Conditions: Healthy
Keywords: Peer Review Research
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 26
Healthy volunteers: yes

Brief summary:
The study to be performed will utilize already FDA-approved marketed products in healthy adults for the purpose to generate data for establishing rate of drug delivery of Transderm Scop® TDDS (transdermal drug delivery system) in healthy adults and to ensure safety of individuals utilizing these types of products.

Detailed description:
Transdermal drug delivery systems (TDDS) available in the form of patches are convenient, attractive, and easy to use systems. Scopolamine patches are very popular TDDS available on the United States market today. Accurate determination of the rate and extent of drug release and absorption is crucial to ensure the safety of individuals using these and other types of patches. Delivery rate can be determined early in the development process by using in vitro skin flux permeation studies, and later in humans by accurately quantifying residual drug from patches post-wear and in pharmacokinetic studies. In this proposal, the investigators will employ two types of evaluation to determine the rate and extent of drug release and absorption from RLD (reference listed drug) Transderm Scop® TDDS (transdermal drug delivery system), namely residual drug analysis post-wear and pharmacokinetic analysis in healthy adult volunteers. In addition, the investigators will compare the plasma drug concentrations following patch and intravenous administration of Scopolamine, in order to determine the absolute bioavailability of these patches. The investigators will conduct residual drug analysis of TDDS following in vivo wear using highly sensitive validated quantification methods. Positive outcomes of this project will identify appropriate methods to determine the rate and extent of drug release and absorption from TDDS, and will help regulatory agencies in the development of Guidances for Industry regarding the characterization of drug release and absorption kinetics to ensure the safety of individuals utilizing these types of products

Arms:
arm 1: Each of the subjects will receive a single intravenous dose of 0.4 mg scopolamine hydrobromide and will wear the Transderm Scop® patch (1.5 mg) for 3 days in a crossover design with adequate washout in between. Subjects will be randomized to Group 1 (Transderm Scop® first followed by intravenous scopolamine hydrobromide) and remaining subjects will be randomized to Group 2 (intravenous scopolamine hydrobromide first followed by Transderm Scop®). arm 2: Each of the subjects will receive a single intravenous dose of 0.4 mg scopolamine hydrobromide and will wear the Transderm Scop® patch (1.5 mg) for 3 days in a crossover design with adequate washout in between. Subjects will be randomized to Group 1 (Transderm Scop® first followed by intravenous scopolamine hydrobromide) and remaining subjects will be randomized to Group 2 (intravenous scopolamine hydrobromide first followed by Transderm Scop®).

Interventions: intervention 1: Transderm Scop® intervention 2: Intravenous scopolamine hydrobromide
Intervention descriptions: intervention 1: TDDS dosage is 1.5 mg/72 hrs intervention 2: 0.4 mg via intravenous injection

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
ABSOLUTE BIOAVAILABILITY/PHARMACOKINETIC AND RESIDUAL DRUG ANALYSIS 
OF THE TRANSDERM SCŌP® SYSTEM IN HEALTHY ADULTS 
 
Short title: Scopolamine Release from Transdermal Patches in Healthy Adults 
 
Principal Investigator: 
Nicole K. Brogden (contact), PharmD, PhD 
 
Medically Accountable Investigator: 
Ken-ichi Ueda, MD 
 
 
Principal investigator contact:  
Nicole K. Brogden, PharmD, PhD 
Assistant Professor, Department of Pharmaceutical Sciences and Experimental Therapeutics 
University of Iowa College of Pharmacy 
115 S. Grand Ave, S421 
Iowa City, IA 52242 
Phone: 319-335-8752 
Fax: 319-335-9349 
Email: nicole-brogden@uiowa.edu 
 
 
09 December 2016 
 
 
 


 
 
 
 
Study title:  
 
Absolute Bioavailability/Pharmacokinetic and Residual 
Drug Analysis of the Transderm Scōp® System in Healthy 
Adults  
Principal Investigator 
 
