Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
  • A61K31/37—Coumarins, e.g. psoralen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• BZLlOl tested at a 1 :10 dilution (15 ⁇ g/ ml), demonstrated >50% growth inhibition on four of the five cell lines (Campbell, 2002). BZLlOl showed >50% growth inhibition on a panel of lung, prostate and pancreatic cancer cell lines. BZLlOl at the same dose did not cause >25% of growth inhibition on normal human mammary cells (HuMEC), demonstrating selectivity to cancer cells (Table 1). More so, BZLlOl had a mild mitogenic effect on normal human lymphocytes. In cell cycle analysis, BZLlOl caused an S phase burst and Gl arrest. BZLlOl also attenuated mitochondrial membrane potential causing caspase-independent high molecular grade (HMG) apoptosis. [0004] There is a need for therapies for treatment of patients having metastatic cancers.
• HMG high molecular grade
• the inventor has found that an extract of Scutellaria barbata D. Don is well- tolerated at doses much higher than previously reported.
• the extract of Scutellaria barbata D. Don is well-tolerated at dosages of at least about 20 g of soluble material extracted from Scutellaria barbata D. Don.
• the extract of Scutellaria barbata D. Don may be conveniently provided in a dosage unit suitable for administration to a patient.
• a dosage unit comprising at least about 20 g of soluble matter extracted from Scutellaria barbata D. Don.
• the unit dose further comprises at least one excipient, especially at least one excipient other than water, and in particular at least one taste-masking agent, sweetener or both.
• the dosage unit is in an form suitable for oral administration, e.g. an aqueous (water-based) composition or a dry powder suitable for reconstitution with water. The inventor has found that the dosage unit is suitable for administration to a cancer patient, especially a cancer patient suffering from breast cancer or a gynecological cancer, such as uterine cancer.
• the invention provides a method of treating cancer, comprising administering to a cancer patient at least about 20 g per day of soluble matter extracted from Scutellaria barbata D. Don.
• the cancer is selected from breast cancer and one or more gynecological cancers.
• the method includes administering to the patient about 20 g per day to about 200 g per day of soluble matter extracted from Scutellaria barbata D. Don.
• the inventor has also determined that addition of an excipient, such as a taste- masking agent, to a high dose of a pharmaceutical composition comprising an extract of Scutellaria barbata D. Don attenuates the bitter taste of the extract.
• an excipient such as a taste- masking agent
• high doses of Scutellaria barbata D. Don e.g. at least about 20 g soluble matter per dose or per day
• a taste-masking agent or other agent is desirable for making the composition palatable for consumption of high dosages of Scutellaria barbata D. Don extract, such as for the treatment of cancer.
• a pharmaceutical composition e.g.
• cancer for the treatment of cancer, especially breast or gynecological cancer
• excipient other than water such as at least one taste-masking agent, sweetener or both
• members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellarin which are the anti-cancer actives that the inventor has identified as being necessary for the anti-cancer activity of an extract of Scutellaria barbata D. Don.
• high molecular weight compounds e.g. compounds with high molecular weights (e.g.
• the pharmaceutical composition is depleted of high molecular weight compounds, and in some embodiments is substantially free of high molecular weight compounds.
• the composition contains a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin, containing about 1 part Luteolin, about 1.1 parts Apigenin, About 4.8 parts Scutellarein and about 34 parts Scutellarin.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.61 to about 2 parts Apigenin, about 2.5 to about 9.4 parts Scutellarein, and about 15 to about 70 parts
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1% to about 99% is active soluble matter, of which active soluble matter about 1.7% to about 3.2% is Luteolin, about 2% to about 3.4% is Apigenin, about 7.9% to about 15.8% is Scutellarein, and about 49% to the balance of active soluble matter is Scutellaria
• the composition is used to treat a breast cancers selected from one or more of is advanced breast cancer, metastatic breast cancer, treatment-refractory breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, and/or triple-negative breast cancer.
• Some embodiments described herein provide a method of treating cancer, especially one or more breast and/or gynecological cancers, comprising administering to the patient an effective amount of a composition comprising at least one excipient other than water (such as at least one taste-masking agent, sweetener or both), and one or more members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellaria
• the composition is used to treat a breast cancers selected from one or more of is advanced breast cancer, metastatic breast cancer, treatment-refractory breast cancer, ER- negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, and/or triple-negative breast cancer.
• the effective amount of the composition comprises at least 0.25 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellaria In some embodiments, the effective amount of the composition comprises at least 0.27 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin. In some embodiments, the composition comprises at least about 0.35 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the effective amount of the composition contains about 0.35 g - 2 g, about 0.35 g - 1.1 g, about 0.35 -1 g, about 0.35 g to about 0.8 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the invention provides a dosage unit comprising a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the dosage unit comprises at least about 0.25 g, at least about 0.27 g, or at least about 0.35 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the dosage unit further comprises at least one excipient other than water, such as a taste masking agent, a sweetener or both.
• the dosage unit is substantially free of high molecular weight compounds extracted from Scutellaria barbata D. Don.
• the compositions are employed in a method of treating cancer, such as breast cancer and/or one or more gynecological cancers.
• the cancer is a breast cancer, such as advanced breast cancer, metastatic breast cancer, treatment-refractory breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, and/or triple-negative breast cancer.
• the inventor has further discovered processes for making pharmaceutical compositions using the aerial portions of Scutellaria barbata D. Don as starting materials. Such processes are particularly useful for making compositions comprising Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the inventor has described a process of making a pharmaceutical composition, comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D.
• the refined extract contains Apigenin, Luteolin, Scutellarein, and Scutellarin.
• at least one pharmaceutically acceptable excipient other than water is selected from taste masking agents and sweeteners.
• Don improves the clinical characteristics of the pharmaceutical composition.
• a large amount of soluble matter extracted from Scutellaria barbata D. Don is inactive, reducing the amount of soluble matter by removing molecules having molecular weights above a predetermined cutoff will greatly reduce the bulk of a pharmaceutical composition derived from an extract of Scutellaria barbata D. Don.
• a large part of the soluble matter extracted from Scutellaria barbata D. Don into water is soluble fiber, which is not absorbed in the intestines and tends to promote gastrointestinal upset, bloating, gas and diarrhea.
• removing at least part of the soluble fiber by reducing the burden of soluble matter extracted from Scutellaria barbata D.
• the invention provides a pharmaceutical composition comprising 1 part of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin and less than about 50 parts of high molecular weight compounds having molecular weights greater than a predetermined cutoff, wherein the predetermined cutoff is from 1,000 grams/mole to about 20,000 grams/mole.
• the inventor has also discovered a process of making a pharmaceutical composition, comprising: (a) contacting aerial parts of Scutellaria barbata D.
• Some embodiments also provide a process of making a refined extract of Scutellaria barbata D. Don, comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D. Don from the mixture to produce a crude extract; and (c) separating high molecular weight compounds from the crude extract to form the refined extract of Scutellaria barbata D. Don.
• Some embodiments further provide a process of making a pharmaceutical composition, comprising combining at least one pharmaceutically acceptable excipient other than water with one or more members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellarin to form the pharmaceutical composition.
• at least one pharmaceutical excipient other than water is selected from taste masking agents and sweeteners.
• Some embodiments provide a process of making a pharmaceutical dosage unit comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D.
• FIG. 1 shows the effect of various active compounds extracted from Scutellaria barbata D. Don on the reactive oxygen species (ROS) generation, as measured by DCFDA fluorescence.
• ROS reactive oxygen species
• FIG. 2 shows the effect of various active compounds extracted from Scutellaria barbata D. Don on reactive oxygen species (ROS) generation, as measured by dihydroethidium (HE) fluorescence.
• FIG. 3 shows the effect of various active compounds extracted from Scutellaria barbata D. Don on mitochondrial reactive oxygen species (ROS) generation, as measured by
• FIG. 4 shows the effect of various active compounds extracted from Scutellaria barbata D. Don on the generation of comets in treated cells.
• FIG. 5 shows the effect of various active compounds extracted from Scutellaria barbata D. Don on the ATP generation in treated cells.
• This invention relates to pharmaceutical compositions and unit dosages that contain active agents isolated from an extract of Scutellaria barbata, at to the methods of using those extracts for the treatment of cancer.
• the herb from which the active compounds are isolated is selected from the species of Scutellaria barbata D. Don of the Labiatae Family.
• this invention relates to methods of using extracts of Scutellaria barbata D. Don, whereby the extract of Scutellaria barbata D. Don is administered to a patient at heretofore uncharacterized dosages.
• the invention further relates to administration of extracts of Scutellaria barbata D. Don, active agents and combinations of active agents derived from extracts of Scutellaria barbata D. Don, especially water extracts of Scutellaria barbata D. Don.
