A programme to develop a skin patch containing two medicines (physostigmine and hyoscine), Study 1: Assessment of blood levels of the two medicines and any associated symptoms in healthy male participants wearing prototype skin patches

INTERVENTION: 1. Generic drug name: physostigmine and hyoscine (transdermal patch) 2. Dosage: study planned as single dose (72‐hour application) three‐way crossover 3. Method and frequency of administration: design was a randomised, single‐centre, double‐blind, single‐dose (72‐hour application), three‐way crossover study 4. Follow up: safety monitoring, blood sampling for pharmacokinetics and pharmacodynamics, patch adhesion and irritancy assessments, ECG, ocular function assessments and cognitive function assessments were performed for 72 hours after the application of the patch (this included 24 hours after patch removal) The PHP formulations tested were F1, F2 and F3. The patches were identical in size (37 cm2) and shape and only differed in the adhesive used for each group. The plan was for each subject to wear each formulation of the patch in turn for 72 hours occasions separated by a washout period of 4 days between removal and new application. On each occasion, blood samples were taken before and after patch application to measure the amounts of the two medicines (physostigmine and hyoscine). In addition, the activity of the enzyme acetylcholiesterase (AchE) was measured in these blood samples. The effects of the patch were assessed by recording the condition of the skin under the patch at set times and any symptoms that were experienced. Heart rate, blood pressure, electrical activity of the heart (ECG), tests of vision and cognitive function were also recorded at set times. CONDITION: Potential risk of poisoning by nerve agent ; Injury, Occupational Diseases, Poisoning PRIMARY OUTCOME: ; 1. Plasma concentrations of hyoscine and physostigmine measured by liquid chromatography‐tandem mass spectrometry (LC‐MS‐MS)): blood samples collected at the following times: 0 hours (pre‐dose) and 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours after patch application on Day 1, 2, 4, 6, 8, 10, 12 and 24 hours after patch removal; 2. Acetylcholinesterase activity measured by spectrophotometry: blood samples collected at the following times: Day –1, 0 hours (pre‐dose) and 2, 4, 6, 8, 10, 12, 24, 36 and 48 hours after patch application on Day 1; 2, 4, 6, 8, 10, 12 and 24 hours after patch removal; SECONDARY OUTCOME: Adhesion score measured by visual inspection of degree of patch adhesion to skin at 24 and 48 hours after application INCLUSION CRITERIA: 1. Healthy male participants 2. Aged between 18 and 40 years inclusive 3. Body Mass Index (BMI) = 18 and = 31 kg/m2, and body weight = 60 and = 110 kg 4. Able to understand the informed consent discussion, which included information about potential risks and effects of the test materials, and signed the informed consent form 5. Medical history without major pathology (e.g. cardiac, immunological, endocrine or neurological disorders, cancer or other wasting diseases) 6. Human immunodeficiency virus (HIV), hepatitis B and hepatitis C negative 7. No clinically significant abnormalities at the pre‐study screening, and subject’s GP had not advised against inclusion 8. Computerised 12‐lead ECG recording without clinically relevant signs of pathology and conductance disturbances as judged by the investigator