CA2634931A1 - Nutraceutical therapeutic formulation - Google Patents
Nutraceutical therapeutic formulation Download PDFInfo
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- CA2634931A1 CA2634931A1 CA002634931A CA2634931A CA2634931A1 CA 2634931 A1 CA2634931 A1 CA 2634931A1 CA 002634931 A CA002634931 A CA 002634931A CA 2634931 A CA2634931 A CA 2634931A CA 2634931 A1 CA2634931 A1 CA 2634931A1
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- 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
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
Abstract
A pharmaceutical composition including a salt of rhodizonic acid, an OH anion-generating base, a non-toxic acid, a quinone, a salt-containing sulfite, catechol and, optionally, an acetogenin. The formulation demonstrates positive effects against cancer, autoimmune disease, viruses and provides antioxidant protection against peroxyl, hydroxy! and super oxide radicals.
Description
THERAPEUTIC FORMULATION
BACKGROUND AND SUMMARY OF THE INVENTION
1. Field of the Invention The present invention generally relates to a therapeutic composition. More particularly, the present invention relates to a pharmaceutical, nutraceutical, or nutratherapeutical formulation that includes antioxidants. The formulation demonstrates positive effects against cancer, autoimmune disease, viruses and provides antioxidant protection against peroxyl, hydroxyl and super oxide radicals.
II. Description of the Relevant Art It is well known that free radicals are chemically reactive molecules that damage cellular structure and function. Free radicals are oxidants that damage and destroy healthy cells. Oxygen-based free radicals include peroxyls (ROO-), superoxides (02-) and hydroxyls (-OH). Sources of free radicals include ultraviolet radiation, carcinogens, and high-fat processed foods. It is also known that physical stress and even normal cell function in the production of energy are both sources for the creation and release of free radicals. A broad variety of disease states have been linked to the presence of free .radicals, including arthritis, cancer, heart dysfunction, atherosclerosis, hyperoxia, stroke, cataractogenesis, retinal damage, liver injury, sexual dysfunction, periodontis, vasospasms, dermatitis, and asthma.
In response to the overwhelming presence of oxygen-based free radicals in our natural environment, attention has focused on antioxidants, compounds that can inhibit the cellular damage caused by free radicals. Natural sources of antioxidants are known and include vitamins C and E, broccoli, alpha-Lipoic acid, grapeseed, and green tea extract. While offering an avenue to obtaining the positive effects of antioxidants, the ' dosages of these natural foods needed to offset the oxidants is extremely high.
Attempts have been made to provide concentrated antioxidants as a pharmaceutical, a nutraceutical, or a nutratherapeutical according to various formulations. Each of these formulations included tetrahydroxy-1,4-quinone (C6H406) (hereinafter referred to occasionally as "THQ") (in its free form and its sulfited form), croconic acid (in its free form and its sulfited form), and catechol as active ingredients.
These formulations have gone by various names, including "Entelev ," "Cantron " (in three versions), "Cance{l ," and "Protocel " (in three versions). Perhaps the best known of these early attempts at providing an effective anti-cancer, anti-viral formulation is the "Cantron " composition which had, in addition to catechol, varied amounts of croconic acid (in its free form and its disulfited form), THQ (in its free form and its sulfited form) and rhodozonic acid, the latter converting in part to croconic acid (in its free form and its disulfited form) during the formulation process. Various additional ingredients to these formulations include copper, potassium, triquinoyl, leuconic acid, and traces of inositol.
While providing some improvement in the state of the art, these formulations have not proven either fully effective or completely desirable. These shortcomings include unmanageable and inadequate dosing requirements, undesirable physical characteristics of the composition, and safety issues related to the manufacturing process.
Dosage management has been a problem with these compositions in that the liquid of known formulations needs to be four to five times per day. This is an extremely difficult schedule to follow even under the best of circumstances. The problem is further compounded by the difficulty of traveling with these compositions which is bulky. The container top is subject to loosening because of the gases naturally generated by the .composition.
