SUPPLEMENT THAT ENHANCES INTRACELLULAR CONCENTRATION OF BIOACTIVE MOLECULES THROUGH INHIBITION OF MULTIDRUG RESISTANT (MDR) EFFLUX PUMPS

Abstract

Described is a natural product-containing supplement that enhances intracellular concentration of bioactive molecules through inhibition of MDR efflux pumps. Specifically described are dosage forms for administration to a subject, the dosage forms having at least four ingredients selected from the group consisting of apigenin, cannabidiol, chrysin, harmine, caffeic acid, piperine, nobiletin, Hypericum perforatum extract, bee propolis, oleanolic acid, biochanin, luteolin, vanillin, honokiol, pterostilbene, and withaferin A. Upon administration to a mammalian subject, the dosage forms generally inhibit mis-regulated MDR efflux pumps that are responsible for pushing out good nutrients from the cell—thus increasing intracellular concentration of health-promoting compounds.

Claims

1. A dosage form for administration to a subject, the dosage form comprising at least four ingredients selected from the group consisting of apigenin, cannabidiol, chrysin, harmine, caffeic acid, piperine, nobiletin, Hypericum perforatum extract, bee propolis, oleanolic acid, biochanin, luteolin, vanillin, honokiol, pterostilbene, and withaferin A.

2. The dosage form of claim 1, wherein the dosage form further comprises one or more of chitosan, menthol, piperine, or yucca saponins.

3. The dosage form of claim 2, wherein the dosage form comprises from about 140 to about 205 milligrams of chitosan, from about 5 to about 30 milligrams of menthol, and/or from about 100 to about 400 milligrams of yucca saponins.

4. The dosage form of claim 1, wherein the selected at least four ingredients, when present, are present in the following amounts: from about 25 to about 150 milligrams of apigenin, from about 7 to about 30 milligrams of cannabidiol, from about 180 to about 240 milligrams of chrysin, from about 8 to about 25 milligrams of harmine, from about 75 to about 180 milligrams of caffeic acid, from about 8 to about 30 milligrams of piperine, from about 60 to about 100 milligrams of nobiletin, from about 200 to about 525 milligrams of Hypericum perforatum extract, from about 275 to about 410 milligrams of bee propolis, from about 50 to about 120 milligrams of oleanolic acid, from about 5 to about 30 milligrams of biochanin, from about 20 to about 60 milligrams of luteolin, from about 10 to about 30 milligrams of vanillin, from about 10 to about 40 milligrams of honokiol, from about 180 to about 215 milligrams of pterostilbene, and from about 60 to about 100 milligrams of withaferin a.

5. The dosage form of claim 1, wherein the dosage form is selected from the group consisting of a softgel, capsule, tablet, gel, powder, gummy, liquid, effervescent, bar, topical patch, serum, lotion, and cream.

6. The dosage form of claim 1, further comprising: at least one other active ingredient that is pumped out of a subject's cell by at least one efflux pump(s).

7. The dosage form of claim 1, comprising: cannabidiol, bee propolis, chrysin, piperine, chitosan, luteolin, and trans-pterostilbene.

8. A method of enhancing intracellular concentration of at least one bioactive molecule in a subject, the method comprising: administering the dosage form of claim 1 to the subject.

9. A method of enhancing intracellular concentration of at least one bioactive molecule in a subject, the method comprising: administering a combination of at least four selected ingredients to the subject, wherein the at least four ingredients are selected are from the group consisting of apigenin, cannabidiol, chrysin, harmine, caffeic acid, piperine, nobiletin, Hypericum perforatum extract, bee propolis, oleanolic acid, biochanin, luteolin, vanillin, honokiol, pterostilbene, and withaferin A, wherein administration of the composition regulate at least four efflux pumps of the subject, wherein the efflux pumps are selected from the group consisting of efflux pumps ABCG2 (more commonly referred to as Breast Cancer Resistance Protein or “BCRP”), Cytochrome P.sub.4502C8 (“CYP2C8”), MDR-TB, multidrug resistance-associated protein 1 (“MRP1” or “ABCC1”), Multidrug resistance-associated protein 2 (“MRP2,” “canalicular multispecific organic anion transporter 1,” “cMOAT,” ATP-binding cassette sub-family C member 2 (“ABCC2”), P-glycoprotein (P-glycoprotein 1 also known as multidrug resistance protein 1, ATP-binding cassette sub-family B member 1 or “P-gp”), and UGT-1A9 (UDP glucuronosyltransferase family 1 member A9).

