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dc.contributor.advisorSteenekamp, J.H.
dc.contributor.advisorHamman, J.H.
dc.contributor.authorWeyers, Morné
dc.date.accessioned2021-12-02T07:29:21Z
dc.date.available2021-12-02T07:29:21Z
dc.date.issued2021
dc.identifier.urihttps://orcid.org/0000-0002-0441-5356
dc.identifier.urihttp://hdl.handle.net/10394/38080
dc.descriptionPhD (Pharmaceutics), North-West University, Potchefstroom Campusen_US
dc.description.abstractTherapeutic macromolecules are relatively large molecules (> 500 Da) that possess pharmacological characteristics that can be used for the treatment of various diseases. However, from a drug delivery point of view, many of these compounds exhibit unfavorable pharmacokinetic properties due to poor solubility and/or poor membrane permeation characteristics. The latter is mainly due to the lipid-like barrier imposed by epithelial mucosal layers, which have to be crossed by drug molecules in order to exert a therapeutic effect. Furthermore, most macromolecular therapeutics (e.g. protein and peptide drugs) have very low oral bioavailability, which necessitates an invasive parenteral route of administration (i.e., intravenous or subcutaneous injection). Bioenhancers may potentially benefit patients by making systemic delivery of these poorly bioavailable drugs possible via alternative routes of administration (i.e., oral, nasal, buccal, or pulmonary routes of administration) and may also reduce dose size of small molecular drugs and thereby reduce treatment costs. Intranasal drug administration offers a multitude of advantages, including non-invasive painless application, direct entry of the drug into the systemic circulation, avoidance of first-pass metabolism in the liver, increased drug bioavailability, rapid absorption and effect, and improved patient compliance. Particulate drug carrier systems provide additional advantages, such as protection of the drug from enzymatic degradation, increased drug dissolution rates, intensified and prolonged contact of the formulation with the nasal mucosa, and controlled release of the drug. Developing microparticulate dosage forms containing functional excipients (e.g. piperine) as absorption enhancers for enhanced nasal delivery therefore provides a promising alternative for non-invasive delivery of macromolecules. The aim of this study was to synthesize chitosan microparticles for nasal macromolecular compound delivery by using an adaptive ionic gelation method with tripolyphosphate as cross-linking agent. Microparticles prepared by this ionic gelation method targeted two distinctive particle size ranges varying approximately 10 times (i.e., one order of magnitude) from each other. Synthesized microparticles incorporated FITC-dextran (FD-4) as a model macromolecular compound with addition of piperine as a bioenhancer. The FD-4 encapsulated microparticles were evaluated for nasal membrane compound delivery studies to evaluate effects of particle size on drug permeation across excised nasal epithelial tissues. Particles were also formulated into a thermosensitive gel base and characterized in terms of thermal behavior and rheology. Thermosensitive gel formulations containing the microparticulate formulations were evaluated for FD-4 release by performing ex vivo transport studies. Rheometry results demonstrated that the sol-to-gel transition point occurred at a temperature of 34°C, which confirmed that the thermosensitive gel was suitably formulated to be used for the particulate formulations in nasal compound delivery systems. The cumulative percentage transport of FD-4 achieved from the microparticulate formulations in the thermosensitive gel (0.368 ± 0.083%), demonstrated to be greater than that of the control group (FD-4 alone, 0.296 ± 0.170%). The dissolution studies revealed a biphasic release pattern with an initial burst release phase followed by a sustained release phase. Results from the study demonstrated that the adaptive ionic gelation method employed could successfully and repeatably produce FD-4 encapsulated microparticles, which could be transported efficiently across nasal tissue. This study therefore contributes to advancements in ionic gelation techniques for the formulation of nasal drug delivery systems for macromolecular therapeutics.en_US
dc.language.isoenen_US
dc.publisherNorth-West University (South-Africa)en_US
dc.subjectBioenhancersen_US
dc.subjectChitosanen_US
dc.subjectCytochrome P450en_US
dc.subjectDrug absorption enhanceren_US
dc.subjectEffluxen_US
dc.subjectFITCdextran 4en_US
dc.subjectIonic gelationen_US
dc.subjectMacromolecularen_US
dc.subjectMicroparticulateen_US
dc.subjectNasalen_US
dc.subjectPiperineen_US
dc.subjectTripolyphosphateen_US
dc.titleFormulation of microparticulate dosage forms for enhancing nasal macromolecular compound deliveryen_US
dc.typeThesisen_US
dc.description.thesistypeDoctoralen_US
dc.contributor.researchID10096078 - Steenekamp, Jan Harm (Supervisor)
dc.contributor.researchID10223703 - Hamman, Johanna Hendriena (Supervisor)


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