Clinical trial NCT04918667: Effect of Gamma-cyclodextrin on the Bioavailability of Berberine
Official title: A Phase I, Randomized, Crossover, Double-blind, Pharmacokinetic Study of Berberine Released From Cyclodextrin in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Drug Absorption
Keywords: Berberine
gamma-cyclodextrin
Pharmacokinetic
Bioavailability
Berberine MetX™ Ultra Absorption
Lead sponsor: EuroPharma, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Scientific Center of Drug and Medical Technologies Expertise of the Ministry of Health, Armenia
name: Cardiomed LLC, Armenia
name: Institute of Fine Organic Chemistry of the National Academy of Science, Armenia
name: Phytomed AB, Sweden
First posted: 2021-06-09
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: In this study, we will evaluate the relative bioavailability of Berberine (BB) from capsules containing Indian Barberry (Berberis aristate DC.) Bark and Root Extract in the blood plasma of healthy subjects after oral administration of:

A. Capsules containing Berberine and GCD (BBA Berberine MetX™ Ultra Absorption, 250 mg) B. Capsules containing Berberine (BB, Berberine MetX™, 500 mg) - (reference product).

Detailed description: Study Background

A growing body of evidence suggests that gamma-cyclodextrin (GCD) can increase the clinical efficacy of water-insoluble biologically active compounds with low bioavailability. GCD is the most bio adaptable and helpful to increase the absorption of many drugs, including Berberine from Indian Barberry (Berberis aristate DC.) Bark and Root Extract by forming inclusion complexes or GCD/drug conjugates.

Berberine has been recommended in traditional practice and recognized by modern science to support healthy blood sugar†, cholesterol and triglyceride levels, and overall metabolic health. But despite these findings, standard Berberine can still be difficult for the body to absorb and use effectively.

It's estimated that only about five percent of any given dosage of Berberine makes it into the bloodstream, so finding a way to enhance absorption is key to the full advantage of its benefits.

Hypothesis: gamma-cyclodextrin increases absorption and bioavailability of Berberine from Berberine MetX™ Ultra Absorption capsules.

The study aims to provide experimental evidence supporting or rejecting this hypothesis.

This will be a double-blind, crossover design, pharmacokinetic study, where 16 healthy human volunteers will be randomly assigned to receive two different formulations BBA, and BB, in two consecutive phases of the study:

* Phase A. All patients take capsules BBA., provide blood samples in 0.5, 0.75, 1, 2, 4, 6, 12, 24, and 48 hours (9 points) after administration following washout period for two weeks.
* Phase B. All patients take capsules BB, provide blood samples in 0.5, 0.75, 1, 2, 4, 6, 12, 24, and 48 hours (9 points) after administration following washout period for two weeks.

Subjects will be in the clinic from not less than 11 hours pre-dose to ensure at least 10 hours fasting before administering the investigational product. They will remain in the facility post-dose until at least 24 hours each period, provided they are not suffering from any adverse event.

The concentration of Berberine in all blood samples will be determined using a validated for a limit of detection, accuracy, and precision analytical method (HPLC-MS) with the internal standard - digoxin. Appropriate mathematical methods and Kinetic 4.4.1 software will be used to generate basic pharmacokinetic parameters.

Eligibility criteria: Inclusion Criteria:

* Healthy volunteers, as determined by medical history, physical examination, and clinical laboratory testing,
* Willingness to stay in the unit overnight for the duration of the study,
* Provide a signed written informed consent.

Exclusion Criteria:

* overweight (BMI \>35 kg/m2),
* pregnancy,
* lactation,
* drug abuse,
* use of dietary supplements or any form of medication (with the exception of oral contraceptives),
* heavy smokers, or ex-smokers with a remote history (\> one pack/day),
* frequent alcohol consumption (\>20 g ethanol/d),
* adherence to a restrictive dietary regimen,
* physical activity of more than 5 h/wk,
* respiratory tract infections, or suspicion thereof in the last 14 days before dosing,
* history or presence of disease in the kidneys and heart, lungs, liver, gastrointestinal tract, endocrine organs or other conditions such as metabolic disease known to interfere with the absorption, distribution, metabolism, and excretion of drugs,
* malignancy,
* autoimmune disorders such as (but not limited to) lupus erythematosus, multiple sclerosis, rheumatoid arthritis, or sarcoidosis,
* any other disease or condition, which, in the opinion of the Investigator, would make the subject unsuitable for this study,
* currently taking medications known to be CYP2C9 inducers (i.e., carbamazepine and rifampicin).

Primary outcomes:
measure: The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of berberine incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose
measure: The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose
Secondary outcomes:
measure: The absorption rate constants (Ka, h-1) of berberine incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose
measure: The absorption rate constants (Ka, h-1) of berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose
measure: Maximum plasma concentration (Cmax, ng/ml) of Berberine incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Maximum plasma concentration (Cmax, ng/ml) of Berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Time to reach maximum plasma concentration, Tmax (h) of berberine incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Time to reach maximum plasma concentration, Tmax (h) of berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Mean absorption time MAT (h) of berberine incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Mean absorption time MAT (h) of berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
Other outcomes:
measure: Relative bioavailability (%) of berberine incorporated in gamma-cyclodextrin
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Effect of gamma-cyclodextrin on absorption rate constant (Ka, h-1) of berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Effect of gamma-cyclodextrin on the maximal concentration (ng/ml) of berberine in blood
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Effect of gamma-cyclodextrin on time (h) to reach maximum plasma concentration of berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
measure: Effect of gamma-cyclodextrin on Mean absorption time (h) of berberine
timeFrame: 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose
Locations:
city: Yerevan
country: Armenia
facility: CARDIOMED Family Health Center, LLC of the Ministry of Health of the Republic of Armenia
city: Yerevan
country: Armenia
facility: Institute of Fine Organic Chemistry of the National Academy of Science
city: Yerevan
country: Armenia
facility: Scientific Center of Drug and Medical Technologies Expertise
city: Vaxtorp
country: Sweden
facility: Phytomed AB
state: HL
Study officials:
affiliation: Scientific Center of Drug and Medical Technologies Expertise of the Ministry of Health, Armenia
name: Aghavni Ginosyan, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CARDIOMED Family Health Center, LLC of the Ministry of Health of the Republic of Armenia
name: Samvel Hairumyan, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Fine Organic Chemistry of the National Academy of Science, Armenia
name: Areg Hovhannisyan, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Phytomed AB, Sweden
name: Alexander G Panossian, PhD
role: STUDY_DIRECTOR
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