Population: 
 
Nicole K. Brogden, PharmD, PhD 
 
Healthy, non-smoking adults age 18-65 years  
Number of Sites: 
 
Single site: University of Iowa College of Pharmacy/ 
University of Iowa Clinical Research Unit  
Study Duration: 
 
Approximately up to 12 months 
 
Subject Participation Duration: 
Approximately 5 – 7 weeks, including the screening period 
Description of Study Design 
This will be a two arm, open-label, crossover, two treatment sessions study (n=24 healthy adult subjects) 
with one week washout period between each study session. The two study sessions include an intravenous 
administration of scopolamine hydrobromide and a transdermal administration of a single strength of the 
reference listed drug (RLD) Transderm Scōp® patch. Each subject will be his/her own control.  
 
Study products 
 
Transderm Scōp® patch containing scopolamine (1.5 mg) to be worn for 3 days (72 hr) 
 
Single intravenous (0.4 mg) administration of scopolamine hydrobromide (0.4 mg/mL) 
 
Study enrollment 
Only adult subjects who meet the inclusion/exclusion criteria will be eligible for enrollment into the 
study. Twenty-four subjects will be recruited, and ten alternates who could replace subjects who drop out 
from the study for any unforeseen reason. The study population selected for this study includes healthy 
adult men and women ages 18 to 65, inclusive. Enrollment will continue until 24 complete the study. The 
selection criteria are designed to exclude persons who might have medical conditions that could pose a 
safety risk and persons whose medical conditions might interfere with objectives and results of the study. 
 
Inclusion Criteria 
Subjects are eligible for this study if they fulfill the inclusion criteria specified below: 
1. Men or non-pregnant women of any ethnic background between the age of 18 and 65 years old. 
2. Subjects must be non-smokers (must have refrained from the use of nicotine-containing substances, 
including tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, patch or electronic 
cigarettes) over the previous 12 months and are not currently using tobacco products. 
3. Provide written informed consent before initiation of any study procedures. 
4. Available for follow-up for the planned duration of the study. 
5. Able to communicate well with the investigators.  
6. Able to adhere to the study protocol schedule, study restrictions and examination schedule.  
7. Subjects who are within their ideal body weight (BMI between 18-29.9 kg/m2). 
8. Demonstrate comprehension of the protocol procedures and knowledge of study, as demonstrated a 
study member filling out a consent checklist form to verify that the subject understands all aspects of 
the study including the purpose, procedures, risks and benefits. 


 
 
 
 
9. Subjects deemed to be healthy as judged by the Medically Accountable Investigator (MAI) and 
determined by medical history, physical examination, and medication history. 
10. Negative urine drug screening test.   
11. Have a normal blood pressure (systolic: 90-140 mmHg; diastolic: 50-90 mmHg) and heart rate (55-
100 bpm). 
12. Have normal screening laboratories for WBC, Hgb, Hct, platelets, sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, ALT, AST, and total bilirubin. 
13. Have normal screening laboratories for urine protein and urine glucose.  
14. Female subjects must be of non-childbearing potential (defined as surgically sterile [i.e. history of 
hysterectomy or tubal ligation] or postmenopausal for more than 1 year [no bleeding for 12 
consecutive months]), or if of childbearing potential must be non-pregnant at the time of enrollment 
and on the morning of the first day of each study treatment session, and must agree to use hormonal 
or barrier birth control such as implants, injectables, combined oral contraceptives, some intrauterine 
devices (IUDs), sexual abstinence, or a vasectomized partner.  
15. Agrees not to participate in another clinical study during the study period unless the study is in the 
follow up phase and it has been 1 month since the subject received any experimental agents or 
treatments. The subject also agrees not to participate in an investigational drug study for at least 1 
month after last procedure day. 
16. Agrees not to donate blood to a blood bank throughout participation in the study and for at least 2 
months after last procedure day. 
17. Have a normal ECG; must not have the following to be acceptable: pathologic Q wave abnormalities, 
significant ST–T wave changes, left ventricular hypertrophy, right bundle branch block, left bundle 
branch block (sinus rhythm is between 55–100 beats per minute).  
Exclusion Criteria 
Subjects will be excluded for any of the following conditions/reasons: 
1. Women who are pregnant or lactating or have a positive serum pregnancy test at enrollment or 
positive urine pregnancy test on the morning of the first day of any procedure session.  
2. Smokers (current use or use over the previous 12 months of nicotine-containing substances, including 
tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, patch or electronic cigarettes)). 
3. Participation in any ongoing investigational drug trial or clinical drug trial period unless the study is 
in the follow up phase and it has been ≥ 1 month since the subject received any experimental agents 
or treatments..  
4. Abnormal vital signs, defined as:  
 
Hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 
mmHg) at rest on 2 separate days. 
 
Heart rate <55 at rest on 2 separate days 
 
Respiratory rate ≤ 11 to ≥ 18 breaths per minute 
5. Temperature >38.0ºC (100.4ºF) or symptoms of an acute self-limited illness such as an upper 
respiratory infection or gastroenteritis within 7 days of application of the scopolamine TDDS. 
6. History of chronic obstructive pulmonary disease. 
7. Positive urine drug screening test. 
8. Use of any prescription medication during the period 0 to 30 days or over-the counter medication 
during the period 0 to 3 days before entry to the study (vitamins, herbal supplements and birth control 
medications not included).  
9. Use of medications or treatments that would significantly influence or exaggerate responses to the test 
product or that would alter inflammatory or immune response to the product (e.g. antihistamines 
[within 72 hours prior to dosing], systemic or topical corticosteroids [within 3 weeks prior to dosing], 
cyclosporine, tacrolimus, cytotoxic drugs, immune globulin, Bacillus Calmette-Guerin [BCG], 
monoclonal antibodies, radiation therapy).  


 
 
 
 
10. Donation or loss of greater than one pint of blood within 60 days of entry to the study.  
11. Any prior serious adverse reaction or hypersensitivity to scopolamine, or any of the inactive 
ingredients in the patch (light mineral oil, polyisobutylene, polypropylene and aluminized polyester 
film).  
12. Have a diagnosis of schizophrenia or other major psychiatric diagnosis.  
13. Received an experimental agent (vaccine, drug, biologic, device, blood product or medication) within 
1 month before enrollment in this study or expects to receive an experimental agent during the study.  
14. Medical history of a serious chronic condition, including (but not limited to):  allergic conditions such 
as anaphylaxis, asthma or generalized drug reactions; any seizure disorder; glaucoma (open or closed 
angle); history of pyloric or urinary bladder neck obstruction; intestinal obstruction; difficulty 
swallowing; stomach or bowel problems (e.g, blockage, muscle weakness, ulcerative colitis, Crohn’s 
disease); bleeding disorders; acid reflux disease; myasthenia gravis; allergy to belladonna alkaloids; 
impaired hepatic or renal function. 
15. Any condition that would, in the opinion of the MAI, place the subject at an unacceptable risk of 
injury or render the subject unable to meet the requirements of the protocol.  
16. Inability to communicate or co-operate with the investigators.  
17. Medical history of significant dermatologic diseases or conditions, such as atopy, psoriasis, vitiligo or 
conditions known to alter skin appearance or physiologic response (e.g. diabetes, porphyria). 
18. History of significant dermatologic cancers (e.g. melanoma, squamous cell carcinoma), except basal 
cell carcinomas that were superficial and did not involve the investigative site. 
19. History of consumption of alcohol within 24 hours prior to dose administration.  
20. Subject has an obvious difference in skin color between arms or the presence of a skin condition, 
excessive hair at the application site, sunburn, raised moles and scars, open sores at application site, 
scar tissue, tattoo, or coloration that would interfere with placement of test articles, skin assessment, 
or reactions to drug.  
21. Use of monoamine oxidase inhibitors 21 days prior to study. 
22. Within 4 weeks prior to dosing, use of medications or treatments that would significantly influence or 
exaggerate responses to the test product or that would alter inflammatory or immune response to the 
product or agents deemed to be immunosuppressive as determined by physician investigator. 
23. Planned MRI scan of the head during TDDS wear. 
Study schedule 
For the treatments, either the patch will be applied behind the ear or the drug will be intravenously 
administered. Blood samples will be obtained as follows (based on administration route): 
 