• an extract of Scutellaria barbata D. Don is well- tolerated at doses much higher than previously reported, e.g. at least about 20 g/day of soluble material extracted from Scutellaria barbata D. Don may be administered to a patient without inducing any dose-limiting toxicities.
• the inventor has administered 20 g/day, 30 g/day, and 40 g/day of soluble matter extracted from Scutellaria barbata D.
• the inventor has identified a dose of at least about 20 g/day, and particularly from about 20 g/day to about 200 g/day, as being within the scope of the present invention.
• the extract of Scutellaria barbata D. Don may be conveniently provided in a dosage unit suitable for administration to a patient.
• a dosage unit comprising at least about 20 g of soluble matter extracted from Scutellaria barbata D. Don.
• the unit dose further comprises at least one excipient, especially at least one excipient other than water, and in particular at least one taste-masking agent, sweetener or both.
• the dosage unit is in an form suitable for oral administration, e.g. an aqueous (water-based) composition or a dry powder suitable for reconstitution with water.
• the dosage unit is suitable for administration to a cancer patient, especially a cancer patient suffering from breast cancer or a gynecological cancer, such as uterine cancer.
• the dosage unit comprises about 20 g to about 200 g of soluble matter extracted from Scutellaria barbata D. Don.
• the dosage unit comprises about 2O g - 100 g, about 20 g - 60 g, about 20 g - 50 g, about 20 g - 40 g, about 20 g, about 30 g, about 40 g, about 5O g, about 60 g, or about 4O g - about 100 g of soluble matter extracted from Scutellaria barbata D. Don.
• the inventor having also identified the anti-cancer active compounds of Scutellaria barbata D. Don (i.e. Luteolin, Apigenin, Scutellarein, and Scutellarin), and their concentrations in the soluble matter extracted from Scutellaria barbata D.
• the invention also provides a dosage unit at least about 0.25 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellaria
• Some embodiments provide a dosage unit at least about 0.27 g, at least about 0.35 g, about 0.35 g - 4 g, about 0.35 g - 2 g, about 0.35 g - 1.1 g, about 0.35 g to about 1 g, or about 0.35 g to about 0.8 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the invention further provides a method of treating cancer, comprising administering to a cancer patient at least about 20 g per day of soluble matter extracted from Scutellaria barbata D. Don.
• the cancer is selected from breast cancer and one or more gynecological cancers.
• said cancer is a breast cancer.
• the breast cancer is advanced breast cancer, metastatic breast cancer, treatment-refractory breast cancer, ER-negative breast cancer, PR- negative breast cancer, HER2 -negative breast cancer, and/or triple-negative breast cancer.
• the method includes administering to the patient about 20 g per day to about 200 g per day of soluble matter extracted from Scutellaria barbata D. Don.
• the patient is given about 20 g per day - 100 g per day, about 20 g per day - 6O g per day, about 20 g per day - 5O g per day, about 20 g per day - 4O g per day, or about 40 g per day - 100 g per day of soluble matter extracted from Scutellaria barbata D. Don.
• the soluble matter extracted from Scutellaria barbata D is administered about 20 g per day - 100 g per day, about 20 g per day - 6O g per day, about 20 g per day - 5O g per day, about 20 g per day - 4O g per day, or about 40 g per day - 100 g per day of soluble matter extracted from Scutellaria barbata D.
• Don comprises at least about 0.25 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the soluble matter extracted from Scutellaria barbata D. Don comprises at least about 0.27 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the soluble matter extracted from Scutellaria barbata D. Don comprises at least about 0.35 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• Don comprises about 0.35 g - 4 g, about 0.35 g - 2 g, about 0.35 g - 1.1 g, about 0.35 g - 1 g, about 0.35 g - 0.8 g, about 0.35 - 0.75 g, or about 0.7 g - 2 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• an excipient such as a taste- masking agent
• Don e.g. at least about 1 g soluble matter per dose or per day
• a taste-masking agent or other agent is desirable for making the composition palatable for consumption of high dosages of Scutellaria barbata D.
• Don extract such as for the treatment of cancer.
• a pharmaceutical composition e.g.
• cancer for the treatment of cancer, especially breast or gynecological cancer
• excipient other than water such as at least one taste-masking agent, sweetener or both
• members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellarin which are the anti-cancer actives that the inventor has identified as being necessary for the anti-cancer activity of an extract of Scutellaria barbata D. Don.
• the inventor has also found that high molecular weight compounds, e.g.
• the pharmaceutical composition is depleted of high molecular weight compounds, and in some embodiments is substantially free of high molecular weight compounds.
• the composition contains a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin, containing about 1 part Luteolin, about 1.1 parts Apigenin, About 4.8 parts Scutellarein and about 34 parts Scutellarin.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.9 to about 1.3 part Apigenin, about 3.9 to about 6 parts Scutellarein, and about 37 to about 43 parts Scutellarin. In some embodiments, the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.61 to about 2 parts Apigenin, about 2.5 to about 9.4 parts Scutellarein, and about 15 to about 70 parts Scutellarin.
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1% to about 99% is active soluble matter, of which active soluble matter about 1.7% to about 3.2% is Luteolin, about 2% to about 3.4% is Apigenin, about 7.9% to about 15.8% is Scutellarein, and about 49% to the balance of active soluble matter is Scutellarin.
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1% to about 3% is active soluble matter, of which active soluble matter about 1.7% to about 3.2% is Luteolin, about 2% to about 3.4% is Apigenin, about 7.9% to about 15.8% is Scutellarein, and about 49% to the balance of active soluble matter is Scutellaria
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1.5% to about 2.1% is active soluble matter, of which active soluble matter about 1.7% to about 3.2% is Luteolin, about 2% to about 3.4% is Apigenin, about 7.9% to about 15.8% is Scutellarein, and about 49% to the balance of active soluble matter is Scutellaria
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1% to about 99% is active soluble matter, of which active soluble matter about 1.9% to about 3% is Luteolin
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1% to about 3% is active soluble matter, of which active soluble matter about 1.9% to about 3% is Luteolin, about 2.2% to about 3.2% is Apigenin, about 9.2% to about 14.5% is Scutellarein, and about 60% to the balance of active soluble matter is Scutellarin.
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1.5% to about 2.1% is active soluble matter, of which active soluble matter about 1.9% to about 3% is Luteolin, about 2.2% to about 3.2% is Apigenin, about 9.2% to about 14.5% is Scutellarein, and about 60% to the balance of active soluble matter is Scutellarin.
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1% to about 50% is active soluble matter, of which active soluble matter about 2.2% to about 2.7% is Luteolin, about 2.4% to about 2.9% is Apigenin, about 10.5% to about 13.2% is Scutellarein, and about 72% to the balance of active soluble matter is Scutellarin.
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1% to about 3% is active soluble matter, of which active soluble matter about 2.2% to about 2.7% is Luteolin, about 2.4% to about 2.9% is Apigenin, about 10.5% to about 13.2% is Scutellarein, and about 72% to the balance of active soluble matter is Scutellarin.
• the composition contains about 1 g to about 200 g soluble matter, of which soluble matter about 1.5% to about 2.1% is active soluble matter, of which active soluble matter about 2.2% to about 2.7% is Luteolin, about 2.4% to about 2.9% is Apigenin, about 10.5% to about 13.2% is Scutellarein, and about 72% to the balance of active soluble matter is Scutellarin.
• the composition is used to treat a breast cancers selected from one or more of is advanced breast cancer, metastatic breast cancer, treatment- refractory breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2- negative breast cancer, and/or triple-negative breast cancer.
• Some embodiments described herein provide a method of treating cancer, especially one or more breast and/or gynecological cancers, comprising administering to the patient an effective amount of a composition comprising at least one excipient other than water (such as at least one taste-masking agent, sweetener or both), and one or more members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellaria
• the composition is used to treat a breast cancers selected from one or more of is advanced breast cancer, metastatic breast cancer, treatment-refractory breast cancer, ER- negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, and/or triple-negative breast cancer.
• the effective amount of the composition comprises at least 0.25 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellaria In some embodiments, the effective amount of the composition comprises at least 0.27 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin. In some embodiments, the composition comprises at least about 0.35 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin. In some embodiments, the effective amount of the composition contains about 0.27 g to about 4 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the effective amount of the composition contains about 0.35 g to about 4 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin. In some embodiments, the effective amount of the composition contains about 0.35 g - 2 g, about 0.35 g - 1.1 g, about 0.35 -1 g, about 0.35 g to about 0.8 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains: about 1 part Luteolin, about 1.1 parts Apigenin, About 4.8 parts Scutellarein and about 34 parts Scutellarin; about 1 part Luteolin, about 0.9 to about 1.3 part Apigenin, about 3.9 to about 6 parts Scutellarein, and about 37 to about 43 parts Scutellarin; about 1 part Luteolin, about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin; about 1 part Luteolin, about 0.61 to about 2 parts Apigenin, about 2.5 to about 9.4 parts Scutellarein, and about 15 to about 70 parts Scutellarin; about 6.7 mg to about 90 mg of Luteolin, about 8.9 mg to about 90 mg of Luteolin, about 8.9 mg to about 50 mg of Luteolin, about 8.9 mg to about 30 mg of Luteolin, about 8.
