The Absorption of Bioactive Berberine in Human

January 26, 2021 updated by: University of Florida

To Test the Efficacy of Novel Berberine Emulsification by TPGS or Quillaja Extract on the Absorption of Berberine Compared to Berberine Powder in Humans

Berberine from medicinal plants has therapeutic activities against multiple chronic diseases. But its absorption rate is very low. The objective of this study is to test if adding TPGS or Quillaja extract as an emulsifier enhance the absorption of berberine in human.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Berberine is widely used as an herbal medicine and many health benefits. These well-documented in the literature including lowering blood lipids and glucose, having anti-inflammatory and anti-tumor activity, preventing and delaying neurodegenerative diseases (Alzheimer, Parkinson and Huntington disease) and preventing obesity. However, the absorption rate of berberine is very low. The study team believes adding TPGS or Quillaja extract as an emulsifier enhance the absorption of berberine in human.

The bioavailability of berberine is extremely low. Only 0.5% of orally ingested berberine are absorbed in small intestine and about 0.36% can enter the systemic circulation. About 56% of ingested berberine was not absorbed and additional 43.5% is lost due to metabolism in small intestine.

Vitamin E TPGS (a water-soluble form of vitamin E) is a food additive approved by FDA. It has the potential to increase the absorption of drugs and dietary supplements. TPGS is an effective inhibitor of P-glycoproteins that are responsible for decreased absorption rate of many drugs including berberine. TPGS has the potential be a safe and effective adsorption enhancer for berberine and other bioactive botanicals.

Quillaja extract is a natural GRAS (generally recognized as safe) food-grade surfactant/emulsifier ingredient rich in saponins and sapogenins. It is purified from the Quillaja Saponaria Molina tree which is native to Chile. Quillaja extract is an approved ingredient for use in Food and Beverages by FDA under Title 21 CFR 172.51. It is an approved food additive in the European Union under code E 999. Quillaja extract is an attractive alternative emulsifier for berberine formulation because it meets consumers' demand for natural ingredient. Quillaja extract provides additional benefits of anti-inflammation and cholesterol lowering to dietary supplement. Some early study before 2000 suggested that Quillaja saponin DS-1 promote the absorption of insulin and aminoglycoside antibiotics via the ocular and nasal route by reducing permeability of epithelial barrier. However, it is not known whether quillaja affect absorption of berberine in vivo or in human.

Specific Aims:

  1. To determine whether TPGS or Quillaja extract emulsification increase the bioavailability of orally ingested berberine in human volunteers by increasing its plasma concentration time curve (AUC), peak concentration (Cmax), and elimination half time (T1/2).
  2. To determine whether TPGS or Quillaja extract emulsification alter phase I metabolism, phase II metabolism, or metabolism by gut microbiota for orally ingested berberine in human

The hypothesis of this research is that TPGS or Quillaja extract emulsification enhances the bioavailability of orally ingested berberine in human by altering it metabolism and pharmacokinetic profiles.

Advertisement will be in the form of flyers. Contact information of investigators will be included in the flyer. All participants will be received written and oral information regarding the natural and potential risks of the study. The informed consent form will be given to the participants to get consent in a private room 7 days before the study.

Screening, Tolerability Test and Informed Consent: Subject will take two capsules of the reference berberine dietary supplement with 8 ounces of room temperature water and subject will remain in a fasted state for 4 hours. After completing 4 hours period, a standard lunch with water will be served. If subject experiences diarrhea after taking supplement, she/he will immediately report to the Principle Investigator, Dr. Wang or the Study coordinator. The result of tolerability test will base on the self-assessment of diarrhea. Twelve participants will be chosen having no symptoms of diarrhea Experiment process: Participants will be advised to avoid berberine, vitamin E TPGS or Quillaja extract supplements and foods, excessive amount of alcohol from the beginning of 7-day run in period to the end of the study.

