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Technical Problems with sensitivity of mass spectral detector
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| Name | Class |
|---|---|
| Phytomed AB, Sweden | UNKNOWN |
| Scientific Center of Drug and Medical Technologies Expertise of the Ministry of Health, Armenia | UNKNOWN |
| CARDIOMED Family Health Center, LLC of the Ministry of Health of Armenia |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Red ginseng HRG80 | Active Comparator | 16 subjects will receive 200 mg of red ginseng preparation HRG80 in one capsule |
|
| Red ginseng HRG80 incorporated in gamma-cyclodextrin | Experimental | 16 subjects will receive 200 mg of red ginseng preparation HRG80 incorporated in gamma-cyclodextrin in two chewable tablets |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| HRG80™ Red Ginseng | Dietary Supplement | Capsules containing red ginseng preparation HRG80 capsules, 200 mg - reference product |
|
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Aghavni T Ginosyan, PhD, MD | Scientific Center of Drug and Medical Technologies Expertise of the Ministry of Health of the Republic of Armenia | Principal Investigator |
| Samvel Hairumyan, PhD, MD | CARDIOMED Family Health Center, LLC of the Ministry of Health of the Republic of Armenia | Principal Investigator |
| Areg Hovhannisyan PhD of A Hovhannisyan | Institute of Fine Organic Chemistry of the National Academy of Science, Armenia | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CARDIOMED Family Health Center, LLC of the Ministry of Health of the Republic of Armenia | Yerevan | Armenia | ||||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33918329 | Background | 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. | |
| 28086165 | Background |
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| ID | Term |
|---|---|
| C023792 | gamma-cyclodextrin |
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| Institute of Fine Organic Chemistry of the National Academy of Science Yerevan, Armenia | UNKNOWN |
A comparative study with the positive control, parallel groups, randomized, crossover design
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| HRG80™ Red Ginseng + gamma cyclodextrin | Combination Product | Chewable tablets containing red ginseng preparation HRG80 (100 mg) incorporated in gamma-cyclodextrin (GCD) - experimental modified product |
|
|
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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Institute of Fine Organic Chemistry of the National Academy of Science |
| Yerevan |
| Armenia |
| Scientific Center of Drug and Medical Technologies Expertise | Yerevan | Armenia |
| Phytomed AB | Våxtorp | HL | 31275 | Sweden |
| 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. |
| 29158964 | Background | 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. |
| 24235859 | Background | 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. |
| 29883635 | Background | 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. |
| 22717707 | Background | 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. |
| 33113141 | Background | 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. |
| 33333914 | Background | 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. |
| 17891389 | Background | 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. |