10. The method according to claim 9, wherein the subject ingests the selected at least four ingredients, when selected, in the following amounts on a daily basis: from about 25 to about 150 milligrams of apigenin, from about 7 to about 30 milligrams of cannabidiol, from about 180 to about 240 milligrams of chrysin, from about 8 to about 25 milligrams of harmine, from about 75 to about 180 milligrams of caffeic acid, from about 8 to about 30 milligrams of piperine, from about 60 to about 100 milligrams of nobiletin, from about 200 to about 525 milligrams of Hypericum perforatum extract, from about 275 to about 410 milligrams of bee propolis, from about 50 to about 120 milligrams of oleanolic acid, from about 5 to about 30 milligrams of biochanin, from about 20 to about 60 milligrams of luteolin, from about 10 to about 30 milligrams of vanillin, from about 10 to about 40 milligrams of honokiol, from about 180 to about 215 milligrams of pterostilbene, and from about 60 to about 100 milligrams of withaferin a.

11. A method of enhancing intracellular concentration of at least one bioactive molecule in a subject, the method comprising: administering the dosage form of claim 1 to the subject so as to enhance intracellular concentration of the at least one bioactive molecule in the subject.

12. A method of making the dosage form of claim 1, the method comprising: admixing the selected ingredients to form an admixture, and associating the admixture into or with the dosage form.

13. The method according to claim 12, further comprising including an inactive ingredient and/or at least one pharmaceutical excipient into the admixture.

Description

DETAILED DESCRIPTION

[0024] Phytonutrients are the “medicinal” component of plants and are commonly a starting point in the drug discovery process. The phytonutrients described herein have generally been extracted (e.g., from raw plant/fungal material) and/or standardized to the respective compounds for assimilation into the dosage form(s). Such processing increases reproducibility and quality, reduces the bulk of the selected phytonutrients and allows for smaller, easier to swallow dosage forms.

[0025] Although the phytonutrients (and other ingredients) are readily commercially available, processes for extracting phytonutrients are known in the art and may be advantageously utilized herein.

[0026] Efflux pumps relevant to this disclosure include ABCG2 (more commonly referred to as Breast Cancer Resistance Protein or “BCRP”), Cytochrome P.sub.4502C8 (“CYP2C8”), MDR-TB, multidrug resistance-associated protein 1 (“MRP1” or “ABCC1”), Multidrug resistance-associated protein 2 (“MRP2”) also called canalicular multispecific organic anion transporter 1 (“cMOAT”) or ATP-binding cassette sub-family C member 2 (“ABCC2”), P-glycoprotein (P-glycoprotein 1 also known as multidrug resistance protein 1, ATP-binding cassette sub-family B member 1 or “P-gp”), and UGT-1A9 (UDP glucuronosyltransferase family 1 member A9).

[0027] Examples of substances that are useful for incorporation in the dosage forms described herein include apigenin, cannabidiol, chrysin, harmine, caffeic acid, piperine, nobiletin, Hypericum perforatum extract, bee propolis, oleanolic acid, biochanin, luteolin, vanillin, honokiol, pterostilbene, and withaferin A. Each such substance is a naturally occurring, albeit purified product (e.g., a flavonoid) that inhibits at least one MDR efflux pump in a subject's cell. Taken together (e.g., administered to a subject who would benefit from such therapy in a non-naturally occurring combination of at least four such substances at dosages and as described herein), the combined substances are believed to act synergistically to inhibit the activity of various MDR efflux pumps in a cell (and at the micromolar level) to reduce ejection of various different beneficial phytonutrients from the treated cell, which joint action greatly enlarges the range of each substance's inherent function, activity, and utility. Such synergistic action reduces ejection of the various bioactive health-promoting compounds from the subject's cells by inhibiting several (e.g., at least four) different MDR efflux pumps as described herein, which pumps would otherwise work together to remove the health-promoting compounds from the cell. Administration of the described dosage forms to a subject thus allows the health-promoting compounds to act beneficially in the cell for a longer period of time, thus treating the subject and/or preventing the occurrence of a malady.

[0028] Apigenin is a flavone that is readily commercially available. It has been used as a traditional medicine due to its physiological functions as an antioxidant and anti-inflammatory, its role in lowering blood pressure, and its antibacterial and antiviral properties. Apigenin inhibits the P-gp, BCRP, and MRP2 efflux pumps. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 25 to about 150 milligrams of apigenin. The amount can be adjusted for divided doses of the dosage form.

[0029] Cannabidiol (“CBD”) is a compound that is readily commercially available. Cannabidiol inhibits the P-gp efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 7 to about 30 milligrams of cannabidiol. The amount can be adjusted for divided doses of the dosage form.

