences. Apart from their advantageous properties of biocompatibility and non-toxicity (alginate possesses ‘generally recognised as safe’ (GRAS) status), alginate polymers exhibit a unique property of forming gels in mild, aqueous conditions at room temperature using divalent metal ions, principally calcium, as crosslinking agents. Microencapsulation of a hydrophilic active (gentamicin sulphate) and a hydrophobic NSAID (ibuprofen) in alginate gel microspheres was accomplished by molecular diffusion of the drug species into microspheres produced by impinging aerosols of alginate solution and CaCl2 cross-linking solution. A mean particle size in the range of 30-50 µm was obtained and high drug loadings of around 35% and 29% weight/dry microspheres weight for gentamicin sulphate and ibuprofen respectively. Released gentamicin sulphate was found to retain at least 80% activity against Staphylococcus epidermidis while Ibuprofen retained around 50% activity against Candida albicans. Direct encapsulation of propranolol HCl in alginate gel microspheres was achieved using the impinging aerosols technique. Environmental Scanning Electron Microscopy (ESEM) revealed smooth spherical hydrated microspheres (40-50 µm) in diameter. Microspheres formulated using the lowest CaCl2 crosslinking concentration (0.1M) exhibited the highest drug loading (14%, w/w of dry microspheres) and highest encapsulation efficiency (66.5%). Minor propranolol release (<4%) was measured from hydrated alginate microspheres in 2h in SGF, whereas 35% release occurred from dried microspheres. The majority of the drug load (90%) was released in 5h and 7h from hydrated and dried microspheres respectively in simulated intestinal fluid (SIF). Lysozyme and insulin were also successfully encapsulated directly in alginate gel microspheres by the impinging aerosols technique. Smooth spherical hydrated protein-loaded microspheres (30-60 µm) in diameter were observed. Limited drug or protein release was measured in SGF demonstrating the protective capacity of the microspheres towards acid labile protein and peptide therapeutics. Released insulin was found to retain 75% activity using the ARCHITECT® assay, whereas lysozyme was found to exhibit at least 80% bioactivity using the Micrococcus lysodeikticus assay. The virtual absence of drug and protein release in SGF and the retention of high levels of biological activity demonstrate the potential of alginate gel microspheres, for improving oral delivery of biopharmaceuticals. Bovine serum albumin (BSA), as a model antigen for oral vaccine delivery, was encapsulated in dried alginate microspheres using aerosolisation and freeze drying (Chapter 6). Maltodextrin was utilised as a cryoprotectant. Protein release was inhibited in SGF compared to hydrated microspheres. BSA release from dried microspheres was limited to 6% in 2h in SGF and 90% release occurred in SIF in 10h following incubation in SGF. Preservation of the protein structure during formulation and exposure to SGF was indicated. Overall, the results of these investigations demonstrate that aerosolisation techniques offer potential for preparation of gelatin nanoparticles with controlled size range and dried vaccine formulations based on alginate microspheres. The impinging aerosols technique is capable of producing alginate gel microspheres of utility for controlled oral delivery of a range of therapeutic molecules.
Keyword gelatin nanoparticles
alginate gel microspheres
in vitro release

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Created: Wed, 06 Jun 2012, 13:35:14 EST by Mrs Dewi Hariyadi on behalf of Library - Information Access Service