Effect of Gamma-cyclodextrin on the Bioavailability of Ginsenosides

Drug Absorption Clinical Trial

Official title:

Dissolution and Pharmacokinetic of Ginsenosides Released From Cyclodextrin Based Chewable Tablets: a Comparative, Randomized, Crossover, Open-label Study in Healthy Human Subjects.

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04932265
• Other study ID #: EP-1008
• Status: Suspended
• Phase: Phase 1
• Start date: September 1, 2021
• Est. completion date: December 26, 2025

Study information

• Verified date: September 2023
• Source: EuroPharma, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 3
• Est. completion date: December 26, 2025
• Est. primary completion date: December 20, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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).

Related Conditions & MeSH terms

• Drug Absorption

Intervention

Dietary Supplement:
• HRG80™ Red Ginseng
Capsules containing red ginseng preparation HRG80 capsules, 200 mg - reference product

Combination Product:
• HRG80™ Red Ginseng + gamma cyclodextrin
Chewable tablets containing red ginseng preparation HRG80 (100 mg) incorporated in gamma-cyclodextrin (GCD) - experimental modified product

Locations

Country	Name	City	State
Armenia	CARDIOMED Family Health Center, LLC of the Ministry of Health of the Republic of Armenia	Yerevan
Armenia	Institute of Fine Organic Chemistry of the National Academy of Science	Yerevan
Armenia	Scientific Center of Drug and Medical Technologies Expertise	Yerevan
Sweden	Phytomed AB	Vaxtorp	HL

Sponsors (5)

Lead Sponsor	Collaborator
EuroPharma, Inc.	CARDIOMED Family Health Center, LLC of the Ministry of Health of Armenia, Institute of Fine Organic Chemistry of the National Academy of Science Yerevan, Armenia, Phytomed AB, Sweden, Scientific Center of Drug and Medical Technologies Expertise of the Ministry of Health, Armenia

Countries where clinical trial is conducted

Armenia,  Sweden, 

References & Publications (9)

Elshafay A, Tinh NX, Salman S, Shaheen YS, Othman EB, Elhady MT, Kansakar AR, Tran L, Van L, Hirayama K, Huy NT. Ginsenoside Rk1 bioactivity: a systematic review. PeerJ. 2017 Nov 17;5:e3993. doi: 10.7717/peerj.3993. eCollection 2017. — View Citation

Kim HK. Pharmacokinetics of ginsenoside Rb1 and its metabolite compound K after oral administration of Korean Red Ginseng extract. J Ginseng Res. 2013 Oct;37(4):451-6. doi: 10.5142/jgr.2013.37.451. — View Citation

Li Z, Wang M, Wang F, Gu Z, Du G, Wu J, Chen J. gamma-Cyclodextrin: a review on enzymatic production and applications. Appl Microbiol Biotechnol. 2007 Nov;77(2):245-55. doi: 10.1007/s00253-007-1166-7. Epub 2007 Sep 22. — View Citation

Pan W, Xue B, Yang C, Miao L, Zhou L, Chen Q, Cai Q, Liu Y, Liu D, He H, Zhang Y, Yin T, Tang X. Biopharmaceutical characters and bioavailability improving strategies of ginsenosides. Fitoterapia. 2018 Sep;129:272-282. doi: 10.1016/j.fitote.2018.06.001. Epub 2018 Jun 5. — View Citation

Quan LH, Jin Y, Wang C, Min JW, Kim YJ, Yang DC. Enzymatic transformation of the major ginsenoside Rb2 to minor compound Y and compound K by a ginsenoside-hydrolyzing beta-glycosidase from Microbacterium esteraromaticum. J Ind Microbiol Biotechnol. 2012 Oct;39(10):1557-62. doi: 10.1007/s10295-012-1158-1. Epub 2012 Jun 21. — View Citation

Rivero-Barbarroja G, Benito JM, Ortiz Mellet C, Garcia Fernandez JM. Cyclodextrin-Based Functional Glyconanomaterials. Nanomaterials (Basel). 2020 Dec 15;10(12):2517. doi: 10.3390/nano10122517. — View Citation

