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Buccal drug delivery for the treatment of xerostomia: designing a novel freeze-dried formulation of pilocarpine hydrochloride

Student thesis: Doctoral ThesisDoctor of Philosophy

Radiotherapy is a life-saving treatment for head and neck cancers, but almost 100% of patients develop dry mouth (xerostomia) because of radiation-induced damage to their salivary glands. Local delivery direct to the buccal mucosa has the potential to provide a rapid onset of drug action within the buccal mucosa while sparing systemic drug exposure and off-target effects. Therefore, the aim of this research was to produce a novel buccal fast disintegrating freeze-dried pilocarpine HCl tablet for the treatment of xerostomia. The chemical stability of pilocarpine HCl was investigated thoroughly for the determination of the formulation strategy following the 5-stage melting determination approach developed in this project. Pilocarpine HCl was characterised using powder X-ray diffraction (PXRD), optical differential scanning calorimetry (DSC), thermogravimetric analyser (TGA), high-pressure liquid chromatography (HPLC), DSC, back titration, thermogravimetric analyser – mass spectrometer (TGA-MS), liquid chromatographymass spectrometry (LC-MS) and polarimetry. The results indicated that pilocarpine HCl underdoes disprportionation during melting, and the characterisation of the newly discovered solid-state epimerisation showed that at the onset of melting of the drug is nearly a racemic mixture of pilocarpine HCl with its inactive form isopilocarpine HCl. Therefore, freeze-drying as a formulation strategy was a suitable technique to maintain the chemical stability of pilocarpine HCl. Freeze-dried tablets were successfully produced containing 11% (w/w) sodium bicarbonate, 33% (w/w) gelatin and 56% (w/w) of mannitol and 5 mg of pilocarpine HCl. All batches passed the BP quality control tests. The average weight, width, length and drug content were 22.1 ± 0.6 mg, 13.4 ± 0.3 mm, 23.1. ± 0.4 mm and 4.8 ± 0.01 mg, respectively (n=6, ± SD). A novel quality control in-vitro digital assay was designed to measure the disintegration time of the buccal tablets. Results showed that freeze-dried pilocarpine HCl tablets were fully disintegrated, in 0.7, 0.1 and 0.05 mL of the phosphate buffer saline at 37°C within 10 seconds (n=3). In conclusion, the novel aspects of this PhD project were; 1) a thorough investigation of the stability of pilocarpine HCl revealed an unreported disproportionation and novel solid-state epimerisation of the API; 2) a new in-vitro digital image disintegration assay was developed as a quality control test for the measurement of disintegration time of fast disintegrating tablets, and 3) a unique freeze-dried formulation of buccal pilocarpine HCl was successfully designed.
Original languageEnglish
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Award date1 Jul 2020

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