[0030] Chrysin is a flavone that is readily commercially available. It has been used for bodybuilding, treating anxiety, inflammation, gout, HIV/AIDS, preventing cancer, erectile dysfunction (ED), and baldness. It inhibits the BCRP efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 180 to about 240 milligrams of chrysin. The amount can be adjusted for divided doses of the dosage form.

[0031] Harmine is a compound that is readily commercially available. It has been used for treating diabetes. It inhibits the BCRP efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 8 to about 25 milligrams of harmine. The amount can be adjusted for divided doses of the dosage form.

[0032] Caffeic acid is a compound that is readily commercially available. It inhibits the P-gp, MRP1, MRP2, and BCRP efflux pumps. It is used in supplements for boosting athletic performance, exercise-related fatigue, weight loss, cancer, HIV/AIDS, and herpes. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 75 to about 180 milligrams of caffeic acid. The amount can be adjusted for divided doses of the dosage form.

[0033] Piperine is a compound that is readily commercially available. It has been shown to help relieve nausea, headaches, and poor digestion and has anti-inflammatory properties. It inhibits the P-gp, CYP2C8, BCRP, MRP1, and MRP2 efflux pumps. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 8 to about 30 milligrams of piperine. The amount can be adjusted for divided doses of the dosage form.

[0034] Nobiletin is a flavonoid that is readily commercially available. It has been used to rescue bulbectomy-induced memory impairment. It inhibits the P-gp, and MRP1 efflux pumps. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 60 to about 110 milligrams of nobiletin. The amount can be adjusted for divided doses of the dosage form.

[0035] Hypericum perforatum extract (“St. John's Wort”) that is readily commercially available. The extract is known to have antidepressant properties and has been used to treat mild to moderate depression, anxiety, and sleep disorders. It inhibits the P-gp, and MRP1 efflux pumps. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 200 to about 525 milligrams of H. perforatum extract. The amount can be adjusted for divided doses of the dosage form.

[0036] Bee propolis is readily commercially available. It inhibits the P-gp, MRP1, MRP2, and BCRP efflux pumps. It is used to treat diabetes, cold sores, swelling (inflammation), and sores inside the mouth (oral mucositis). As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 275 to about 410 milligrams of bee propolis. The amount can be adjusted for divided doses of the dosage form.

[0037] Oleanolic acid is a compound that is readily commercially available. It exhibits antitumor and antiviral properties. It inhibits the MRP1 efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 50 to about 120 milligrams of oleanolic acid. The amount can be adjusted for divided doses of the dosage form.

[0038] Biochanin A is an O-methylated isoflavone that is readily commercially available. It exhibits antitumor and cardiovascular properties. It inhibits the P-gp efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 5 to about 30 milligrams of biochanin. The amount can be adjusted for divided doses of the dosage form.

[0039] Luteolin is a flavone that is readily commercially available. It has been used for treating hypertension, inflammatory disorders, and cancer. It inhibits the P-gp, and MRP2 efflux pumps. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 20 to about 60 milligrams of luteolin. The amount can be adjusted for divided doses of the dosage form.

[0040] Vanillin is a compound that is readily commercially available. It is the primary component of the extract of vanilla bean. It inhibits the MDR-TB efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 10 to about 30 milligrams of vanillin. The amount can be adjusted for divided doses of the dosage form.

[0041] Honokiol is a lignin compound and is readily commercially available. It inhibits the P-gp, MRP1, MRP2, and BCRP efflux pumps. It has been identified as having therapeutic potential in anxiety, pain, cerebrovascular injury, epilepsy, and cognitive disorders including Alzheimer's disease. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 10 to about 40 milligrams of honokiol. The amount can be adjusted for divided doses of the dosage form.

[0042] Pterostilbene is a compound that is readily commercially available. It exhibits antioxidant, anti-inflammatory, and anti-carcinogenic properties leading to improved function of normal cells and inhibition of malignant cells. It inhibits the UGT-1A9 efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 180 to about 215 milligrams of pterostilbene. The amount can be adjusted for divided doses of the dosage form.

[0043] Withaferin A is a compound that is readily commercially available. Withaferin A is a steroidal lactone, derived from Acnistus arborescens or Withania somnifera (Indian Winter cherry). W. somnifera, commonly called “ashwagandha,” is used to treat asthma, diabetes, hypertension, stress, arthritic diseases, and cancer. It inhibits the MDR-TB efflux pump. As used herein, a typical daily dosage form (e.g., for daily oral administration to an adult human subject) contains from about (plus or minus 5% by weight) 60 to about 100 milligrams of withaferin A. The amount can be adjusted for divided doses of the dosage form.