• the invention provides a dosage unit comprising a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the dosage unit comprises at least about 0.25 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the dosage unit comprises at least about 0.27 g, or at least about 0.35 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the dosage unit comprises about 0.35 g to about 4 g, about 0.35 g to about 2 g, about 0.35 g to about 1.1 g, about 0.35 g to about 1 g, about 0.35 g to about 0.8 g, or about 0.7 g to about 2 g of the combination of Luteolin, Apigenin, Scutellarein, and
• the dosage unit further comprises at least one excipient other than water, such as a taste masking agent, a sweetener or both.
• the dosage unit is substantially free of high molecular weight compounds extracted from Scutellaria barbata D. Don.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains: about 1 part Luteolin, about 1.1 parts Apigenin,
• the compositions are employed in the treatment of cancer, such as breast cancer and/or one or more gynecological cancers.
• the cancer is a breast cancer, such as advanced breast cancer, metastatic breast cancer, treatment-refractory breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, and/or triple-negative breast cancer.
• the inventor has further discovered processes for making pharmaceutical compositions using the aerial portions of Scutellaria barbata D. Don as starting materials. Such processes are particularly useful for making compositions comprising Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the inventor has described a process of making a pharmaceutical composition, comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D. Don from the mixture to produce a crude extract; (c) separating high molecular weight compounds from the crude extract to form a refined extract; (d) optionally evaporating some, substantially all or all of the water from the refined extract or adding additional water to the refined extract; and (e) combining the refined extract with at least one pharmaceutically acceptable excipient other than water, to form the pharmaceutical composition.
• the refined extract contains Apigenin, Luteolin, Scutellarein, and Scutellarin.
• at least one pharmaceutically acceptable excipient other than water is selected from taste masking agents and sweeteners.
• soluble fiber which is not absorbed in the intestines and tends to promote gastrointestinal upset, bloating, gas and diarrhea.
• removing at least part of the soluble fiber by reducing the burden of soluble matter extracted from Scutellaria barbata D. Don, while preserving the mixture of Luteolin, Apigenin, Scutellarein, and Scutellarin in the composition, results in an improved anti-cancer drug.
• the invention provides a pharmaceutical composition comprising 1 part of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin and less than about 50 parts of high molecular weight compounds having molecular weights greater than a predetermined cutoff, wherein the predetermined cutoff is from 1,000 grams/mole to about 20,000 grams/mole.
• the pharmaceutical composition comprises about 1 part of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin and less than about 40 parts, less than about 30 parts, less than about 20 parts, less than about 10 parts, less than about 5 parts, less than about 2 parts, less than about 1 part, less than about 0.5 parts, about 0.01 to about 40 parts, about 0.01 to about 20 parts or about 0.01 to about 10 parts of the high molecular weight compounds.
• the cutoff for the high molecular weight compounds is: 10,000 grams/mole; 5,000 grams/mole; 2,000 grams/mole; 1,000 grams/mole; or in a range of about 1,000 grams/mole to about 10,000 grams/mole; about 1,000 grams/mole to about 5,000 grams/mole or about 1,000 grams/mole to about 2,000 grams/mole.
• the pharmaceutical composition comprises at least one excipient other than water. In some embodiments, at least one excipient other than water is a taste masking agent, a sweetener or both. The inventor has found that the pharmaceutical composition described herein is conveniently prepared as a dosage unit comprising a pharmaceutical composition described herein.
• the dosage unit comprises at least about 18 mg of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin. In some embodiments, the dosage unit comprises: about 0.25 g to about 4 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin; about 0.27 g to about 4 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin; about 0.35 to about 4 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin; about 0.35 to about 2 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin; about 0.35 to about 1.1 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin; about 0.35 to about 1 g of the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin; about 0.35 to about 1
• the composition in addition to the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin, the composition further comprises at least one excipient other than water. In some embodiments, at least one excipient other than water is selected from taste masking agents, sweeteners, or both.
• the invention provides method of treating cancer comprising administering to a cancer patient an effective amount of a pharmaceutical composition or a dosage form described herein.
• the cancer is one or more breast cancers and/or gynecological cancers, such as breast or uterine cancer.
• a breast cancer such as advanced breast cancer, metastatic breast cancer, treatment-refractory breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, and/or triple-negative breast cancer.
• the inventor has also discovered a process of making a pharmaceutical composition, comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D.
• Some embodiments also provide a process of making a refined extract of Scutellaria barbata D. Don, comprising: (a) contacting aerial parts of Scutellaria barbata D.
• Some embodiments further provide a process of making a pharmaceutical composition, comprising combining at least one pharmaceutically acceptable excipient other than water with one or more members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellarin to form the pharmaceutical composition.
• at least one pharmaceutical excipient other than water is selected from taste masking agents and sweeteners.
• Some embodiments provide a process of making a pharmaceutical dosage unit comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D. Don from the mixture to produce a crude extract; and (c) separating high molecular weight compounds from the crude extract to form a refined extract; and (d) combining the refined extract with at least one excipient other than water to form the pharmaceutical dosage unit.
• at least one excipient other than water is selected from taste-masking agents and sweeteners.
• compositions and unit dosages described herein contain soluble matter (i.e. matter that is soluble in water) that is extracted from Scutellaria barbata, specifically the aerial parts of Scutellaria barbata D. Don.
• Herba Scutellaria barbata D. Don (Lamiaceae) of the Labiatae family- Ban Zhi Lian (BZL) is grown mainly, though not exclusively, in areas southeastern of the Yellow River (Huang Po) in the provinces of Sichuan, Jiangsu, Jiangxi, Fujian, Guangdong, Guangxi and Shaanxi.
• the plant is harvested in late summer and early autumn after it blooms (May- June).
• the aerial part is cut from the root. Only the aerial parts (leaves and stems) are used for the preparation of compositions and dosage units described herein.
• Table 1 depicts nomenclature for the herb, Scutellaria barbata D. Don, from which extracts of this invention are obtained, listed by family, genus, species and tradition Chinese name, of this invention.
• Table 1 Pharmaceutical Compositions
• compositions for the treatment of cancer.
• the invention provides pharmaceutical compositions ("compositions") for treatment of gynecological cancers and breast cancer.
• compositions are for the treatment of breast cancer, especially those breast cancers that have been considered by oncologists to be especially difficult to treat, which are described in greater detail below, but which include: advanced breast cancer, metastatic breast cancer, breast cancer that is negative for one or more hormone receptors (e.g. ER-negative, PR-negative, and/or HER2 -negative breast cancers), and breast cancers that have been unsuccessfully treated previously with one or more cancer therapies, such as radiation therapy, proton therapy, and/or chemotherapy.
• cancer therapies such as radiation therapy, proton therapy, and/or chemotherapy.
• the invention provides a pharmaceutical composition comprising at least one excipient other than water, and one or more members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the composition comprises each of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• a taste -masking agent such as a flavoring or other taste-masking agent, a sweetener, or both, to make the compositions more palatable, thereby enhancing patient comfort with the treatment, and potentially enhancing patient compliance.
• at least one excipient other than water is selected from taste masking agents and sweeteners.
• an excipient other than water means that the composition must contain some excipient aside from water, though it may also contain water, if water is an appropriate excipient for the particular form of the dosage unit in which the pharmaceutical composition is present.
• Scutellaria barbata D. Don extracts (e.g. at least 20 g soluble matter extracted from Scutellaria barbata D. Don or higher) cause stomach upset, bloating, gas and/or diarrhea in at least some patients.
• high molecular weight compounds extracted from Scutellaria barbata D. Don are inactive against breast and/or gynecological cancers and tend to induce gastrointestinal distress, especially at doses of, or exceeding, 20 g/day.
• stomach discomfort could, at least for some patients, result in poor patient compliance or even discontinuance of therapy.
• removing at least some of the high molecular weight compounds from the soluble matter extracted from Scutellaria barbata D. Don e.g. by nanofiltration
• the bulk amount of soluble matter that must be administered to patients will be reduced, and the gastrointestinal discomfort associated with high concentrations of soluble matter extracted from Scutellaria barbata D. Don will be reduced.
• the inventor herein provides teaching of compositions that are depleted, and in some cases substantially free, of high molecular weight compounds.
