Effect of Gamma-cyclodextrin on the Bioavailability of Ginsenosides

Study Overview
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Brief Summary
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This study will evaluate the relative bioavailability of ginsenosides Rg5, Rk1, and Ck of Red ginseng HRG80 preparations containing gamma-cyclodextrin (GCD) in the blood plasma of healthy subjects after oral administration of two different formulations of HRG80: A. Capsules containing red ginseng preparation HRG80 (reference product) B. Chewable tablets containing red ginseng preparation HRG80 and GCD (modified product). Dissolution testing measures the rate and extend water solubility of ginsenosides from the reference (A) and the modified (B) products. The difference of in vitro dissolution profiles between the reference (A) and modified (B) products will be assessed.

Detailed Description
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A growing body of evidence suggests that gamma-cyclodextrin (GCD) can increase the clinical efficacy of water-insoluble biologically active compounds, which have low bioavailability. GCD is the most bio adaptable and applicable to increase the absorption of many drugs, including ginsenosides of Panax ginseng, by forming inclusion complexes or the form of GCD/drug conjugates. Ginsenosides have absolute bioavailability in the range from 0.2% to 48%, depending on the chemical structure and water solubility. Hypothesis: gamma-cyclodextrin increases absorption and bioavailability of active constituents - Ginsenosides Rg5, Rk1, and Compound K (CK). The study aims to provide experimental evidence supporting or rejecting this hypothesis. Sixteen healthy volunteers will be randomly assigned to receive two formulations, A and B, in two consecutive phases (Phase 1 and Phase) of an open-label study with a crossover design. All patients will provide blood samples in each phase in each phase in 0.5, 0.75, 1, 2, 4, 6, 12, 24, and 48 hours (9 points) after drug administration, following will be a washout period for two weeks. Subjects will be fasting for 10.00 hours before administering the investigational product. They will remain in the clinic post-dose until at least 24.00 hours each period, provided they are not suffering from any adverse event. The concentration of ginsenosides Rg5, Rk1, and Ck in all blood samples will be determined using a validated 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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Dissolution and Pharmacokinetic of Ginsenosides Released From Cyclodextrin Based Chewable Tablets: a Comparative, Randomized, Crossover, Open-label Study in Healthy Human Subjects.

Conditions
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Drug Absorption

Intervention / Treatment
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* Dietary Supplement: HRG80™ Red Ginseng
* Combination Product: HRG80™ Red Ginseng + gamma cyclodextrin


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, the gastrointestinal tract, endocrine organs, or other conditions such as the metabolic disease is 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
Interventional Model Description: A comparative study with the positive control, parallel groups, randomized, crossover design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Red ginseng HRG80<br>16 subjects will receive 200 mg of red ginseng preparation HRG80 in one capsule | Dietary Supplement: HRG80™ Red Ginseng<br>* Capsules containing red ginseng preparation HRG80 capsules, 200 mg - reference product<br>* Other names: HRG80™ Red Ginseng Energy;|
| Experimental: Red ginseng HRG80 incorporated in gamma-cyclodextrin<br>16 subjects will receive 200 mg of red ginseng preparation HRG80 incorporated in gamma-cyclodextrin in two chewable tablets | Combination Product: HRG80™ Red Ginseng + gamma cyclodextrin<br>* Chewable tablets containing red ginseng preparation HRG80 (100 mg) incorporated in gamma-cyclodextrin (GCD) - experimental modified product<br>* Other names: HRG80™ Red Ginseng Energy Chewable;|

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 Rg5. | The changes from the baseline the concentration (ng/ml) of Rg5 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of Rk1. | The changes from the baseline the concentration (ng/ml) of Rk1 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| The area under the plasma concentration versus time curve (AUC, expressed in ng x h/mL) of ginsenoside Ck | The changes from the baseline the concentration (ng/ml) of ginsenoside Ck in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The absorption rate constant (Ka, h-1) of Rg5 | The absorption rate constants (Ka, h-1) of Rg5 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| The absorption rate constant (Ka, h-1) of Rk1 | The absorption rate constants (Ka, h-1) of Rk1 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| The absorption rate constant (Ka, h-1) of Ck | The absorption rate constants (Ka, h-1) of Ck in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Maximum plasma concentration (Cmax, ng/ml), of Rg5 | Maximum plasma concentration (Cmax, ng/ml), of Rg5 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Maximum plasma concentration (Cmax, ng/ml), of Rk1 | Maximum plasma concentration (Cmax, ng/ml), of Rk1 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Maximum plasma concentration (Cmax, ng/ml), of Ck | Maximum plasma concentration (Cmax, ng/ml), of Ck in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Time to reach maximum plasma concentration, Tmax (h) of Rg5 . | Time to reach maximum plasma concentration, Tmax (h) of Rg5 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Time to reach maximum plasma concentration, Tmax (h) of Rk1 | Time to reach maximum plasma concentration, Tmax (h) of Rk1 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Time to reach maximum plasma concentration, Tmax (h) of Ck. | Time to reach maximum plasma concentration, Tmax (h) of Ck in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Mean absorption time MAT (h) of Rg5 | Mean absorption time MAT (h) of Rg5 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Mean absorption time MAT (h) of Rk1 | Mean absorption time MAT (h) of Rk1 in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 
| Mean absorption time MAT (h) of Ck | Mean absorption time MAT (h) of Ck in blood plasma obtained after oral administration of the experimental product A or the active comparator B. | 0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ginsenosides Rg5, Ginsenosides Rk1, Compound K (CK)., Red ginseng HRG80, gamma-cyclodextrin, pharmacokinetic, relative bioavailability