60 min pre-application and then up to 120 hr (5 days), during 3 day wear and 2 day post patch 
removal 
 
60 min pre-IV administration and then up to 48 hr (2 days) post start of IV administration 
 
Residual drug analysis determination of strength  
In conjunction with the above described study, residual drug analysis will also be conducted for the worn 
patches. All items coming into contact with the patch during application and removal from the subject and 
storage for analytical retention are analyzed for drug content. 
 
After application of the patch to the subject, the pouch, release liner and all items coming into contact 
with the patch are retained for analysis.  
 
The worn patch is retained for drug content analysis.  
 
Upon removal of the product after prescribed wear period, the skin (at site of application) is swabbed 
and the swab is retained for drug content analysis. 
 
 
 


 
 
 
 
Study Objectives 
The objectives of these studies are: 1) to determine the absolute bioavailability of scopolamine patch, 2) 
to determine the residual drug content in worn patches, and 3) determine absorption rates from patches 
based on residual drug content and derived PK parameters. 
 
Study Outcome Measures 
The outcomes of this study ae to determine pharmacokinetic parameters of scopolamine in healthy adult 
subjects. The primary outcome measure of the study is to determine the maximum serum concentration of 
scopolamine (Cmax). The secondary outcome measures include clearance (Cl), volume of distribution (V), 
elimination rate constant (Kel), time of maximum serum concentration (Tmax) of scopolamine, and area 
under the serum concentration-time curve (AUC). In addition, we will determine residual drug content 
from worn Transderm Scōp® patches to estimate total amount of absorbed scopolamine. 
 
Pharmacokinetic and statistical considerations 
Pharmacokinetics (PK) Analyses 
Scopolamine concentrations will be measured in serum samples collected from each subject. Actual 
sampling times will be used to estimate PK parameters. Non compartmental and compartmental analyses 
will be conducted to estimate the primary PK parameters such as clearance (Cl), volume of distribution 
(V), elimination rate constant (Kel), maximum serum concentration (Cmax); time of maximum serum 
concentration (Tmax) and area under the serum concentration-time curve (AUC). Absolute bioavailability 
will be calculated as follows:    
 
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑏𝑖𝑜𝑎𝑣𝑖𝑙𝑎𝑏𝑖𝑙𝑖𝑡𝑦= 
𝐴𝑈𝐶𝑝𝑎𝑡𝑐ℎ/𝐷𝑜𝑠𝑒𝑝𝑎𝑡𝑐ℎ
𝐴𝑈𝐶𝐼𝑉/𝐷𝑜𝑠𝑒𝐼𝑉
 
Equation 1: For determination of the absolute bioavailability for the Transderm Scōp® patch.  The patch 
refers to the Transderm Scōp® transdermal system. 
 
Statistical Analysis Plan 
Descriptive statistics for drug content (i.e., arithmetic mean, median, standard deviation, minimum 
amount, maximum amount, coefficient of variation) will be calculated. In addition, mass balance will be 
calculated. Drug content in the unworn patch will be analyzed, the mean amount will be calculated and 
will be used to estimate amount of drug absorbed after wearing the transdermal system. Unworn systems 
will all be from the same lot (as printed on the patch pouch), and a minimum of 10 unworn systems will 
be analyzed for drug content. Drug absorption will be determined by subtracting the residual drug content 
from the initial drug amount as mentioned on the product label.