• a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin may otherwise be referred to herein as "active soluble matter” as opposed to “inactive soluble matter", which includes “high molecular weight compounds” as well as compounds that are not high molecular weight compounds but are not active in the treatment of breast and/or gynecological cancers.
• the mass of soluble matter is equal to the sum of masses of active soluble matter (Luteolin, Apigenin, Scutellarein, and Scutellarin) and inactive soluble matter.
• the mass of inactive soluble matter is the sum of the masses of high molecular weight compounds and other inactive compounds.
• high molecular weight compounds refers to those compounds that are co-extracted with Luteolin, Apigenin, Scutellarein, and Scutellarin during the process of water extraction of Scutellaria barbata D. Don, and that have molecular weights of, or greater than, a predetermined cut-off.
• the cut-off may be somewhere from 1,000 g/mol to about 10,000 g/mol. In some embodiments, the cutoff of 10,000 grams per mole will suffice to remove a high percentage of soluble fiber from the soluble extract of Scutellaria barbata D.
• the cut-off is in the range of 750-20,000 g/mol, preferably in the range of 750-10,000 g/mol, and more particularly 750- 5,000 g/mol.
• Particular cut-offs include: 750 g/mol; 1,000 g/mol; 2,000 g/mol; 5,000 g/mol; and 10,000 g/mol.
• compositions and dosage units provided herein are substantially free of high molecular weight compounds.
• substantially free means that the composition or dosage unit contains less than some predetermined fraction of high molecular weight compounds than were contained in a "crude extract," which is a water extract of aerial parts of Scutellaria barbata D. Don that been treated (e.g. filtered or decanted) to remove insoluble matter (e.g. stems, leaves and insoluble portions thereof) but has not been otherwise treated to remove high molecular weight compounds.
• the predetermined fraction is 1/10 (0.1), 1/20 (0.05), 1/50 (0.02), 1/100 (0.01), 1/200 (0.005), 1/500 (0.002) or 1/1000 (0.001).
• Particular values for "substantially free of high molecular weight compounds" can also be expressed relative to the total mass of soluble matter extracted from Scutellaria barbata D. Don contained in the pharmaceutical composition.
• a composition that is substantially free of high molecular weight compounds contains less than about 10 wt%, less than about 5 wt%, less than about 1 wt%, less than about 0.5 wt% or less than about 0.1 wt% of high molecular weight compounds relative to the total amount of soluble matter extracted from Scutellaria barbata D. Don.
• Particular values for "substantially free of high molecular weight compounds" further be expressed as a mass proportion relative to the amount of Luteolin, Apigenin, Scutellarein, and Scutellarin contained in the composition. In some embodiments, about 1% to about 99% of soluble matter extracted from Scutellaria barbata D.
• active soluble matter of which active soluble matter about 1.7% to about 3.2% is Luteolin, about 2% to about 3.4% is Apigenin, about 7.9% to about 15.8% is Scutellarein, and about 49% to the balance of active soluble matter is Scutellarin
• compositions and dosage units provided herein are depleted of high molecular weight compounds.
• the term "depleted” as used herein means that the composition or dosage unit contains less than some predetermined fraction of high molecular weight compounds than were contained in a "crude extract," which is described in the previous paragraph.
• the predetermined fraction is 9/10 (0.9), 8/10 (0.8), 7/10 (0.7), 6/10 (0.6), 1/2 (0.5), 1/3 (0.333) or 1/4 (0.25).
• Particular values for "depleted of high molecular weight compounds” can also be expressed relative to the total mass of soluble matter extracted from Scutellaria barbata D. Don contained in the pharmaceutical composition.
• a composition that is depleted of high molecular weight compounds contains less than about 90 wt%, less than about 80 wt%, less than about 70 wt%, less than about 60 wt% or less than about 50 wt% of high molecular weight compounds relative to the total amount of soluble matter extracted from Scutellaria barbata D. Don.
• Particular values for "depleted of high molecular weight compounds” further be expressed as a mass proportion relative to the amount of Apigenin, Luteolin, Scutellarein and Scutellarin contained in the composition.
• soluble matter extracted from Scutellaria barbata D. Don in the pharmaceutical composition is active soluble matter, of which active soluble matter about 1.7% to about 3.2% is Luteolin, about 2% to about 3.4% is Apigenin, about 7.9% to about 15.8% is Scutellarein, and about 49% to the balance of active soluble matter is Scutellarin.
• active compounds Liuteolin, Apigenin, Scutellarein, and Scutellarin
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.61 to about 2 parts Apigenin, about 2.5 to about 9.4 parts Scutellarein, and about 15 to about 70 parts Scutellarin. In some embodiments, the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.9 to about 1.3 part Apigenin, about 3.9 to about 6 parts Scutellarein, and about 37 to about 43 parts Scutellarin.
• the composition contains a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin, containing about 1 part Luteolin, about 1.1 parts Apigenin, About 4.8 parts Scutellarein and about 34 parts Scutellarin.
• compositions provided herein may be produced by a process that includes extracting active compounds from aerial parts (stems and/or leaves) of Scutellaria barbata D. Don, e.g. with water.
• water includes pure water (e.g. water for injection, distilled water, double deionized water, filtered distilled water, etc.) as well as aqueous solutions that consist of water and one or more minor solid or liquid solutes, so long as the majority of the extraction medium is water and the solute or solutes do not materially affect the extraction properties of water.
• the process also includes removing a portion of high molecular weight compounds from the extract of Scutellaria barbata D.
• a process of making a pharmaceutical composition comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D. Don from the mixture to produce a crude extract; (c) separating high molecular weight compounds from the crude extract to form a refined extract; and (e) combining the refined extract with at least one pharmaceutically acceptable excipient other than water, to form the pharmaceutical composition.
• the process also includes (d) optionally evaporating some, substantially all or all of the water from the refined extract or adding additional water to the refined extract.
• at least one pharmaceutically acceptable excipient other than water is selected from taste masking agents and sweeteners.
• the pharmaceutical composition may be further combined with suitable packaging to form a suitable dosage unit.
• the aerial parts of Scutellaria barbata D. Don are combined with water and heated to a suitable temperature above room temperature, especially about 4O 0 C, and more preferably from about 5O 0 C to about 8O 0 C, optionally at elevated pressures.
• the mixture should be cooked long enough to extract the active compounds into the aqueous phase of the mixture, but not so long as to unnecessarily waste energy or cause breakdown in the active compounds. Some period longer than about 10 minutes, but less than about 2 days is suitable, though periods of 30 minutes to 6 hours are generally considered suitable. More particular values are recited in the examples herein.
• Don are separated from the aqueous phase by some suitable method. Larger parts may be removed by straining the mixture through a sieve, whereas smaller parts may be removed by filtration. The filtration may be performed in stages, with each stage involving passage through one or more filters of successively smaller pore size.
• High molecular weight compounds may be removed by a suitable method, such as nanofiltration or size exclusion chromatography.
• the volume of the solution may be reduced, e.g. by evaporating off part of the water.
• the solution may also be freeze dried or otherwise desiccated to form a dry residue, which may be pulverized to form a powder.
• the resulting refined extract can then be combined with at least one excipient, especially an excipient other than water, to form the pharmaceutical composition.
• the excipient other than water is a taste masking agent or a sweetener.
• the excipient other than water contains a taste masking agent.
• Other embodiments provide a process of making a pharmaceutical composition, comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D. Don from the mixture to produce a crude extract; (c) separating high molecular weight compounds from the crude extract to form a refined extract; and (e) combining the refined extract with a pharmaceutically acceptable excipient to form the pharmaceutical composition. Some embodiments also include (d) optionally evaporating some, substantially all or all of the water from the refined extract or adding additional water to the refined extract.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.61 to about 2 parts Apigenin, about 2.5 to about 9.4 parts Scutellarein, and about 15 to about 70 parts Scutellarin. In some embodiments, the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin.
• the combination of Luteolin, Apigenin, Scutellarein, and Scutellarin contains about 1 part Luteolin, about 0.9 to about 1.3 part Apigenin, about 3.9 to about 6 parts Scutellarein, and about 37 to about 43 parts Scutellarin.
• the composition contains a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin, containing about 1 part Luteolin, about 1.1 parts Apigenin, About 4.8 parts Scutellarein and about 34 parts Scutellarin.
• a process of making a composition comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D. Don from the mixture to produce a crude extract; and (c) separating high molecular weight compounds from the crude extract to form a refined extract.
• the refined extract may be further processed to produce a dosage unit as described herein.
• the refined extract is depleted of high molecular weight compounds.
• the refined extract is substantially free of high molecular weight compounds.
