Extemporaneously compounded buccal pilocarpine preparations, acceptability and pilot testing for the treatment of xerostomia (dry mouth) in Australia Rose Motawade Lawendy Estafanos Bachelor of Pharmacy (Honours) Master of Pharmacy A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2019 School of Pharmacy i Abstract Xerostomia, the subjective feeling of dry mouth, is characterised by hypofunctioning salivary glands in which either the quantity or quality of saliva is reduced. It is a common symptom for a variety of diseases such as rheumatic and dysmetabolic diseases, and is the primary symptom associated with Sjögren’s syndrome. Xerostomia is also caused by treatments such as radiotherapy to the head and neck region and is a side effect of a range of medications. People with xerostomia usually experience dryness of mouth, lips and throat. They are more susceptible to dental caries, oral mucositis and enhanced tooth decay. They have problems with moistening, chewing and swallowing foods and taste alterations associated with reduction in salivary flow can affect their ability to taste food. These consequences can lead to decreased food consumption, which can cause malnutrition and further suppression of their immune defence mechanisms with increased risk of morbidity and reduced quality of life. Some approaches to managing xerostomia include sipping fluids such as water more frequently to moisten the oral mucosa, chewing sugar free gum to stimulate more saliva secretion, and using saliva replacement gels or drops. However, these strategies often do not provide sufficient relief due to the short-term effect they produce. Thus, a strong rationale exists for the development and evaluation of a medication to help treat dry mouth symptoms. Pilocarpine oral tablets (Salagen) are available in at least 24 countries including the USA, Canada and the UK, and a wide range of countries across Europe, South America and Asia, for the treatment of radiation-induced xerostomia and xerostomia as a result of Sjögren’s syndrome. Pilocarpine is a non-selective muscarinic agonist that stimulates the muscarinic cholinergic receptors on the surface of exocrine glands, including salivary glands and sweat glands, resulting in increased salivation and sweating. An oral dose of 5 mg pilocarpine in the form of tablets or capsules to be taken three times daily produces the most effective therapeutic response in terms of subjective relief of dry mouth according to many clinical studies. An oral dosage form of pilocarpine is not commercially available in Australia. Pilocarpine is only commercially available as 1% and 2% eye drops, which are registered on the Australian Register of Therapeutic Goods (ARTG) for the treatment of glaucoma. When these eye drops were given by mouth for the treatment of dry mouth as part of a previous clinical trial, which was done in an inpatient palliative population within a hospital setting, they tasted unpleasant to most of the patients and were not acceptable as a dosage form for dry mouth treatment for that reason. This thesis investigates the potential to use pilocarpine dosage forms that can be compounded in pharmacies for delivering 5 mg pilocarpine in the treatment of dry mouth. ii Two buccally delivered formulations of pilocarpine were selected for study. Buccal delivery was selected, rather than using tablets or capsules that are designed to be swallowed whole and absorbed via the gastrointestinal tract, to optimise pilocarpine delivery to the salivary glands. Troches and orally dissolving tablets (ODTs) containing 5 mg of pilocarpine were compounded and subjected to quality and stability assessments. The ODTs passed the British Pharmacopeia (BP) tests for uniformity of weight and uniformity of drug content. In vitro dispersion time, in vitro disintegration time, in vivo disintegration time, wetting time and water absorption ratio tests all indicated that the compounded ODTs disintegrated instantaneously. The ODTs had an average hardness of 1.28 kg/cm2, as they were compounded by manual moulding rather than conventional tableting machines in which the high pressure applied results in a more compact product. Nonetheless, the ODTs passed the friability test, with no more than 1% loss of weight in the test conditions. The troches passed the BP tests for uniformity of weight and uniformity of drug content, and troches had an average hardness value of 2 kg/cm2 across the three tested batches. Pilocarpine content was assessed during storage of ODTs and troches in their final packaging for up to 18 months, and indicated that storage of ODTs and troches in their final packs for up to one year under shelf life conditions is associated with maintenance of more than 90% of the original