BACKGROUND AND SUMMARY OF THE INVENTION
1. Field of the Invention The present invention generally relates to a therapeutic composition. More particularly, the present invention relates to a pharmaceutical, nutraceutical, or nutratherapeutical formulation that includes antioxidants. The formulation demonstrates positive effects against cancer, autoimmune disease, viruses and provides antioxidant protection against peroxyl, hydroxyl and super oxide radicals.
II. Description of the Relevant Art It is well known that free radicals are chemically reactive molecules that damage cellular structure and function. Free radicals are oxidants that damage and destroy healthy cells. Oxygen-based free radicals include peroxyls (ROO-), superoxides (02-) and hydroxyls (-OH). Sources of free radicals include ultraviolet radiation, carcinogens, and high-fat processed foods. It is also known that physical stress and even normal cell function in the production of energy are both sources for the creation and release of free radicals. A broad variety of disease states have been linked to the presence of free .radicals, including arthritis, cancer, heart dysfunction, atherosclerosis, hyperoxia, stroke, cataractogenesis, retinal damage, liver injury, sexual dysfunction, periodontis, vasospasms, dermatitis, and asthma.
In response to the overwhelming presence of oxygen-based free radicals in our natural environment, attention has focused on antioxidants, compounds that can inhibit the cellular damage caused by free radicals. Natural sources of antioxidants are known and include vitamins C and E, broccoli, alpha-Lipoic acid, grapeseed, and green tea extract. While offering an avenue to obtaining the positive effects of antioxidants, the ' dosages of these natural foods needed to offset the oxidants is extremely high.
Attempts have been made to provide concentrated antioxidants as a pharmaceutical, a nutraceutical, or a nutratherapeutical according to various formulations. Each of these formulations included tetrahydroxy-1,4-quinone (C6H406) (hereinafter referred to occasionally as "THQ") (in its free form and its sulfited form), croconic acid (in its free form and its sulfited form), and catechol as active ingredients.
These formulations have gone by various names, including "Entelev ," "Cantron " (in three versions), "Cance{l ," and "Protocel " (in three versions). Perhaps the best known of these early attempts at providing an effective anti-cancer, anti-viral formulation is the "Cantron " composition which had, in addition to catechol, varied amounts of croconic acid (in its free form and its disulfited form), THQ (in its free form and its sulfited form) and rhodozonic acid, the latter converting in part to croconic acid (in its free form and its disulfited form) during the formulation process. Various additional ingredients to these formulations include copper, potassium, triquinoyl, leuconic acid, and traces of inositol.
While providing some improvement in the state of the art, these formulations have not proven either fully effective or completely desirable. These shortcomings include unmanageable and inadequate dosing requirements, undesirable physical characteristics of the composition, and safety issues related to the manufacturing process.
Dosage management has been a problem with these compositions in that the liquid of known formulations needs to be four to five times per day. This is an extremely difficult schedule to follow even under the best of circumstances. The problem is further compounded by the difficulty of traveling with these compositions which is bulky. The container top is subject to loosening because of the gases naturally generated by the .composition.
The physical characteristics of known formulations also make use of these compositions problematic. Specifically, the known compositions are designed to be orally ingested. However, the oral liquid has an extremely foul metallic taste. Users historically found the composition unappetizing, this problem being compounded by the user's need to consume the composition four or five times daily. Beyond taste, the dark black liquid of known compositions is itself visually unappealing. The color of the known compositions is known to stain teeth, clothing, furniture, and carpeting.
Of concern to manufacturers is the production process itself. The manufacturing procedure of the formula is extremely dangerous as the oxidation process to create the various compounds causes the release of a highly toxic and acidic gas. The manufacturing method of known compositions also causes the release of hazardous nitrous peroxides into the atmosphere, causing pollution and possible ozone damage.
Experience has taught that the larger the volume of product being produced, the more dangerous the chemical reaction. So dangerous is the manufacturing procedure for known compositions that production on a large scale may lead to injury or death, which is the reason that previous manufacturing has been done on a small scale only.
Because of the level of pernicious nitric fumes generated, even protective wear that ' would ordinarily be effective (such as gas masks) fail to protect the operator.