• the process of making a pharmaceutical composition comprises combining at least one pharmaceutically acceptable excipient other than water (e.g. a taste-masking agent and/or a sweetener) with one or more members of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellarin to form the pharmaceutical composition.
• at least one pharmaceutical excipient other than water is selected from taste masking agents and sweeteners.
• dose refers to an amount of the pharmaceutical composition administered in a single occurrence.
• a daily dose is an amount of the pharmaceutical composition administered in a day. Doses may be administered once daily (Q.D.), twice-daily (b.i.d.), trice daily (t.i.d.), four times daily (q.i.d.), etc.
• the term "dosage unit" is a single, pre-manufactured form of the pharmaceutical composition that consists of one or more doses of the pharmaceutical composition, or some fraction of a dose of the pharmaceutical composition that can be combined with other dosage units to form a single dose.
• the dosage unit consists of a single day's dose of the pharmaceutical composition.
• the dosage unit may adapted to be administered as a single daily dose (Q.D.) or may be divided into two, three, four or more doses (b.i.d., t.i.d., or q.i.d., respectively) to be administered at different times of the day, or may be administered as a single dose.
• the dosage unit may comprise some fraction (e.g. half, a third, a fourth, a fifth) of a single dose.
• a dosage unit may also be a solution for injection of a particular volume, e.g. 20 mL to 1000 mL, for administration via a drip line or similar intravenous administration method, or even via a nasopharyngeal tube.
• dosage units include tablets, capsules, powders and solutions (elixirs).
• Tablets include tablets to be swallowed, tablets to be chewed and swallowed and tablets adapted to dissolve on the tongue and be swallowed, with or without a liquid swallowing aid, such as water.
• Suitable excipients for tablets include binding agents, fillers, disintegrants, dispersants, glidants, ant-sticking and anti-caking agents, as well as taste- masking agents and sweeteners.
• Capsules include capsules to be swallowed whole as well as capsules adapted to be dissolved in a liquid excipient, such as water. Capsules also include capsules to be opened and their contents dissolved in a suitable excipient, such as water. Suitable excipients for capsules include dispersants, fillers, taste-masking agents and sweeteners. [0066] Powders include powders that have been packaged in a suitable container for transportation and storage, such as a foil pouch, a sealed vial, etc. Suitable excipients for powders include dispersants, fillers, taste-masking agents and sweeteners.
• Solutions include water-based solutions containing water, an excipient other than water and active soluble matter extracted from Scutellaria barbata D. Don (Luteolin, Apigenin, Scutellarein, and Scutellarin).
• solutions are packaged in a suitable sealed container and packaged with instructions for administration of the solution to a patient.
• the water-based solution may or may not contain an excipient other than water.
• compositions described herein should be administered to patients, and importantly can be tolerated by patients, at levels that were heretofore not contemplated. It has surprisingly been found, for example, that compositions as described herein can be administered to patients at high doses, i.e. doses greater than 10 or 12 grams per day of soluble material extracted from Scutellaria barbata D. Don.
• a pharmaceutical dosage unit comprising at least about 20 grams of an active pharmaceutical ingredient that contains at least one member of the group consisting of Apigenin, Luteolin, Scute llarein and Scute llarin.
• the active pharmaceutical ingredient contains each of Luteolin, Apigenin, Scutellarein, and Scutellaria
• the dosage unit is an oral dosage unit.
• the dosage unit further comprises at least one excipient other than water.
• the dosage unit comprises at least one excipient selected from taste masking agents and sweeteners.
• the dosage unit comprises at least about 20 grams of the active pharmaceutical ingredient.
• the dosage unit is capable of being split between two or more doses for administration in a single day.
• the pharmaceutical dosage unit comprises an active pharmaceutical ingredient containing at least about 20 grams of soluble material extracted from Scutellaria barbata D. Don.
• the soluble material extracted from Scutellaria barbata D. Don contains one or more of Apigenin, Luteolin, Scutellarein and Scutellarin; preferably it contains all four of Apigenin, Luteolin, Scutellarein and Scutellarin.
• the soluble material contains each of Apigenin, Luteolin, Scutellarein and Scutellarin in proportions of about: about 1 part Luteolin, about 0.61 to about 2 parts Apigenin, about 2.5 to about 9.4 parts Scutellarein, and about 15 to about 70 parts Scutellarin; about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin; about 0.9 to about 1.3 part Apigenin, about 3.9 to about 6 parts Scutellarein, and about 37 to about 43 parts Scutellarin; or about 1 part Luteolin, about 1.1 parts Apigenin, About 4.8 parts Scutellarein and about 34 parts Scutellarin.
• the soluble material extracted from Scutellaria barbata D. Don is depleted, or substantially free, of high molecular weight compounds.
• the dosage unit is an oral dosage unit (e.g. a tablet to be swallowed whole, chewed and swallowed or allowed to dissolve on the tongue and swallowed, a capsule to be swallowed whole, a capsule to be opened and its contents dissolved in a suitable liquid excipient to be swallowed, a capsule to be dissolved whole in a suitable excipient, a powder to be dissolved in a suitable excipient, which may include a taste masking agent, a sweetener, etc. and/or water).
• an oral dosage unit e.g. a tablet to be swallowed whole, chewed and swallowed or allowed to dissolve on the tongue and swallowed, a capsule to be swallowed whole, a capsule to be opened and its contents dissolved in a suitable liquid excipient to be swallowed, a capsule to be dissolved whole in a suitable ex
• the dosage unit further comprises at least one excipient other than (e.g. in addition to) water.
• the dosage unit comprises at least one excipient selected from taste masking agents and sweeteners.
• the dosage unit comprises at least about 20 grams of the active pharmaceutical ingredient (e.g. 20-200 grams per dosage unit, 20-100 grams per dosage unit or 20-60 grams per dosage unit).
• the pharmaceutical dosage unit comprises an active pharmaceutical ingredient containing at least about at least 0.25 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellaria
• the pharmaceutical dosage unit comprises at least about 0.27 g of Luteolin, Apigenin,
• the pharmaceutical dosage unit comprises about 0.35 g - 4 g, 0.35 g - 2 g , 0.35 g - 1.1 g, 0.35 g - 1 g, or 0.35 g - 0.8 g of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the pharmaceutical dosage unit comprises about 0.25 g, about 0.27 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, about 1.7 g, about 1.8 g, about 1.9 g, about 2 g, about 2.1 g, about 2.2 g, about 2.3 g, about 2.4 g, about 2.5 g, about 2.6 g, about 2.7 g, about 2.8 g, about 2.9 g, about 3 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, of about 4
• the soluble material extracted from Scutellaria barbata D. Don contains one or more of Apigenin, Luteolin, Scutellarein and Scutellarin; preferably it contains all four of Apigenin, Luteolin, Scutellarein and Scutellarin.
• the soluble material contains each of Apigenin, Luteolin, Scutellarein and Scutellarin in proportions of about: about 1 part
• Luteolin about 0.61 to about 2 parts Apigenin, about 2.5 to about 9.4 parts Scutellarein, and about 15 to about 70 parts Scutellarin; about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin about 0.75 to about 1.64 parts Apigenin, about 3.1 to about 7.5 parts Scutellarein, and about 20.4 to about 54.7 parts Scutellarin; about 0.9 to about 1.3 part Apigenin, about 3.9 to about 6 parts Scutellarein, and about 37 to about 43 parts Scutellarin; or about 1 part Luteolin, about 1.1 parts Apigenin, About 4.8 parts Scutellarein and about 34 parts Scutellarin.
• the soluble material extracted from Scutellaria barbata D. Don is depleted, or substantially free, of high molecular weight compounds.
• the dosage unit is an oral dosage unit (e.g. a tablet to be swallowed whole, chewed and swallowed or allowed to dissolve on the tongue and swallowed, a capsule to be swallowed whole, a capsule to be opened and its contents dissolved in a suitable liquid excipient to be swallowed, a capsule to be dissolved whole in a suitable excipient, a powder to be dissolved in a suitable excipient, which may include a taste masking agent, a sweetener, etc. and/or water).
• an oral dosage unit e.g. a tablet to be swallowed whole, chewed and swallowed or allowed to dissolve on the tongue and swallowed, a capsule to be swallowed whole, a capsule to be opened and its contents dissolved in a suitable liquid excipient to be swallowed, a capsule to be dissolved whole in a suitable ex
• the dosage unit further comprises at least one excipient other than (e.g. in addition to) water.
• the dosage unit comprises at least one excipient selected from taste masking agents and sweeteners.
• the dosage units described herein may be produced by a process according to the invention.
• a process of making a pharmaceutical dosage unit comprising: (a) contacting aerial parts of Scutellaria barbata D. Don with water heated to above 4O 0 C for a period at least about 10 minutes to form a mixture; (b) separating the aerial parts of Scutellaria barbata D.