Participants will receive three treatments (A: TPGS emulsified berberine or B:Quillaja extract emulsified berberine soft gel and C: berberine reference powder in hard shell capsules) using a randomized crossover design. Treatment A, B and C provide an equal amount of berberine at 800 mg dose.

Twelve healthy subjects will be randomly assigned into three groups with 4 in each group. Subjects will be asked to collect initial urine samples in an 8-ounce container provided by the study team before taking the supplement and the rest of urine samples will be collected in a different container after taking supplement for 12 hours period. A trained and certified phlebotomist will be hired to draw blood. A catcher will be implanted in the participants forearm for blood draw. After a baseline blood sample is taken, four participants in group A will receive at two capsules of TPGS emulsified berberine in soft gel (2x400mg) and four subjects in group B will receive four capsules of the Quillaja extract emulsified berberine (4x200mg) in soft shell capsules, and four participants in group C will receive at two capsules of berberine reference powder (2x400mg) in hard shelf. Additional blood samples will be drawn at 0.5 h, 1 h, 2 h, 3h, 4 h, 6 h, 8 h and 12 h for analysis of plasma concentrations of berberine and berberrubine. In addition, the participants will collect all urine samples in a gallon size plastic container during 12 h after the initial dose. A standard breakfast of plain bagel with cream cheese will be given to each participant between 0.5 h and 1 h blood draw. After 4 h blood draw, subjects will be given an identical meal for lunch. Immediately after collection, blood samples will be centrifuged and plasma will be stored at -80 degrees C until analysis. The urine samples will be stored at -80 degrees C until analysis. After two 7-day washout period, the process will be repeated with each group switching over to the other treatment, that is, the group that received treatment A will take treatment B or C and the group that received treatment B will take treatment A or C, the group that received treatment C will take treatment A or B.

Berberine and dihydroberberine in blood exist in nonconjugate free form. A major metabolite berberrubine exists in free form and phase II metabolites including sulfates and glucuronide. In order to analyze berberrubine in all forms, a portion of plasma or urine will be treated with β-glucuronidase from Helix pomatia to hydrolyze its sulfate/glucuronides. Berberine and berberrubine will be extracted from plasma or urine with or without enzyme treatment using solvent or solid phase extraction. The compounds' concentration will be determined using HPLC-ESI-MS/MS method. Pharmacokinetic parameters such as area under the plasma concentration time curve (AUC), peak concentration (Cmax), time at peak concentration (Tmax), and elimination half time (T1/2) will be calculated for berberines, free berberrubine, and total berberrubine. Relative absorption will be expressed as the ratio of calculated AUC's.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
32

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Gainesville, Florida, United States, 32611
        • Food Science and human nutrition department at University of Florida

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

21 years to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Healthy
  • Normal BMI (20-27)

Exclusion Criteria:

  • Pregnancy
  • Gastro-intestinal conditions
  • Diabetics,
  • Alcohol and substance abuse history,
  • Allergy to berberine,
  • Current berberine use,
  • Use of H2 blockers, proton pump inhibitors, blood sugar-lowering agents, or statins