Furthermore, experience has shown that stove wiring, fan motors, vacuum motors and general laboratory equipment must be renewed constantly and at considerable expense due to the presence of these acidic gases. In addition, laboratory cleanliness is all but impossible to maintain given the presence of these gases, resulting in stained walls, floors and furniture. So extreme is the problem that to maintain laboratory cleanliness at even the most rudimentary level the walls must be recoated with paint after the production of each batch. Given these problems, FDA or regulatory authority inspection compliance has been problematic.
Beyond the difficulties associated with the production of known compositions, the known compositions have a variety of demonstrable shortcomings. First, prior compositions fail to produce an optimum effect in that they do not utilize the most effective administration methods or dosages. Second, known compositions are unsafe to manufacture in any significant quantity. Third, known compositions have a black, tarry appearance and are unappealing to the user in appearance. Fourth, known compositions are unappealing to the user in taste.
Accordingly, an improved formulation that demonstrates high antioxidant characteristics, increased efficacy against cancer, autoimmune diseases and a broad array of viruses (including the virus that causes AIDS) while allowing safe manufacture and appeal to the user is desired.
SUMMARY OF THE INVENTION
The present invention overcomes the failings of known compositions and methods of disease treatments as set forth in the prior art by providing a composition that is high in antioxidants, is safe to produce and is adaptable to administration to a patient without the undesirable appeal problems associated with the prior art and is more efficacious against disease states.
The composition of the present invention generally includes a salt of rhodizonic acid and an OH anion-generating base (resulting in croconic acid), a non-toxic acid; a quinone, a salt-containing sulfite, catechol and, optionally, an acetogenin.
It may be characterized as a pharmaceutical, a nutraceutical, or a nutratherapeutical composition.
The composition of the present invention is a strong antioxidant. It is also effective against cancer, autoimmune diseases and viruses. The present composition has shown to be an effective antioxidant that works on all forms of the oxygen-related species of free radicals, including the peroxyl, hydroxyl and super oxide radicals. It is also believed that the composition of the present'invention may have utility in reducing the side effects of radiation therapy and chemotherapy as well as in radio-sensitizing tumors, thus improving the efficacy of radiation therapy.
The composition of the present invention also overcomes the problems discussed above that are commonly associated with its production by the effective elimination of the noxious fumes. This results in improved laboratory conditions and ease of maintenance of proper conditions.
-~ ---=--- --= ---- ._. ... ___ .
The present invention also improves the efficacy of the formula against tumors by providing chronic cytotoxic dosing of tumors and by providing a more consistent supply of antioxidants in the bloodstream, therefore providing a more effective in-vivo method of destroying the pernicious oxygen species of free radicals that are implicated in over 50 disease states.
As a further improvement over the art, the various compositions of the present invention achieve their efficacies without the use of such components as copper, potassium, triquinoyl, leuconic acid and rhodozonic acid. The absence of these components without compromising the effectiveness of the various compositions of the present invention is a testament to the unique approach taken herein. By avoiding such extra components both possible adverse patient reactions and cost may be reduced. -Other advantages and features of the present invention will become apparent from the following detailed description and appended claims.
DESCRIPTION OF THE DRAWINGS
FIG. I is a graph showing a comparison of the antioxidant effect of the formula of the present invention compared with antioxidants obtained from foods and pure vitamin sources.
FIG. 2 is a graph illustrating the time release kinetics of the composition according to the present invention.
FIG. 3 is a graph demonstrating pharmacokinetics of the levels of active ingredient after a single oral dose of the composition of the present invention.
FIG. 4 is a graph that shows the concentration and effect of the tumor-killing composition of the present invention over time.
FIG. 5 is a chart comparing the cytotoxicity of known anticancer pharmaceuticals and known nutraceuticals.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The composition and method of use of the present invention are set forth below.
However, it is envisioned that alternate compositions of the present invention may be adopted without deviating from the present invention. The preferred embodiments are set forth hereafter.
The Composition In general the composition consists of a salt of rhodizonic acid, an OH anion-generating base, a non-toxic acid, a quinone, a salt-containing sulfite, and catechol. An optional component is an acetogenin. The composition of the present invention provides significantly higher levels of antioxidants than the above-mentioned sources of vitamins E and C, broccoli, aipha-Lipoic acid, grapeseed and green tea extract, commonly accepted sources of antioxidants. The concentration of antioxidants of the present invention compared with these known sources is illustrated in Figure 1 in which equivalent amounts of the natural sources are indicated compared with a single dose of the composition of the present invention.
