Healthy
Conditions
Brief summary
to evaluate the bioavailability of ambroxol hydrochloride soft pastilles (test formulation), manufactured by Bolder Arzneimittel GmbH & Co. KG to Boehringer Ingelheim compared to ambroxol hydrochloride syrup (Mucosolvan® adult syrup), manufactured by Boehringer Ingelheim do Brasil Química e Farmacêutica Ltda.
Interventions
DRUGAmbroxol hydrochloride soft pastille
DRUGMucosolvan ® adult syrup
Sponsors
Boehringer Ingelheim
Study design
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* The volunteer is between 18 and 50 years old, is a man or a woman who is not pregnant and/or in breastfeeding regime, and undertakes to use effective birth control method throughout the study period. * Body mass index higher than or equal to 18.5 and lower than or equal to 29.9 kg/m2. * The volunteer is in good health status and is with no clinically significant diseases, at the discretion of the physician as Medical History, measurements of Blood Pressure, Pulse and Temperature, Physical Examination, Electrocardiogram and complementary Laboratory Tests. * Volunteer able to understand the nature and objective of the study, including the risks and adverse effects, with the intention to cooperate with the investigator and act in accordance with the requirements of the entire trial, which has to be confirmed by signing the Informed Consent Form.
Exclusion criteria
* Volunteer has a known hypersensitivity to study drug or chemically related compounds; or to excipients described in adult syrup and/or soft pastille, for example, sorbitol (fructose). * History or presence of gastrointestinal or liver diseases, or other condition that interferes with the absorption, distribution, excretion or metabolism of the drug. * Use of maintenance therapy with any drug, except contraceptives. * Diseases or health problems * History of liver, renal, pulmonary, gastrointestinal, neurological, hematological, psychiatric, cardiac or allergic disease of any cause that requires pharmacological treatment or is considered to be clinically relevant by the investigator; * Electrocardiographic findings not recommended, at the discretion of the investigator the participation in the study. * Additional laboratory test results out of normal values according to the standard of this Potocol, unless they are considered clinically not significant by the investigator. * Tabagism. * Daily intake of more than 5 cups of coffee or tea. * History of alcohol or drug abuse. * Use of regular medication within 2 weeks prior to the initiation of this study, or use of any medication one week before starting this study. * Hospitalization for any reason up to 8 weeks before starting the first treatment period of this study. * Treatment within 3 months prior to this study treatment initiation with any drug that is known to have a well-defined toxic potential in large organs. * Participation in any pharmacokinetic study with more than 300 mL of blood taken or ingested any - study drug within six months preceding the treatment start of this study. * Donation or loss of 450 mL or more of blood within three months preceding the study or who donated more than 1500 mL within 12 months prior to this study treatment initiation. * Pre-Confinement Examination Results * Positive result for urine βHCG test carried out in female volunteers. Other conditions * Any condition that prevents participation in the study as judged by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | 0:00h (hours), 0:15h, 0:30h, 0:45h, 1:00h, 1:15h, 1:30h, 1:45h, 2:00h, 2:20h, 2:40, 3:00, 3:30h, 4:00h, 5:00h, 6:00h, 8:00h, 12:00h, 16:00h, 24:00h, 36:00h and 48:00h | Maximum plasma concentration achieved |
| AUC0-t | 0:00h (hours), 0:15h, 0:30h, 0:45h, 1:00h, 1:15h, 1:30h, 1:45h, 2:00h, 2:20h, 2:40, 3:00, 3:30h, 4:00h, 5:00h, 6:00h, 8:00h, 12:00h, 16:00h, 24:00h, 36:00h and 48:00h | Area under the plasma concentration-time curve, calculated by the trapezoidal methods from time 0 to time t, where t is the time for the last concentration experimentally determined above the Limit of Quantification (LOQ). |
Participant flow
Pre-assignment details
The crossover design 2x2 was used in the study. This is a conventional nonreplicated design with two formulations, two periods, two sequences (RT and TR) where each individual is randomly allocated in one of these sequences.
Participants by arm
| Arm | Count |
|---|---|
| Sequence: TR 01 pastille, single dose of Ambroxol hydrochloride soft pastille 15 mg (Test product) in period 1 and 2.5 mL, single dose, of Mucosolvan ® adult syrup (Reference product) in period 2.
Washout period: 7 days | 18 |
| Sequence: RT 2.5 mL, single dose, of Mucosolvan ® adult syrup (Reference product) in period 1 and 01 pastille, single dose, of Ambroxol hydrochloride soft pastille 15 mg (Test product) in period 2.
Washout period: 7 days | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | Sequence: TR | Sequence: RT | Total |
|---|---|---|---|
| Age, Continuous | 29.39 Years STANDARD_DEVIATION 5.8 | 31.22 Years STANDARD_DEVIATION 7.3 | 30.30 Years STANDARD_DEVIATION 6.6 |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 36 | 0 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
AUC0-t
Area under the plasma concentration-time curve, calculated by the trapezoidal methods from time 0 to time t, where t is the time for the last concentration experimentally determined above the Limit of Quantification (LOQ).
Time frame: 0:00h (hours), 0:15h, 0:30h, 0:45h, 1:00h, 1:15h, 1:30h, 1:45h, 2:00h, 2:20h, 2:40, 3:00, 3:30h, 4:00h, 5:00h, 6:00h, 8:00h, 12:00h, 16:00h, 24:00h, 36:00h and 48:00h
Population: PK set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mucosolvan ® Adult Syrup | AUC0-t | 256.66 ng.h/mL | Geometric Coefficient of Variation 33.36 |
| Ambroxol Hydrochloride Soft Pastille | AUC0-t | 307.00 ng.h/mL | Geometric Coefficient of Variation 28.97 |
p-value: 0.043890% CI: [114.65, 124.79]Anderson-Hauck procedure
Primary
Cmax
Maximum plasma concentration achieved
Time frame: 0:00h (hours), 0:15h, 0:30h, 0:45h, 1:00h, 1:15h, 1:30h, 1:45h, 2:00h, 2:20h, 2:40, 3:00, 3:30h, 4:00h, 5:00h, 6:00h, 8:00h, 12:00h, 16:00h, 24:00h, 36:00h and 48:00h
Population: The pharmacokinetic set (PK Set): 36 subjects provided 1 evaluable value of reference product and 1 evaluable value of test product for the primary PK endpoints (Cmax and AUC0-t) without important protocol violations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Mucosolvan ® Adult Syrup | Cmax | 31.27 ng/mL | Geometric Coefficient of Variation 30.38 |
| Ambroxol Hydrochloride Soft Pastille | Cmax | 35.50 ng/mL | Geometric Coefficient of Variation 28.62 |
p-value: 0.008290% CI: [106.48, 121.1]Anderson-Hauck procedure