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Group A - TPGS emulsified with berberine
After an 8-10 hour overnight fast, Group A will receive two soft capsules of TPGS (400mg) emulsified berberine. Following a 7 day wash out period, Group A participants will then receive four capsules of the Quillaja extract emulsified berberine (200mg). Following another 7 day wash out period, Group A participants will then receive two hard shell capsules of the berberine reference powder 400mg. Each TPGS and berberine reference powder capsules contains 400 mg berberine. Each Quillaja extract capsule contains 200 mg berberine. The total amount of berberine throughout is 800 mg.
Dietary supplement: Berberine
Two capsules of berberine. Each capsule contains 400 mg berberine. The total amount of berberine throughout is 800 mg.
Dietary supplement: TPGS emulsified berberine
Two capsules of TPGS/Quillaja extract emulsified berberine. Each capsule contains 400 mg berberine. The total amount of berberine throughout is 800 mg.
Other Names:
  • Berb-Evail
Dietary supplement: Quillaja extract emulsified berberine
Four capsules of Quillaja extract emulsified berberine. Each capsule contains 200 mg berberine. The total amount of berberine throughout is 800 mg.
Experimental: Group B - Quillaja extract emulsified with Berberine
After an 8-10 hour overnight fast, Group B will receive four soft capsules of Quillaja extract emulsified berberine (400mg). Following a 7 day wash out period, Group B participants will then receive two hard shell capsules of the berberine reference powder (400mg). Following another 7 day wash out period, Group B participants will then receive two soft gel capsules of TPGS emulsified berberine (400mg). Each TPGS and berberine reference powder capsules contains 400 mg berberine. Each Quillaja extract capsule contains 200mg berberine. The total amount of berberine throughout is 800 mg.
Dietary supplement: Berberine
Two capsules of berberine. Each capsule contains 400 mg berberine. The total amount of berberine throughout is 800 mg.
Dietary supplement: TPGS emulsified berberine
Two capsules of TPGS/Quillaja extract emulsified berberine. Each capsule contains 400 mg berberine. The total amount of berberine throughout is 800 mg.
Other Names:
  • Berb-Evail
Dietary supplement: Quillaja extract emulsified berberine
Four capsules of Quillaja extract emulsified berberine. Each capsule contains 200 mg berberine. The total amount of berberine throughout is 800 mg.
Experimental: Group C - Berberine reference powder
After an 8-10 hour overnight fast, Group C will receive two hard shell capsules of the berberine reference powder (400mg). Following a 7 day wash out period, Group C participants will then receive two soft gel capsules of TPGS emulsified berberine (400mg). Following another 7 day wash out period, Group C participants will then receive four capsules of the Quillaja extract emulsified berberine (200mg). Each TPGS and berberine reference powder capsules contains 400 mg berberine. Each Quillaja extract capsule contains 200mg berberine. The total amount of berberine throughout is 800 mg.
Dietary supplement: Berberine
Two capsules of berberine. Each capsule contains 400 mg berberine. The total amount of berberine throughout is 800 mg.
Dietary supplement: TPGS emulsified berberine
Two capsules of TPGS/Quillaja extract emulsified berberine. Each capsule contains 400 mg berberine. The total amount of berberine throughout is 800 mg.
Other Names:
  • Berb-Evail
Dietary supplement: Quillaja extract emulsified berberine
Four capsules of Quillaja extract emulsified berberine. Each capsule contains 200 mg berberine. The total amount of berberine throughout is 800 mg.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
AUC:the area under the concentration-time curve
Time Frame: Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12
To determine change in bioavailability of orally ingested berberine in human volunteers by increasing the area under the concentration-time curve (AUC).
Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12
Cmax: maximum plasma concentration
Time Frame: Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12
To determine change in bioavailability of orally ingested berberine in human volunteers by increasing its plasma concentration peak concentration (Cmax).
Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12
Tmax: the time point of maximum plasma concentration
Time Frame: Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12
To determine change in bioavailability of orally ingested berberine in human volunteers by increasing its the time point of maximum plasma concentration (Tmax).
Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Changes in concentrations of berberine metabolites.
Time Frame: Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12
To determine change in berberine metabolites concentrations.
Pre-dose, Hour 0.5, Hour 1, Hour 2, Hour 3, Hour 4, Hour 6, Hour 8 and Hour 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Florida

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Florida High Tech Corridor Council
Designs for Health, Inc.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Liwei Gu, PhD, Univerisity of Florida
  • Study Director: Yavuz Yagiz, PhD, Univerisity of Florida
  • Study Director: Gary P Wang, MD PhD, FIDSA, Univerisity of Florida

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 25, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 11, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 11, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 5, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 12, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 19, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 27, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 26, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2021

More Information

Terms related to this study

Keywords

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IRB201800017
  • OCR17000 (Other Identifier: University of Florida)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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