Catechol, its Analogs and Equivalents Catechol is a biologically significant organic phenol. It comprises two hydroxyl groups attached to a benzene ring. Catechol demonstrated significant anti-cancer activity in our studies. Catechol, its analogs and equivalents, as used herein may be characterized by the following.
Rs .' R3 Rs I ~ OR2 ORI
where Ri, R2, R3, R4 R5, R6 may be any combination of hydrogen, alkyl, alkenyl hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glyco-saccharide, amino acid, peptide, polypeptide, protein and any of the foregoing attached to a central carbon, nitrogen, oxygen, sulfur, phosphorus or silicon atom. In addition, Ri, R2, R3, R4, R5, R6 may be any of the R groups taken together will. form a C3 to C10 membered ring.
As an antioxidant catechol may include flavone, flavonol, flavanone, isoflavone and anthocyane. Specifically, this may include flavone having the generic structure shown below (as a specific example luteolin is also illustrated):
OH
OH
Nz. O
I / I HO ( NZ11 O
. / ~
O
OH O
luteolin As a flavonol it may have the generic structure shown below (as a specific example quercetin is also illustrated):
OH
OH
\o HO O
O OH
OH O
quercetin As a flavanone it may have the generic structure shown below (as specific examples naringenin and taxifolin are also illustrated):
OH OH
OH OH
HO ( O HO O ~ ~
OH
O
OH O OH O
naringenin taxffolin As an isoflavone it may have the generic structure shown below (as a specific example quercetin is also illustrated):
HO O
0 oH O OH
Genisfein Finally, as an anthocyane it may have the generic structure shown below (as a specific example cyanidin chloride is also illustrated):
OH
OH
X + CI-r HO ~ O . ~.
l oH
OH
cyanidin chloride Acetogenins Acetogenins are active compounds which act as anti-neoplastic agents. It is believed that acetogenins act against cancer by regulating the production of ATP in the mitochondria of unhealthy cells. In some of its embodiments the present invention combines the powerful effect of acetogenins with catechol. The addition of acetogenins in the present composition improve the effectiveness of the catechol by destroying both resistant and non-resistant cells that otherwise might not be destroyed by catechol or acetogenin alone. This is important in that even a small number of cells left intact after treatment can multiply geometrically in little time and can render either catechol or acetogenin useless. Importantly, acetogenins kill multiple drug-resistant cells (MDR
cells) which, in fact, may be resistant to catechol.
The Preferred Composition The preferred composition of the present invention includes the following essential ingredients. Other ingredients (for example, flavorings) may be added without deviating from the scope of the present invention.
= an antioxidant selected from the group consisting of catechol, its analogs and its equivalents in the amount of between 1 g and 10,000 g (10 kg), preferably between 150 g and 750 g = an anti-neoplastic agent selected from the group consisting of acetogenin, its analogs and its equivalents in the amount of between .1 mg and 2,000 g (2 kg) and preferably between 80 grams and 100 grams = an acid selected from the group consisting of croconic acid, its analogs and its equivalents and sulfites of croconic acid, their analogs and their equivalents in the amount of between I g and 1500 g (1.5 kg) and preferably between 15 g and 30g = a quinone selected from the group consisting of tetrahydroxyquinone, its analogs and its equivalents and sulfites of tetrahydroxyquinone, their analogs and their equivalents in the amount of between 1 g and 2,500 g (2.5 kg), preferably between 40 g and 80 g General Method for Making the Preferred Composition The composition of the present invention may be prepared by the foflowing general procedures:
Create a suspension of a salt of. rhodozonic acid (C6O6Na2) and any base that can generate OH anions by mixing both in a flask with water. (it should be noted that analogs and equivalents of rhodozonic acid could be substituted for rhodozonic acid.) The amount of the water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL and 1000 mL (1 L). The amount of the rhodozonic acid is preferably between I g and 7300 g (7.3 kg) and is more preferably between :100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg(OH)2, and Ca(OH)2. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all of the rhodizonic acid is dissolved and the solution becomes bright yellow. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC, 0.116 moles). Preferably the suspension is heated to between 25 C and 100 C. More preferably the suspension is heated to between 90 C and 100 C. The step of dissolving the rhodizonic acid takes about two hours. The new suspension demonstrates a pH of about 13Ø
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL
of water and more preferably to between 300 mL and 1000 mL of water to form a solution.