[0044] Preferably, one or more of chitosan (typically at a daily dosage of from about 140 to about 205 mg), menthol (typically at a daily dosage range of from about 5 to about 20 milligrams), piperine (typically at a daily dosage range of from about 10 to about 30 milligrams), or yucca saponins (typically at a daily dosage range of from about 100 to about 400 milligrams), all of which are readily commercially available, are included in the formulation as adjuvant(s) to increase both bioavailability and small molecule permeability.

[0045] In certain embodiments, other organic or inorganic bioactive ingredients can be included in the formulation in order to enhance efficacy.

[0046] Once being apprised of the instant disclosure, a person of ordinary skill in the art will be readily able to make or prepare the dosage forms using Galenical techniques. Preferably, a finished product delivery forms is selected from the group consisting of a softgel, capsule, tablet, gel, powder, gummy, liquid, effervescent, bar, topical patch, serum, lotion, and cream.

[0047] The described composition is useful as a nutritional supplement capable of increasing the intracellular concentration and efficacy of health-promoting phytonutrients by inhibiting efflux pumps at micromolar amounts, which would otherwise pump them out of the cell.

[0048] The invention is further described with the aid of the following illustrative Examples.

Example I

[0049] The following phytonutrients are thoroughly admixed as close to uniform consistency as possible:

TABLE-US-00001 Apigenin 80 g Cannabidiol 20 g Chrysin 200 g Caffeic acid 125 g Piperine 20 g Chitosan 150 g

[0050] The resulting admixture is divided into 1,000 equal portions each placed into one of 1,000 appropriately-sized hard (or vegan) gelatin capsules with or without a pharmaceutically acceptable diluent.

Example II

[0051] Capsules of EXAMPLE I are administered in a dosing regimen of one capsule daily (e.g., with a nutritious lunch and green tea) to a subject. The treatment regimen is continued for 13 weeks. The described supplement supports the subject's health via, for example, inhibiting efflux pumps.

Example III

[0052] The following phytonutrients are thoroughly admixed as close to uniform consistency as possible:

TABLE-US-00002 Cannabidiol 20 g Harmine 20 g Caffeic acid 100 g Piperine 20 g Chitosan 150 g Yucca saponins 325 g Withaferin a 100 g

[0053] The resulting admixture is divided into 1,000 equal portions each placed into one of 1,000 appropriately-sized hard (or vegan) gelatin capsules with or without a pharmaceutically acceptable diluent.

Example IV

[0054] Capsules of EXAMPLE III are administered in a dosing regimen of one capsule daily to a subject undergoing pharmacological treatment for tuberculosis. The treatment regimen is continued for 6 months. The described supplement supports the subject's health via, for example, assisting in the treatment of tuberculosis. The dosage of the pharmacological treatment for tuberculosis co-administered to the subject may need to be adjusted (e.g., reduced) by the subject's health care provider.

Example V

[0055] The following phytonutrients are thoroughly admixed as close to uniform consistency as possible:

TABLE-US-00003 Cannabidiol 20 g Bee Propolis 350 g Chrysin 40 g Piperine 20 g Chitosan 190 g Luteolin 40 g Trans-Pterostilbene 175 g

[0056] The resulting admixture is divided into 1,000 equal portions each placed into one of 1,000 appropriately-sized hard (or vegan) gelatin capsules with or without a pharmaceutically acceptable diluent.

Example VI

[0057] Capsules of EXAMPLE V are administered in a dosing regimen of one capsule daily (with a dinner of non-junk food by increasing intracellular concentration of the health-promoting compounds found in the good food dinner) to a subject in order to enhance health. The treatment regimen is continued for 26 weeks.

Example VII

[0058] The following phytonutrients are thoroughly admixed as close to uniform consistency as possible:

TABLE-US-00004 Nobiletin 100 g Hypericum perforatum extract 350 g Oleanolic acid 85 g Biochanin 20 g Chitosan 190 g Vanillin 20 g Honokiol 25 g

[0059] The resulting admixture is divided into 1,000 equal portions each placed into one of 1,000 appropriately-sized hard (or vegan) gelatin capsules with or without a pharmaceutically acceptable diluent.

Example VIII

[0060] Capsules of EXAMPLE VII are administered in a dosing regimen of one capsule daily (with a cup of tea) to a subject in order to enhance health. The treatment regimen is continued for a year.

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