• Such dosage units contain a suitable quantity of refined extract to treat cancer, especially breast cancer.
• the dosage units contain at least 0.25 g, at least 0.27 g, at least 0.3 g, at least 0.35 g, or 0.35 g - 4 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the dosage units further comprise a package, such as a foil pack, a bottle, a sachet, a blister pack, or other sealed package.
• the process of making the dosage unit includes a step of packaging the dosage unit in a package.
• Illustrative amounts of active soluble matter (Luteolin, Apigenin, Scutellarein, and Scutellarin) in each dosage unit, or each dose, according to the present invention are set forth in the following Table 2.
• Table 2 Amounts of Active Soluble Matter (Luteolin, Apigenin, Scutellarein, and Scutellarin) in Some Contemplated Dosages/Dosage Units Described Herein
• compositions and dosage units described herein may be used to treat cancer, especially breast and gynecological cancers.
• the inventor has conducted clinical trials in humans of compositions according to the invention and found that administration of 20 grams per day, 30 grams per day or 40 grams per day of soluble material extracted from Scutellaria barbata D. Don were well-tolerated and demonstrated efficacy against breast cancer, especially breast cancer with advanced breast cancer who had previously received at least one round of cancer therapy, an at least one round of chemotherapy.
• treatment-refractory cancers of the breast are particularly difficult to treat, the inventor has provided a method of treating cancer in humans.
• the inventor has provided a method of treating breast cancer in humans, in addition to providing a method of treating one or more sub-types of cancers including metastatic breast cancers.
• Other cancers that may be treated include those that do not express estrogen receptors (ER- negative breast cancer) those that do not express progesterone (PR-negative breast cancers), those that do not express human epidermal growth hormone receptor 2 (HER2 -negative breast cancers).
• ER- negative breast cancer those that do not express progesterone
• HER2 -negative breast cancers human epidermal growth hormone receptor 2
• these categories of breast cancer are not mutually exclusive.
• a breast cancer may be ER-negative and PR-negative (so- called double-negative breast cancer) or may be ER-negative, PR-negative and HER2- negative (triple-negative breast cancer).
• a triple negative breast cancer may be advanced and/or metastatic.
• a metastatic breast cancer may be, and often will be, one that has proven refractory to one or more previous therapeutic approaches.
• the recitation of one characteristic of breast cancer e.g. ER-negative
• the recitation of one characteristic of breast cancer is not intended to exclude other characteristics (e.g. PR-negative) unless clearly stated.
• some embodiments of the invention provide a method of treating cancer, comprising administering to a cancer patient an effective amount of a pharmaceutical composition comprising at least one excipient other than water, and at least one member of the group consisting of Luteolin, Apigenin, Scutellarein, and Scutellarin.
• the composition comprises each of Apigenin, Luteolin, Scutellarein, Scutellarin, wherein at least one excipient other than water is selected from taste masking agents and sweeteners.
• the composition is substantially free of high molecular weight compounds.
• the cancer is breast cancer or a gynecological cancer.
• the cancer is a breast cancer that is at least one of the following: advanced breast cancer, metastatic breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, ER-negative and PR- negative breast cancer, ER-negative, PR-negative and HER2 -negative breast cancer, or breast cancer that has not responded to at least one previous course of cancer treatment.
• Some embodiments of the invention further provide a method of treating a cancer, e.g. a breast or gynecological cancer, by administering to a patient suffering from the cancer a pharmaceutical composition comprising at least about 0.25 g, at least about 0.27 g, at least about 0.3 g, at least about 0.35 g, or about 0.35 g to about 4 g of a combination of Luteolin, Apigenin, Scutellarein, and Scutellaria
• the method comprises administering to a patient a daily dose of about 0.25 g, about 0.27 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, about 1.7 g, about
• the cancer is a breast cancer that is at least one of the following: advanced breast cancer, metastatic breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, ER-negative and PR-negative breast cancer, ER- negative, PR-negative and HER2 -negative breast cancer, or breast cancer that has not responded to at least one previous course of cancer treatment.
• some embodiments provide a method of treating cancer comprising administering to the patient a pharmaceutical dosage unit comprising at least 20 grams of an active pharmaceutical ingredient that contains at
• the dosage unit is an oral dosage unit.
• the dosage unit further comprises at least one excipient other than water.
• the dosage unit comprises at least one excipient selected from taste masking agents and sweeteners.
• the method comprises administering to a patient a daily dose of soluble matter extracted from Scutellaria barbata D.
• Some embodiments described herein provide a method of treating cancer comprising administering to the patient at least 20 grams per day of an active pharmaceutical ingredient that contains at least one member of the group consisting of Apigenin, Luteolin, Scutellarein and Scutellaria
• the active pharmaceutical ingredient is administered in one to four doses per day.
• the cancer is breast cancer or a gynecological cancer.
• the cancer is a breast cancer that is at least one of the following: advanced breast cancer, metastatic breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, ER-negative and PR- negative breast cancer, ER-negative, PR-negative and HER2 -negative breast cancer, or breast cancer that has not responded to at least one previous course of cancer treatment.
• the method comprises administering to a patient a daily dose of soluble matter extracted from Scutellaria barbata D.
• a method of treating cancer comprising administering to the patient a pharmaceutical dosage unit comprising an active pharmaceutical ingredient containing at least 20 g of soluble material extracted from Scutellaria barbata D. Don.
• the dosage unit is an oral dosage unit.
• the dosage unit further comprises at least one excipient other than water.
• the dosage unit comprises at least one excipient selected from taste masking agents and sweeteners.
• the dosage unit comprises at least about 20 grams of the soluble material extracted from Scutellaria barbata D. Don.
• Some embodiments further provide a method of treating cancer comprising daily administering to the patient an active pharmaceutical ingredient that contains at least 15 grams of soluble material extracted from Scutellaria barbata D. Don.
• the active pharmaceutical ingredient is administered in one to four doses per day.
• the cancer is breast cancer or a gynecological cancer.
• the cancer is a breast cancer that is at least one of the following: advanced breast cancer, metastatic breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2 -negative breast cancer, ER-negative and PR-negative breast cancer, ER- negative, PR-negative and HER2 -negative breast cancer, or breast cancer that has not responded to at least one previous course of cancer treatment.
• the particular dosage used to treat the patient is critical to a successful clinical outcome. Accordingly, in some embodiments the patient must be administered at least 20 g/day of soluble material extracted from Scutellaria barbata D. Don.
• the dosage unit comprises at least about 20 grams of the active pharmaceutical ingredient. In some embodiments, the dosage unit comprises at about 20 grams to about 200 grams, about 20 grams to about 100 grams, about 20 grams to about 60 grams, about 20 grams, about 30 grams, about 40 grams, about 50 grams, about 60 grams, about 70 grams, about 80 grams, about 90 grams or about 100 grams of the active pharmaceutical ingredient.
• a preferred mode of administration is oral administration, preferably where the soluble material extracted from Scutellaria barbata D. Don is combined with at least one excipient other than water, such as a taste-masking agent, a sweetener or both.
• Table 3 A shows the degree of inhibition of the activity of several in vitro solid breast cancer tumor cell lines by the extract of this invention.
• Table 3B shows the degree of inhibition of the activity of several in vitro solid cancer tumor cell lines by the extract of this invention.
• the terms “treat”, “treating” and “treatment” refer ameliorating one or more symptoms of a disease state. Successful treatment may be judged by attainment of stable disease, partial or total remission, or partial or total retardation of disease progression. One suitable end point for successful treatment is extension of life expectancy.
• “administer”, “administering” or “administration” refers to the delivery of an extract or extracts of this invention or of a pharmaceutical composition containing an extract or extracts of this invention to a patient in a manner suitable for the treatment of particular cancer being addressed.
• a "patient” refers to a mammal having a tumor, especially a human, and more particularly a female human suffering from one or more gynecological cancers or breast cancer.
• the terms "effective amount” and "therapeutically effective amount” refer synonymously to that amount of a composition or dosage unit which in a patient population has the effect of (1) reducing the size of the tumor; (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) inhibiting to some extent (that is slowing to some extent, preferably stopping) tumor growth; and/or; (4) relieving to some extent (or preferably eliminating) one or more symptoms associated with cancer; (5) stabilizing the growth of the tumor; (6) extending the time to disease progression; (7) improving overall survival.
• a "pharmaceutical composition” refers to a mixture of one or more of the compounds or combinations described herein with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmacological composition is to facilitate administration of an extract or extracts of this invention to patient. [0089] As used herein, the term “pharmaceutically acceptable” means that the agent or excipient is generally regarded as acceptable for use in a pharmaceutical composition.
• a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered composition.