(It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Bring the pH of the solution formed in Step 2 (or the solution formed in the Alternative Step) to between preferably 7.0 and 10.0 and more preferably between 9.0 and 9.4.
STEP 4:
Add tetrahydroxy-1,4-quinone (C6H406) to the solution of Step 3, resulting in a black suspension. The tetrahydroxy-1,4-quinone is provided preferably in an amount of between I g and 2500 g (2.5 kg) and more preferably in an amount of between 40 g and 80 g. (Analogs and equivalents of tetrahydroxy-1,4-quinone may be substituted for tetrahydroxy-1,4-quinone.) STEP 5:
Add water and heat the suspension of Step 4 to completely dissolve all materials.
Preferably between I mL and 2000 mL of water is used, and more preferably between 1000 mL and 1500 mL of water is used. Heating is preferably between 70 C and and is more preferably between 85 C and 100 C. Dissolution of the materials preferably occurs between 1 and 180 minutes and rriore preferably occurs between 5 minutes'and 60 minutes.
STEP 6:
Dissolve a salt containing a sulfite (S03 2) in water and add to the flask of the solution of Step 5. The salt used in Step 6 is preferably taken from the group consisting of Na2SO3, Li2SO3, K2S03, MgSO3, and Ca2SO3. The amount of sulfite used in this step is preferably between I g and 10,000 g (10 kg) and is more preferably between 1000 g (1 kg) and 3000 g (3 kg). The amount of water used in this step is preferably between 9 mL and 20,000 mL and more preferably is in the range of between 5000 mL and mL.
As an alternative to the addition of a salt containing a sulfite a sulfurous acid may be added to the base to generate sodium sulfite in situ.
STEP 7:
Adjust the pH of the solution formed in Step 6 to preferably between 5.0 and 7.9 and more preferably to between 6.5 and 6.9.
STEP 8:
Heat the mixture of Step 7 first to preferably between 60 C and 100 C and more preferably between 90 C and 100 C for preferably between 1 minute and 60 minutes and more preferably between 5 and 10 minutes.
STEP 9:
Heat the mixture of Step 8 first to preferably between 0 C and 100 C and more preferably between 85 C and 95 C for preferably between 1 minute and 180 minutes and more preferably between 45 and 60 minutes. A black precipitate solution will form.
STEP 10:
Allow the solution of Step 9 to cool to preferably between 0 C and 60 C and more preferably to between 20-25 C.
STEP 11:
Dissolve between 1 g and 10,000 g (10 kg) and preferably between 150 g and 750 g of catechol (C6H602) in water and add to the solution of Step 10. The amount of water used in this step is preferably between I mL and 5000 mL and more preferably is in the range of between 1000 mL and 2000 ml. (Analogs and equivalents of catechol may be substituted for catechol.) STEP 12:
Adjust the pH of the suspension of Step 11 to preferably between 1.0 and 12.0 and more preferably to between 7.0 and 7.5.
STEP 13 (OPTIONAL):
An acetogenin (including its analogs and equivalents) may be added to the composition of Step 12 preferably in the amount of between 0.1 mg to 2000 g (2 kg) and, more preferably, in the amount of between 80 g and 100 g. The addition of an acetogenin would enhance the cancerous cell-killing potency of the composition, and particularly on drug-resistant (MDR) cells.
STEP 14:
Increase the final volume of the solution of Step 11 by adding water preferably in ~
the amount of between 5 L and 100 L and more preferably in the amount of between 10 Land 15L.