Tannous M, Caldera F, Hoti G, Dianzani U, Cavalli R, Trotta F. Drug-Encapsulated Cyclodextrin Nanosponges. Methods Mol Biol. 2021;2207:247-283. doi: 10.1007/978-1-0716-0920-0_19. — View Citation

Yoo S, Park BI, Kim DH, Lee S, Lee SH, Shim WS, Seo YK, Kang K, Lee KT, Yim SV, Soung DY, Kim BH. Ginsenoside Absorption Rate and Extent Enhancement of Black Ginseng (CJ EnerG) over Red Ginseng in Healthy Adults. Pharmaceutics. 2021 Apr 2;13(4):487. doi: 10.3390/pharmaceutics13040487. — View Citation

Zhou QL, Zhu DN, Yang YF, Xu W, Yang XW. Simultaneous quantification of twenty-one ginsenosides and their three aglycones in rat plasma by a developed UFLC-MS/MS assay: Application to a pharmacokinetic study of red ginseng. J Pharm Biomed Anal. 2017 Apr 15;137:1-12. doi: 10.1016/j.jpba.2017.01.009. Epub 2017 Jan 6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Relative bioavailability (%) of Rg5 incorporated in gamma-cyclodextrin	Relative bioavailability (%) of Rg5 from 0 to 96 hours defined as the ratio of AUC0-96h for the tested formulation (B) to the AUC0-96h obtained for the reference product (A, 100%), given by the same route of administration in the same dose. F= AUCB/AUCA x 100%.	0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Other	Relative bioavailability (%) of Rk1 incorporated in gamma-cyclodextrin	Relative bioavailability (%) of Rk1 from 0 to 96 hours defined as the ratio of AUC0-96h for the tested formulation (B) to the AUC0-96h obtained for the reference product (A, 100%), given by the same route of administration in the same dose. F= AUCB/AUCA x 100%.	0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Other	Relative bioavailability (%) of Ck incorporated in gamma-cyclodextrin	Relative bioavailability (%) of Ck from 0 to 96 hours defined as the ratio of AUC0-96h for the tested formulation (B) to the AUC0-96h obtained for the reference product (A, 100%), given by the same route of administration in the same dose. F= AUCB/AUCA x 100%.	0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Other	Effect of gamma-cyclodextrin on absorption rate constant (Ka, h-1) of Rg5	The difference in the absorption rate constants (Ka, h-1) of Rg5 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
Other	Effect of gamma-cyclodextrin on absorption rate constant (Ka, h-1) of Rk1	The difference in the absorption rate constants (Ka, h-1) of Rk1 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
Other	Effect of gamma-cyclodextrin on absorption rate constant (Ka, h-1) of Ck	The difference in the absorption rate constants (Ka, h-1) of Ck 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
Other	Effect of gamma-cyclodextrin on the maximal concentration (ng/ml) of Rg5 in blood	The difference in the maximal concentration (ng/ml) of Rg5 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
Other	Effect of gamma-cyclodextrin on the maximal concentration (ng/ml) of Rk1 in blood	The difference in the maximal concentration (ng/ml) of Rk1 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
Other	Effect of gamma-cyclodextrin on the maximal concentration (ng/ml) of Ck in blood	The difference in the maximal concentration (ng/ml) of Ck 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
Other	the dissolution of Rg5	The difference in the dissolution of Rg5 (% of the labeled content, Q) obtained in dissolution testing of the experimental product A or the active comparator B.	0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Other	the dissolution of Rk1	The difference in the dissolution of Rk1 (% of the labeled content, Q) obtained in dissolution testing of the experimental product A or the active comparator B.	0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Other	the dissolution of Ck	The difference in the dissolution of Ck (% of the labeled content, Q) obtained in dissolution testing of the experimental product A or the active comparator B.	0.5, 0.75, 1, 2, 4, 6, 12 and 24 hours, post-dose
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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