Development of amoxicillin suppositories and in vitro/ in vivo evaluations

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dc.contributor.advisor Wu, Zimei
dc.contributor.advisor Hanning, Sara
dc.contributor.author Purohit, Trusha Jaimin
dc.date.accessioned 2021-11-30T23:53:19Z
dc.date.available 2021-11-30T23:53:19Z
dc.date.issued 2021 en
dc.identifier.uri https://hdl.handle.net/2292/57564
dc.description.abstract Background: Rectal drug delivery is a potential route of administration, especially for children in low- and middle-income countries, where pneumonia is a leading cause of childhood death. An inexpensive, accessible, stable rectal formulation suitable for an outpatient setting could help reduce childhood mortality due to pneumonia. This research aimed to develop amoxicillin suppositories using lipophilic and hydrophilic bases and to investigate the mechanisms of absorption of amoxicillin from the rectum as well as influencing factors such as salt form of drug, base, and drug-base interactions. Methods: Hydrophilic suppository base, polyethylene glycol (PEG) 1500:PEG 4000 (70:30 w/w) and lipophilic suppository base, Suppocire® NA 15 (SNA 15) were selected with the aid of differential scanning calorimetry (DSC). Following preformulation studies, a validated high-performance liquid chromatographic (HPLC) method was developed and applied to validate the extraction protocol developed by leveraging the solubility and stability of amoxicillin. The developed HPLC method was then used for in vitro and in vivo quantification of amoxicillin. Amoxicillin sodium (AS) 100 mg and 200 mg conventional suppositories prepared in PEG or SNA 15 base were evaluated using standard pharmacopoeial tests and solid-state characterisation, along with in vitro release and stability over 3 months at 20 ± 0.2 °C. Absolute bioavailability (F) of AS from each suppository was investigated in a rabbit model to determine the extent and mechanism of absorption of amoxicillin along with irritation potential. PEG 1500 shells encapsulating amoxicillin trihydrate (AMT) or AS loaded in SNA 15 core were used to develop a prototype of 250 mg amoxicillin hollow-type (HT) suppository. F of AS vs AMT was predicted using an in vitro-in vivo correlation model developed for the conventional AS suppositories. Results and discussion: A rapid, sensitive, stability-indicating isocratic HPLC method was developed and validated and used for quantitation of amoxicillin. A five-fold increase in solubility and two-fold increase in stability of amoxicillin was achieved by addition of acetate buffer (0.1 M, pH 5.0) in acetonitrile, resulting in an extraction recovery of > 82% for all the samples. The HPLC assay following extraction was found linear (R2 >0.9999) over the range of 0.2 -20 μg/mL. Conventional AS suppositories complied with the pharmacopoeial tests. Solid-state analysis revealed AS distributed as solid dispersion in PEG or as an anhydrous crystalline dispersion in SNA 15 suppositories. In dissolution test, melting and spreading of SNA 15 suppositories accounted for rapid drug release and complete amoxicillin absorption (F close to 100%). AS up to 200 mg in SNA 15 suppositories was rectally absorbed via non-saturated transport, with a double peak PK profile alongside minimal tissue irritation in rabbits. AS was more stable in SNA 15 than PEG suppositories (91% vs 80% at 3 months). Shells prepared with PEG 4000 were found brittle compared with PEG 1500 shells. Solid-state evaluation confirmed the distribution of orthorhombic crystals of AMT and anhydrous crystals of AS in the SNA 15 core of HT suppositories. Slow drug release from AMT HT suppositories (12% at 4 h) led to a predicted F of < 1% compared with 79.4% for AS, corresponding to their solubilities. After three months, PEG 1500 shells were found to protect the drug-loaded core from degradation, with >98% amoxicillin remaining at 25 °C compared with the AS suppositories without shells (90%). Further study is necessary to improve the stability of HT suppository above 37 °C. Conclusion: This research is the first to determine the extent and mechanism of absorption of amoxicillin following rectal administration, which could be affected by the physicochemical properties of the drug salt form and type of formulation. This research highlighted potential for the development of AS HT suppositories for children using SNA 15 base with a PEG shell.
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/nz/
dc.title Development of amoxicillin suppositories and in vitro/ in vivo evaluations
dc.type Thesis en
thesis.degree.discipline Pharmaceutics
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.date.updated 2021-11-05T03:00:24Z
dc.rights.holder Copyright: The author en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en


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