Additional Component - Time Release Mechanism In vitro studies have verified that the above-mentioned Cantron has anti-cancer activity. However, chronic dosing is required in order for this composition to be effective. The half-life of the Cantron formula was thought, at one time, to be between six and eight hours. Importantly, recent studies undertaken by the inventor of the present composition and its method of formulation have shown, surprisingly, that the biomarker for Cantron only stays in the bloodstream for a maximum of two hours and only stays in tumors for one hour.
According to the present invention, the delivery system has been altered by providing a time release formulation to obtain optimum anti-cancer effects by delivering a constant supply of the active ingredients into the bloodstream. It is this chronic exposure to tumors which obtains full efficacy of the present composition.
To effect a time release mechanism in the various compositions of the present invention, once the liquid material is produced as set forth above, the liquid is converted to a dry powder form by techniques such as lypholization, spray or by vacuum drying.
The powder is then coated to produce time release beads or pellets. Capsules (gelatin or non-gelatin) are then filled with the beads or pellets. (The time release beads may be used in animal food such as animal treats as weli.) A description of the time release process may be found in U.S. Patent No. 5,292,461, "Process for the Production of Pellets."
The time release formulation provides significant advantages over the prior art by sustaining an effective amount of the composition in the user's bloodstream at all times while medicated. Effectiveness of the time release formulation of the present composition is addressed below with respect to Figure 2.
Example - Method of Making the Preferred Composition The following is a non-limiting example of a method of producing the preferred composition of the present invention.
A suspension of rhodizonic acid disodium salt (C6O6Na2, 124 g, 0.58 moles) and KOH (2N, 168 g 1, 0.5 L, pH = 12.4) was created by mixing the two components together in a 10 L flask. This suspension was heated for approximately two hours to reflux until all of the rhodizonic acid disodium salt was dissolved and the solution became bright yellow. HCL (2N, 200 ml) was then added to the solution to bring the pH
of the solution formed to 9.2. (It should be noted that while an acid was added to the solution to adjust the pH to its desired level, it may be required in the alternative to use a base to make the same adjustment in a different expe(ment.) Tetrahydroxy-1,4-quinone (C6H406, 50.4 g, 7.1 moles) was added to the solution to achieve a black suspension. Water was next added (1.3 L). The suspension was heated to 90 C
for 10 minutes to completely dissolve all of the materials. Sodium sulfite (Na2SO3, 1490 g, 11.8 moles) was dissolved in 6 L of water and was added to the 10 L flask of the solution. HCI was then added to bring the pH of the solution to 6.5-6.9.
The resulting mixture was heated first to 100 C for 10 minutes and Was then heated again to 90 C for 50 minutes, resulting in the formation of a black precipitate solution. This solution was allowed to cool to room temperature (20-25 C). An amount of Catechol (C6H602, 365 g, 3.12 moles) was dissolved in 2 L of water. This was added to the solution. The pH of this suspension was adjusted to between 7.0-7.5.
The final volume of the solution thus achieved was increased to 13 L by adding water.
Variants of the Preferred Composition While the preferred composition has been set forth above, a number of variations of this composition have demonstrated characteristics that are similar to those of the preferred composition. These variants were prepared according to the following 1. VARIANTS WITH CATECHOL
A. Catechol Plus Acetogenins Catechol (C6H602) in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 150 g and 750 g is combined with an acetogenin preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in Ihe amount of between 80 g and 100 g. There are over 1000 different types of this compound plus extracts from source plants. This powder is then made into pill form or formulated as time release and made into pill form.
B. Catechol plus THQ
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is combined with catechol (C6H602) preferably in the amount of between 1 g and 10,000 g (10 kg) and more preferably in the amount of between 150 g and 750 g. This powder is then made into pill form or formulated as time release and made into pill form.
C. Catechol plus THQ Sulfite STEP 1:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between 1 g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in 3 liters of water and heated at 90 C for 10 minutes to compietely dissolve all materials.
STEP 2:
Dissolve a sulfite-containing salt preferably in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g(3 kg) in 6 L of water and add to the solution created in Step 1.
STEP 3:
Adjust the pH of the solution of Step 2 to 6.5-6.9.