• exemplary pharmaceutically acceptable carriers include solid and liquid diluents. Water, ethanol, propylene glycol, and glycerol are illustrative pharmaceutically acceptable liquid diluents; of these, water is preferred in some embodiments.
• an “excipient” refers to a pharmaceutically inert substance added to a pharmaceutical composition to further facilitate administration of a pharmaceutical composition of this invention.
• excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
• the groups of excipients and active pharmaceutical ingredients are considered mutually exclusive in the pharmaceutical arts.
• the excipient is a taste-masking agent, a sweetener, or both.
• excipient other than water means that the excipient is or contains some excipient other than water, such as a taste-masking agent or a sweetener.
• excipient other than water would include an excipient that contained water and a sweetener or water and a taste -masking agent, but would exclude an excipient that contained water only.
• a pharmaceutical composition comprising an excipient other than water and an active pharmaceutical ingredient may contain the pharmaceutically active ingredient, water, and some other excipient, such as a taste masking agent and/or a sweetener.
• the terms “comprising”, “comprises”, “comprise” and grammatical variants thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
• the terms “include”, “includes”, “contain”, “contains”, “containing” and grammatical variants thereof are likewise inclusive.
• BZL is synonymous with "Scutellaria barbata D. Don.”
• BZLlOl refers to a specific extract of BZL, which has demonstrated activity against cancer cells. In particular, the aerial portions of Scutellaria barbata D. Don are intended.
• Preparative HPLC method B (Table 3) was used to purify Carthamidin (5) and Isocarthamidin (6).
• Isoscutellarein was identified based on LC/MS and ID and 2D NMR analyses. All other compounds (1, 3-6) were identified based on LC/MS and NMR comparison with a commercial reference standard or from an authenticated standard from synthesis. NMR spectra were recorded using a Varian Mercury Plus 400 MHz.
• the HPLC and UV spectrum were recorded using an Agilent Technologies 1200 Series HPLC system, equipped with a DAD detector, and using a Phenomenex Luna C18 (150 x 2.1 mm, 3 ⁇ m) column. The molecular mass was determined using an Applied Agilent Technologies 6210 TOF LC/MS in the negative mode.
• Table 1-1 A summary of the properties of the instrumentation used is set forth in Table 1-1.
• Table 1-1 HPLC methods. The columns listed below were used in isolating compounds 1-6. The same solvent gradient was used for chromatography for all HPLC runs, only the flow rate was different as specified. Gradient: solvent A: 0.1% TFA. solvent B: MeCN; Linear gradient from 10% B to 60% B in 30 min with no up front hold. [0103] The NMR data used to identify compounds 1-6 are set forth below. [0104] Scutellarein (1): CAS# 529-53-3; LC/MS [M-H]- m/z 285.0425. Formula 1 shows the key HMBC correlations of compound (1). The NMR data for compound 1 are set forth in Table 1-2.
• Carthamidin (5) CAS# 479-54-9; LC/MS [M-H]- m/z 287.
• Formula (5) shows the key HMBC correlations of compound (5).
• NMR Data for compound 5 are set forth in Table 1-5.
• BZLlOl is an aqueous extract of the aerial part of Scutellaria Barbata D. Don of the Lamiaceae family.
• Herba Scutellaria Barbata D. Don Choinese pin yin transliteration- Ban Zhi Lian (BZL)) is grown mainly in areas southeastern of the Yellow River (Huang Po) in the provinces of Sichuan, Jiangsu, Jiangxi, Fujian, Guangdong, Guangxi and Shaanxi. The plant is harvested in late summer and early autumn after it blooms.
• the aerial part (leaves and stems) is cut from the root and is used as starting material (BZL).
• BZLlOl Bionovo, Inc., Emeryville, CA.
• the volume of the solution is 1750 ml •
• the extract is concentrated with a vacuum evaporator to reduce the volume of water to 350ml which constitutes a 5: 1 concentration of the original solution
• the dry weight of soluble material in the extract is 12 gm • It is packaged in a sterile, vacuum sealed container
• Example 1 Characterization of Actives from Scutellaria Barbata D. Don
• BZLlOl induces cell death in breast cancer cells but not in non-transformed mammary epithelial cells. This selective cytotoxicity is based on strong induction by BZLlOl of reactive oxygen species (ROS) in tumor cells. As a consequence, BZLlOl- treated cancer cells develop extensive oxidative DNA damage and succumb to necrotic death. Data from the expression profiling of cells treated with BZLlOl are strongly supportive of a death pathway that involves oxidative stress, DNA damage and activation of death-promoting genes.
• ROS reactive oxygen species
• oxidative damage induced by BZLlOl leads to the hyperactivation of poly (ADP-ribose) polymerase (PARP), followed by a sustained decrease in levels of NAD and depletion of ATP, neither of which are observed in non- transformed cells.
• PARP poly (ADP-ribose) polymerase
• the hyperactivation of PARP is instrumental in the necrotic death program induced by BZLlOl, because inhibition of PARP results in suppression of necrosis and activation of the apoptotic death program.
• BZLlOl treatment leads to the selective inhibition of glycolysis in tumor cells, which is evident from the decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate production.
• ROS reactive oxygen species
• the induction of death in cells treated with the compounds was examined using propidium iodide test for cell permeability followed by analysis on FACS. 6.
• the mode of cell death i.e., apoptosis versus necrosis was studied using several criteria: conversion of cells to positivity for binding Annexin V; DNA fragmentation (characteristic of apoptotic death) and decrease in cellular ATP levels (commonly observed during necrotic death)( Figure 5). 1. Induction of the loss of the mitochondrial transmembrane potential (MTP). All of compounds tested induced loss of MTP. 2. Induction of reactive oxygen species (ROS).
• ROS reactive oxygen species
• the mode of cell death i.e., apoptosis versus necrosis was studied using several criteria: conversion of cells to positivity for binding Annexin V; DNA fragmentation (characteristic of apoptotic death) and decrease in cellular ATP levels (commonly observed during necrotic death)( Figure 5).
• CM-H 2 DCFDA is oxidized by cellular hydrogen peroxide, hydroxyl radicals, and various free radical products lying downstream from hydrogen peroxide. It is relatively insensitive to oxidation by superoxide. However, because hydrogen peroxide is produced by dismutation of superoxide, CM-H 2 DCFDA serves as an indirect indicator of superoxide production. As seen in Figure 1 , CM-H 2 DCFDA is oxidized within cells by all tested BZLlOl compounds, though levels of total ROS induced are different. [0122] All the tested compounds also induced superoxide, as determined by staining of cells with dihydroethidium, a cell-permeant indicator that is oxidized selectively by superoxide.
• Cytosolic dihydroethidium exhibits blue fluorescence; however, once this probe is oxidized to ethidium by superoxide, it intercalates within the cell's DNA, staining its nucleus a bright fluorescent red, which is easily detected by flow cytometric methods ( Figure 2).
• Two flavonoids, Apigenin and Luteolin induce generation of superoxide whose origin is identified as mitochondrial.
• a specific detector of mitochondrially derived superoxide, MitoSOX was converted to its fluorescent form by Apigenin and Luteolin, but not by other compounds.
• an inhibitor of mitochondrial respiration sodium azide, NaN 3
• an inhibitor of mitochondrial complex I (dicumarol, not shown) prevented generation of superoxide by Apigenin and Luteolin (Figure 3).
• Apigenin and Luteolin are distinct from other compounds in that they do not induce DNA damage ( Figure 4). However, both are cytotoxic and induce significant cell death characterized as apoptotic based on: annexin V binding, DNA fragmentation, and slight but consistent increase in ATP levels observed during first hours of treatment ( Figure 5). All these features are hallmarks of apoptotic death.
• a - Apigenin A - Carthamidin; L - Luteolin; S - Scutellarein; IC - Isocarthamidin; IS - Isoscutellarein; P - a species having a molecular weight of 320 (believed to be a pentahydroxylflavone).
• Figure 2 Induction of superoxide in SKBr3 cells as determined by staining with dihydroethidium. The indicated compounds were added to cells followed by addition of 5 ⁇ M dihydroethidium. After 20 minute incubation, cells were washed in PBS and analyzed on FACScan for fluorescence.
• Figure 3 Cells were stained with MitoSOX indicator of mitochondrially derived superoxide. Treatments were as described in the Legends to Figure 2.
• Figure 4. Induction of DNA damage in SKBr3 cells by compounds isolated from BZLlOl was analyzed using comet assays. Cells were treated with the indicated compounds at 20 ⁇ g/ml for 15 minutes and analyzed for DNA damage using the Comet assay kit from Trevigen according to the manufacturer's instructions. Briefly, cells were harvested, washed and resuspended with PBS. The cells were combined with molten, low melting point agarose at 37°C and pipetted unto Comet slides.
