Title

Magnetic Marker Monitoring of Furosemide-containing Gastroretentive Formulation in Healthy Male Subjects (Fasting and Fed Conditions)
Characterisation of Gastric Residence of a Furosemide-containing New Gastric Retention System by Means of MMM Measurement and Determination of Pharmacokinetics, Pharmacodynamics and Safety
  • Phase

    Phase 1
  • Study Type

    Interventional
  • Status

    Completed No Results Posted
  • Intervention/Treatment

    furosemide ...
  • Study Participants

    10
Furosemide is a diuretic drug, used in the treatment of oedematous states associated with cardiac, renal, and hepatic disorder, and may be effective in patients unresponsive to thiazide diuretics. Furosemide is also used in the treatment of hypertension.

Absorption of furosemide from the gastrointestinal tract is fairly rapid; bioavailability is 60-70%, but variable and not predictable, with large intra- and inter-individual variability, and are influenced by dosage form, underlying diseases, and by the presence of food after oral administration. Data from animal model show that furosemide administered into the stomach is more rapidly absorbed than if is administered into the small intestine.

To increase the residency of furosemide in the stomach after oral administration, a gastroretentive dosage form (GRDF) of furosemide has been developed. In the current study, the new formulation (30mg furosemide coated tablet) will be tested in healthy male subjects. Absorption will be characterised by an effective and safe imaging technique - Magnetic Marker Monitoring (MMM), based on Fe3O4 added to the drug product to generate magnetic signal that can be used for up to 12 h after furosemide administration to localize the medication in the gastrointestinal tract. Fe3O4 is frequently used as colouring pigment in medicinal products. It does not exhibit own pharmacodynamic activity and is considered as an inactive ingredient.

In the current study, GRDF formulation of furosemide will be evaluated for: gastric residence as well as pharmacokinetic and pharmacodynamic characteristics under fasting and fed conditions. As part of the study, the subjects will be hospitalized for 1 day during each drug administration. The duration of the stay will depend on the intestinal behaviour of the investigational product.
Furosemide is a diuretic drug, widely used in the treatment of oedematous states associated with cardiac, renal, and hepatic disorder, and may be effective in patients unresponsive to thiazide diuretics. Furosemide is also used in the treatment of hypertension.

Absorption of furosemide from the gastrointestinal tract is fairly rapid. Bioavailability is reported as 60-70%, but is variable and not predictable. The rate and extent of absorption show a large intra- and inter-individual variability and are influenced by dosage form, underlying diseases, and by the presence of food after oral administration. Results obtained with an animal model indicate that furosemide administered into the stomach is more rapidly absorbed than if is is administered into the small intestine.

To increase the residency of furosemide in the stomach after oral administration, a gastroretentive dosage form (GRDF) of furosemide has been developed. In this study, the new formulation(30mg furosemide coated tablet) will be tested in healthy male subjects. Absorption will be characterised by imaging technique - Magnetic Marker Monitoring (MMM), which is the most effective and safe imaging technique currently available. MMM is based on a iron-III-oxide (Fe3O4) added to the drug product to generate magnetic signal that can be used to localize the administered medication in the gastrointestinal tract.

Fe3O4 is frequently used as colouring pigment in medicinal products. It does not exhibit own pharmacodynamic activity and thus, it is considered as clinically inactive ingredient. Fe3O4 exhibits a dipole moment and thus, after magnetisation of solid oral dosage forms containing homogenously distributed Fe3O4, the product generates a magnetic signal, which can be used for localisation of the dosage form in the gastrointestinal tract by Magnetic Marker Monitoring technique.