STEP 4:
Heat the mixture of Step 3 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 5:
Catechol (in ranges along the lines set forth above with respect to the preferred embodiment of the present invention) is added and the mixture is stirred to dissolve the catechol. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
D. Catechol plus Croconic Acid STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between 1 g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between I g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step 9 to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt -(C505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS 1 AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 7.4 (6.9-7.9).
STEP 4:
Catechol (in ranges along the lines set forth above with respect to the preferred embodiment of the present invention) was added and the mixture is stirred to dissolve catechol. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
E. Catechol plus Croconic Acid Sulfite STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the -water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between I g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2.. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C5505K2, yield = 20% by HPLC). (Note that as an altemative to forming croconic acid in the suspension croconic acid may be added directly. If this option is selected, preferably between 1 g and 1500g (1.5 kg) and more preferably between 15g and 30g of croconic acid may be added preferably to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution.) ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) ,to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.2 (9.0-9.4).
STEP 4:
-,. - - ----- = --- ---- =- = -- -__ .
Dissolve a sulfite-containing salt preferably in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 3.
STEP 5:
Adjust the pH of the solution of Step 4 to 6.5-6.9.
STEP 6:
Heat the mixture of Step 5 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 7:
Catechol (in ranges along the lines set forth above with respect to the preferred embodiment of the present invention) was added and the mixture was stirred to dissolve catechol. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
II. VARIANTS WITH ACETOGENINS
A. Acetogenin plus THQ
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably. between 40 g and 80 g is niixed with an acetogenin preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g. The components were mixed as solids and were made into pill form or formulated as time release and made into pill form.
B. Acetogenin plus THQ Sulfite STEP 1:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in 3 liters of water and heated at 90 C for 10 minutes to completely dissolve all materials.
STEP 2:
Dissolve a sulfite-containing salt preferably in the amount of between 1 g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 1.
STEP 3:
Adjust the pH of the solution of Step 2 to 6.5-6.9.
STEP 4:
Heat the mixture of Step 3 first (at sub-step (a)) to 4 00 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 5:
This solution is freeze dried to a powder.
STEP 6:
An acetogenin, preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g, is added to the powder in Step 5 The materials are then blended. This blended material is made into pill form or formulated as time release and made into pill form.
C. Acetogenin plus Croconic Acid STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between I mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between I g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between I g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between I g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 7.4 (6.9-7.9) STEP 4:
This solution is freeze dried to a powder.
STEP 5:
An acetogenin in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g is added to the powder from Step 4. This mixture was made into pill form or formulated as time release and made into pill form.
D. Acetogenin plus Croconic Acid Sulfite STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between 1 g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g. ::
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt IC505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between I g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (it should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.0-9.4.
STEP 4:
Dissolve a sulfite-containing salt preferably in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 3.
STEP 5:
Adjust the pH of the solution of Step 4 to 6.5-6.9.
STEP 6:
Heat the mixture of Step 5 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 7:
The solution is freeze dried to a powder.
STEP 8:
An acetogenin preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g is added to the powder from Step 7. This mixture may be made into pill form or formulated as time release and made into pill form.
Ill. VARIANTS WITH THQ
. A. THQ Sulfite pius Croconic Acid Sulfite STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between I mL and 10,000 mL (10 L) and more preferably between 300 mL
and 1000 mL (1 L). The amount of the, rhodozonic acid is preferably between I
g and 7300 g (7.3 kg) and is more preferably between 100 g and 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g.
STEP2:
Heat the suspension created in Step 1 to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC).
STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.0-9.4.
STEP 4:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in the solution of Step 3, resulting in a black suspension.
STEP 5:
Add water (1.3 L) and heat the suspension of Step 4 to 90 C for 10 minutes to completely dissolve all materials.
STEP 6:
Dissolve a sulfite-containing salt preferably in the amount of between 1 g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 5.
STEP 7:
Adjust the pH of the solution of Step 6 to 6.5-6.9.
STEP 8:
Heat the mixture of Step 7 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes, resulting in the formation of a black precipitate solution.
STEP 9:
Allow the solution of Step 8 to cool to room temperature (20-25 C).
STEP 10:
Adjust the pH of the suspension of Step 90 to 7.0-7.5.