• the agarose was allowed to solidify at 4°C for 30-40 min and immersed in cold lysis solution (Trevigen, Inc.) for 30 min at 4 0 C.
• the slides were immersed into freshly prepared alkali solution (300 mM NaCl and 1 mM EDTA) for 20 min and subjected to electrophoresis in the same alkaline buffer at 300 rnA for 30-40 min. Slides were rinsed in water and then fixed in 70% ethanol for 5 min. After air-drying, the nuclei were stained with Sybr green (Trevigen, Inc.) and viewed under a fluorescence microscope. Percentages of cells with comets were quantified by an observer blinded to the identity of the slides.
• FIG. 1 SKBr3 cells were plated on 96 well plates and treated with the indicated compounds for four hours. Cells were lysed in situ and ATP content was analyzed using the ATP Bioluminescence Assay Kit HSII from Roche, on a 96 well plate-based luminometer.
• BZLlOl extract contains chemical compounds with cytotoxic activities. These compounds exhibit different effects on mitochondria and cellular DNA, but all have cytotoxic activity towards human cancer cells. Two of the identified compounds, Apigenin and Luteolin induce mitochondrial superoxide and apoptotic death that is executed through the mitochondrial, or intrinsic, pathway.
• Table 12 Synergistic activity of compounds extracted from Scutellaria barbata
• Example 4 In vivo Efficacy of Actives Derived from BZLlOl in Humans [0139] In order to demonstrate the safety and clinical activity of oral BZLlOl, a combination of active compounds isolated from Scutellaria Barbata D. Don is studied in human patients with advanced breast cancer.
• Eligible patients have histologically confirmed metastatic breast cancer and measurable disease. Patients do not receive any other chemotherapy, hormone therapy or herbal medicine during the trial. Patients receive 350 ml (equivalent to 0.00001-1 gram each of one, two, three, four, five or all members of the group consisting of Apigenin, Luteolin, Scutellarein and Scutellarin) of drug per day until disease progression, toxicity or personal preference caused them to discontinue.
• the primary endpoints are safety, toxicity and tumor response.
• Patients are enrolled and receive drug. Mean age and mean number of prior treatments are recorded. Hematologic, and grade III or IV non-hematologic, adverse events (AEs), if any, are tracked and recorded. Patients who report grade I and II adverse events, such as nausea, diarrhea, headache, flatulence, vomiting, constipation, and fatigue, if any, are noted and recorded. Patients who are evaluable for response are evaluated and those with stable disease (SD) for >90 days and those with SD for >180 days are noted and recorded. Patients who have minor objective tumor regression are also noted and recorded. [0142] Patients are enrolled at one or more suitable research centers and sign informed consent approved by local institutional review boards.
• AEs non-hematologic, adverse events
• liver involvement >50% of liver parenchyma
• lymphangitic pulmonary involvement pulmonary involvement
• central nervous system involvement spinal cord compression not stabilized by therapy for >3 months
• Safety monitoring is conducted on a continuous basis and patients are seen by a physician for examination at baseline at every Y weeks.
• Adverse events are graded using Common Toxicity Criteria version 2, assigned a category by organ system and coded in relation to study drug as remote, possible, probably or definitely related.
• Baseline tumor assessments are done within 14 days of initiation of study drug and every three months. Responses are assessed using RECIST criteria.
• Study drug is administered at every visit, and at this visit compliance and a review of dosages taken was performed.
• Study drug is provided as a liquid in a sealed and labeled aluminum packet containing a full daily dose that is administered in a split dose twice a day. Daily study drug is administered until the determination of tumor progression or dose limiting toxicity is encountered, or until the subject decides to voluntarily discontinue, in which case, the reason for discontinuation is obtained.
• Example 4 Active concentrations in soluble matter extracted from Scutellaria barbata D. Don
• BZLlOl is prepared as described herein. Active compounds, Luteolin, Apigenin, Scutellarein, and Scutellarin, are identified and quantified relative to 1 mg of BZLlOl. The mass of each of Luteolin, Apigenin, Scutellarein, and Scutellarin in 1 mg of soluble matter in BZLlOl is given in table 4-1 : Table 4-1 : Proportions of Luteolin, Apigenin, Scutellarein, and Scutellarin per mg of BZLlOl
• Example 5 Scutellaria barbata D. Don extract in the treatment of treatment-refractive metastatic breast cancer
• BZLlOl an extract of Scutellaria barbata D. Don
• the extract, BZLlOl was prepared essentially as described hereinabove, and was given to patients who had undergone one or more courses of treatment for metastatic breast cancer.
• BZLlOl was given either once per day (q.d.) or twice per day (b.i.d.) as described below.
• 20 gram, 30 gram and 40 gram doses proved to be well tolerated, despite their being far higher than ever reported in the literature relating to Scutellaria barbata. Additionally, several patients demonstrated efficacy as discussed below.
• BZLlOl is an extract of Scutellaria barbata, which evinces a novel mechanism of action. Normal cells depend on citric acid cycle (>85%) and glycolysis ( ⁇ 7%) for energy production. Cancer cells depend on glycolysis (>85%) for energy production. BZLlOl inhibits energy production by inhibiting glycolysis. BZLlOl causes DNA damage and cancer cell death. BZLlOl does NOT cause cell death in normal cells. [0149] The following bases have been propounded for the selective cytotoxic activity of BZLlOl in cancer cells: Tumor cells rely on glycolysis for energy production. This is associated with increased endogenous levels of reactive oxygen species (ROS). Normal cells rely on oxidative phosphorylation for their energy needs.
• ROS reactive oxygen species
• BZLlOl treatment further increases ROS levels in tumor cells leading to hyper-activation of poly ADP ribose polymerase (PARP) and massive oxidative DNA damage.
• PARP poly ADP ribose polymerase
• BZLlOl treatment results only in mild increase of ROS levels and moderate DNA damage without PARP activation.
• Example 5 The major characteristics of the trial outlined in Example 3 and the current, Phase IB trial (Example 5) are compared in the following table 5-1.
• BZLlOl Phase IB Design [0152] Primary: • To determine the maximum tolerated dose of BZLlOl
• DLTs dose limiting toxicities
• Phase IB Preliminary Efficacy a) 21 of 27 were on trial for 28 days or more b) 8/21 (38%) stable >90 days c) 4/21 (19%) stable >180 days d) 18 of 27 were are evaluable by RECIST (at least one measurable lesion and follow- up scan has been completed or is pending) e) 6/18 (33%) stable >90 days f) 3/18 (17%) stable >180 days [0163]
• Tumor response Clinical benefit rate, Complete response, Partial response, Progression of disease
• Duration of response and survival time Duration of overall response, complete response and partial response, Overall survival, and Progression- free survival
• Extracts of Scutellaria Barbata inhibit the growth of breast cancer cells in vitro.
• BZLlOl treatment leads to the inhibition of glycolysis as evident from the decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate production
• BZLlOl invokes selective cell death in cancer cells and not healthy cells
• an extract of Scutellaria barbata D. Don administered at a dose of 20 grams, 30 grams or 40 grams dry weight is effective and well tolerated for the treatment of metastatic breast cancer, and particularly metastatic breast cancer that has proven refractory to treatment.
• daily doses of 15 grams dry weight to 60 grams dry weight of extract of Scutellaria barbata D. Don are effective in treating ER negative breast cancer, PR negative breast cancer, Her2/neu negative breast cancer and/or triple negative breast cancer, including those that have metastasized to other tissues. It is also considered that these doses are useful for the treatment of other ER negative, PR negative, Her2/neu negative and triple negative cancers.
• BZLlOl doses of 20, 30 and 40 grams dry weight per day are particularly useful for treatment of the aforementioned cancers, especially ER negative breast cancer, PR negative breast cancer, Her2/neu negative breast cancer and/or triple negative breast cancer, including those breast cancers that have metastasized to other tissues.
• Additional clinical trials of BZLlOl can be carried out following the methodology set forth in Example 4. A patient who has been diagnosed with cancer is treated with 20 grams dry weight, 30 grams dry weight or 40 grams dry weight (or some other amount greater than 15 grams dry weight, e.g. from about 15-60 grams dry weight) of BZLlOl and evaluated as set forth in Example 4, with appropriate modification depending upon the condition to be treated.
• Exemplary cancers to be treated include adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, Adult CNS brain tumors, Children CNS brain tumors, breast cancer, Castleman Disease, cervical cancer, Childhood Non-Hodgkin's lymphoma, colon and rectum (colorectal) cancer, endometrial cancer, esophagus cancer, Ewing's family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyageal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children's leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, lung carcinoid tumors, Non-Hodgkin's lymphom

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