The aim of the current study is to evaluate the GRDF formulation of furosemide for: gastric residence, pharmacokinetic and pharmacodynamic characteristics under fasting and fed conditions. As part of the study, the subjects will be hospitalized for 1 day during each drug administration (i.e. a total of two days). The duration of the stay will depend on the intestinal behaviour of the investigational product. The MMM monitoring be performed for up to 12 h after furosemide administration. For pharmacokinetic determinations, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) will be used to analyze furosemide in plasma.
Study Started
Jun 30
2013
Primary Completion
Aug 31
2013
Study Completion
Aug 31
2013
Last Update
Dec 12
2013
Estimate

Drug GRDF furosemide

The GRDF furosemide tablet contains Fe3O4, which serves as an inactive magnetic marker to allow monitoring of the tablet transit through the gastrointestinal tract, using the MMM imaging technique.

  • Other names: GRDF furosemide is a gastro retentive dosage form of furesomide

GRDF furosemide fasting conditions Experimental

Subjects will be tested under fasting conditions after administration of GRDF Furosemide.

GRDF furosemide fed conditions Experimental

Subjects will be tested under fed conditions after administration of GRDF Furosemide.

Criteria

Inclusion Criteria:

sex: male
ethnic origin: Caucasian
age: 18 years to 55 years
body-mass index (BMI): > or = 19 kg/m² and < or = 27 kg/m²
good state of health
non-smoker or ex-smoker for at least 1 month
written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subjects participating in the clinical trial

Exclusion Criteria:

existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient
existing hepatic and/or renal diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient
existing gastrointestinal diseases or pathological findings, which might interfere with the safety and tolerability or with gastric emptying and the gastrointestinal transport (e.g. inflammatory bowel diseases, ileus)
history of relevant central nervous system (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders
any surgery at the gastrointestinal tract, which might interfere with the safety of the test product or any stomach reduction like Bioenterics Intragastric Balloon (BIB) or gastric banding
known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations
known allergic reactions to sulphonamide
subjects with severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
heart rate < 50 bpm or > 90 bpm
systolic blood pressure of < 100 mmHg and > 140 mmHg, diastolic blood pressure of < 60 mmHg and >90 mmHg
laboratory values, especially for sodium, potassium, calcium, creatinine, urea, uric acid, and blood glucose out of normal range unless the deviation from normal is judged as not relevant for the clinical trial by the investigator
positive anti-human immunodeficiency virus-test (if positive to be verified by western blot), surface antigen of the hepatitis B virus (HBs-AG)test [if positive to be verified by test for hepatitis B Core (HBc-IgM)] or anti-hepatitis C virus-test
renal failure with anuria
coma and praecoma hepatica
severe hypokalemia and/or hyponatremia
hypovolemia or dehydration
subjects with manifest or latent diabetes mellitus or gout
subjects with cerebrovascular insufficiency or coronary heart disease
subjects with bladder outlet obstruction (BOO) e.g. prostatic hypertrophy, hydronephrosis or ureteral stenosis
hypoproteinemia
liver cirrhosis and simultaneous limitation of kidney function
acute or chronic diseases which could affect gastric emptying and the gastrointestinal transport
history of or current drug or alcohol dependence
positive alcohol or drug test at screening examination
regular intake of alcoholic food or beverages of ≥ 40 g pure ethanol for male per day
subjects who are on a diet which could affect gastric emptying and the gastro-intestinal transport
regular intake of caffeine containing food or beverages of ≥ 500 mg caffeine per day
subjects with claustrophobia
ferromagnetic implants or any other magnetic disturbance, which can affect the Magnetic Marker Monitoring measurement
blood donation or other blood loss of more than 400 ml within the last two months prior to individual enrolment of the subject
participation in a clinical trial during the last two months prior to individual enrolment of the subject
regular treatment with any systemically available medication including all ototoxic medication like aminoglycosides and medication which could affect gastric emptying and the gastrointestinal transport (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists) or antibiotics
subjects, who report a frequent occurrence of migraine attacks
subjects suspected or known not to follow instructions
subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial
subjects who have forfeited their own freedom by administrative or legal award, or who are under guardianship or have been admitted in a sanitary or social institution
No Results Posted