pilocarpine content. A pilot study was conducted to establish parameters for the experimental design of an acceptability study. A group of 20 healthy volunteers (age range between 24-39 years, 10 males and 10 females) sucked a whole non-medicated troche until it was completely dissolved and the time was recorded. Participants also sucked flavoured non-medicated troches (lemon, chocolate, mint, raspberry and unflavoured) until they got a sense of flavour, and then spat out the troche; troche weight remaining and time of sucking were recorded. The average time taken to suck a whole troche until completion was 2.29 minutes (SD = 0.73). Participants got a sense of flavour within 10 seconds of sucking troches. The estimated average total quantity of pilocarpine that would be absorbed after sucking five different-flavoured troches, each for 10 seconds, if the troches were medicated, was 1.9 and 1.8 mg when calculated by troche weight change and sucking time respectively. An acceptability study was performed to determine which dosage form and flavour should be selected for use in a clinical trial of a compounded buccal pilocarpine product. Participants were healthy volunteers (n=34) and people with dry mouth (n=14). Seven of the dry mouth participants were previous head and neck cancer patients who were treated with either chemotherapy/radiotherapy and/or surgery, three patients were diagnosed with Sjögren’s syndrome, two patients had medication- induced dry mouth and the other two patients did not identify the cause of their xerostomia. The study was done in two steps. Firstly, participants tasted five medicated troches (lemon, chocolate, mint, raspberry and unflavoured) for 10 seconds and selected their favourite flavour. Secondly, each iii participant tried a non-medicated troche and ODT, both flavoured with the selected favourite flavour, and considered which dosage form they preferred. Participants with dry mouth symptoms completed a 15-question xerostomia questionnaire and rated the change in their flavour preferences before and after experiencing xerostomia. Raspberry was the preferred flavour among the dry mouth participants and lemon among the healthy volunteers. Regarding the dosage form preference, ODTs were the preferred dosage form by 70% of the healthy volunteers and all of the dry mouth participants. The majority of participants with dry mouth reported experiencing changes in their preferences towards two or more of the four flavours tasted as a result of xerostomia. Based upon the results of the acceptability study, the 5 mg pilocarpine raspberry flavoured ODTs were investigated for their efficacy in the treatment of dry mouth of different aetiologies using a series of double-blinded placebo controlled N-of-1 clinical trials in a cohort of 8 participants with dry mouth symptoms. The age of the participants ranged from 37-85 years (median 62.5 years), five participants were males and three were females. An N-of-1 trial is a double-blind, randomised, controlled multi- crossover trial consisting of 3 cycles (18 days of treatment). Each cycle contained two periods: 3- days treatment, 3- days placebo. The first day of each period was considered to be the washout and data collected was not included in analysis. The order of treatment and placebo was randomly allocated for each cycle with the ODTs being taken three times a day before meals. Participants completed questionnaires after each dose and collected saliva samples 1 hour after each morning and evening dose. Eight participants with dry mouth completed the trial. Of these, five (63%) responded to treatment, but for three participants the pilocarpine ODTs did not improve their xerostomia compared to placebo. A detailed report of the results was written and sent to each participant and their Medical Practitioner. In summary, this study has found that ODTs would be an appropriate dosage form for the delivery of pilocarpine in the treatment of xerostomia, but that it may be a useful tool in the treatment of xerostomia for only some patients. Raspberry flavour can be used in compounding the 5 mg pilocarpine ODTs to help disguise the bitter taste of pilocarpine. With the N-of-1 methodology that we adopted in this study, obtaining individualized results for each participant can be easily achieved, with useful detailed information for the participants in terms of their individual response to 5 mg pilocarpine ODTs in comparison to placebo. Future research requires a larger N-of-1 trial, with an estimated 36 participants to complete the 18-day trial to provide a population-estimate of the efficacy of 5 mg pilocarpine ODTs. iv Declaration by author This thesis is composed of my original work, and contains no material previously published or written by