Effect of Gamma-cyclodextrin on the Bioavailability of Berberine

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I, Randomized, Crossover, Double-blind, Pharmacokinetic Study of Berberine Released From Cyclodextrin in Healthy Volunteers

Conditions
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Drug Absorption

Intervention / Treatment
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* Combination Product: Berberine incorporated in gamma cyclodextrin
* Dietary Supplement: Berberine


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Berberine MetX™ Ultra Absorption<br>16 healthy subjects will receive orally 500 mg of berberine in two capsules of Berberine MetX™ Ultra Absorption. | Combination Product: Berberine incorporated in gamma cyclodextrin<br>* Experimental modified product. One capsule contains 250 mg of Berberine from Indian Barberry (Berberis aristate DC.) Bark and Root Extract incorporated in gamma-cyclodextrin<br>* Other names: Berberine MetX™ Ultra Absorption, 250 mg;|
| Active Comparator: Berberine MetX™<br>16 healthy subjects will receive orally 500 mg of berberine in one capsule of Berberine MetX™ (reference product). | Dietary Supplement: Berberine<br>* Active comparator. One capsule contains 500 mg of Berberine from Indian Barberry (Berberis aristate DC.) Bark and Root Extract<br>* Other names: Berberine MetX™, 500 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of berberine incorporated in gamma-cyclodextrin | The changes from the baseline the concentration (ng/ml) of berberine in blood plasma obtained after oral administration of the experimental product BBA. | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose | 
| The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of berberine | The changes from the baseline the concentration (ng/ml) of berberine in blood plasma obtained after oral administration of the active comparator BB. | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The absorption rate constants (Ka, h-1) of berberine incorporated in gamma-cyclodextrin | The absorption rate constants (Ka, h-1) of berberine obtained after oral administration of the experimental modified product BBA. | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose | 
| The absorption rate constants (Ka, h-1) of berberine | The absorption rate constants (Ka, h-1) of berberine obtained after oral administration of the active comparator BB. | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 and 96 hours, post-dose | 
| Maximum plasma concentration (Cmax, ng/ml) of Berberine incorporated in gamma-cyclodextrin | Maximum plasma concentration (Cmax, ng/ml), of berberine obtained after oral administration of the experimental modified product BBA | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose | 
| Maximum plasma concentration (Cmax, ng/ml) of Berberine | Maximum plasma concentration (Cmax, ng/ml), of berberine - obtained after oral administration of the active comparator BB. | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose | 
| Time to reach maximum plasma concentration, Tmax (h) of berberine incorporated in gamma-cyclodextrin | Time to reach maximum plasma concentration, Tmax (h) of berberine obtained after oral administration of the experimental modified product BBA | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose | 
| Time to reach maximum plasma concentration, Tmax (h) of berberine | Time to reach maximum plasma concentration, Tmax (h) of berberine obtained after oral administration of the active comparator BB. | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose | 
| Mean absorption time MAT (h) of berberine incorporated in gamma-cyclodextrin | Mean absorption time MAT (h) of berberine obtained after oral administration of the experimental modified product BBA | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose | 
| Mean absorption time MAT (h) of berberine | Mean absorption time MAT (h) of berberine obtained after oral administration of the active comparator BB | 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72, and 96 hours, post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Berberine, gamma-cyclodextrin, Pharmacokinetic, Bioavailability, Berberine MetX™ Ultra Absorption