STEP 11:
Increase the final volume of the solution of Step 11 to 13 L by adding the requisite amount of water. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
C. THQ plus Croconic Acid STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between I mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between 1 g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between I g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C5O5K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (it should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.0-9.4.
STEP 4:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in the solution of Step 3, resulting in a black suspension.
STEP 5:
Add water (1.3 L) and heat the suspension of Step 4 to 90 C for 10 minutes to completely dissolve all materials.
STEP 6:
Allow the solution of Step 5 to cool to room temperature (20-25 C).
STEP 7:
Adjust the pH of the suspension of Step 6 to 7.0-7.5.
STEP 8:
Increase the final volume of the solution of Step 7 to 13 L by adding the requisite amount of water. This mixture was freeze dried to a powder and made into pill 'form or formulated as time release and made into pill form.
Individual Component Compositions Many of the positive effects may be delivered by treatment using individual components. Specifically, catechol (between I g - 10,000 g), tetrahydroxyquinone (in its free and sulfited forms) (between I g - 2500 g), and croconic acid (in its free and sulfited forms) (between I g - 1500 g) may be individually delivered in the forms discussed herein, including both tablet (in both time release and non-time release forms), a powder, a gel capsule, an intravenous liquid, and transdermally.
Administration of the Composition Regardless of the selected composition, the formulation of the present invention may be administered in any one of a variety of methods. A combination of these methods may also be used. These methods include liquid, powder or gel forms.
The composition may be administered externally by transdermal delivery. Regardless of the form of the composition the objective is to achieve and maintain an effective amount of the composition in the patient's blood stream and at the tumor site. The forms of delivery discussed hereafter eliminate the negative appeal of the dark black liquid of earlier compositions while improving dosage compliance, optimum efficiency, and eliminate the staining of teeth and clothing that was an inherent characteristic of these earlier compositions.
Intravenous Administration When administered in liquid form, the composition may be introduced via intravenous delivery. Intravenous administration particularly assures that an effective amount of the composition can be maintained in the patient's bloodstream at all times.
As a further variant of the intravenous form of administration the composition of the present invention may be injected directly into the patient.
Oral Administration When administered in liquid form, the composition may also be introduced orally.
An optional approach for oral administration for the iiquid composition is administrative by way of a gel capsule.
As set forth above, an altemative to the liquid form of the composition is to convert the liquid composition form to a dry powder form. The dry powder may then be tabletized and conveniently administered as a tablet (including sublinqual tablets) or may be coated with a time release agent then encapsulated as discussed above.
Oral forms of the composition of the present invention as described above :should be taken every two hours during waking hours in either one or two tablets or capsules. ;.
The patient is given a double dose before retiring for the night. No more than six hours should elapse between doses. Transdermal Administration As an alternative to the intravenous and oral techniques for administering the composition of the present invention, the composition may be delivered transdermally by use of a patch or a transdermal gel. If administered as a patch, a single patch is attached to the patient's pulse point and is replaced every four to twelve hours. In either event, the transdermal delivery mechanism provides a constant supply of the active ingredients of the present invention to the patient's bloodstream.
Effectiveness of the Composition The time-release kinetics of the composition of the present invention are set forth in Figure 2 which shows percentage release along the Y-axis and time along the X-axis.
As shown, release exceeds 90% after 12 hours. Release of 100% is achieved after13 hours. Figure 3 illustrates the levels of active ingredient after a single oral ingestion of the composition of the present invention. Concentration is shown on the Y-axis and time (in hours) is shown on the X-axis.
In addition to its high-antioxidant concentration, the composition of the present invention has demonstrated significant anti-cancer effects. The composition provides a tumor-killing approach to resolution of a broad variety of cancers. The concentration of the tumor-killing composition over time is shown in Figure 4. According to this graph, the surviving fraction of cancer cells (shown in the Y-axis) versus concentration (shown in the X-axis) is illustrated. The exposure is generally ineffective over two hours but begins to provide maximum effect over twenty-four hours. The concentration is clearly effective at seven days.
The composition of the present invention demonstrates high cytotoxicity when compared with anticancer pharmaceuticals and nutraceuticals. This comparison is shown in Figure 5 in anticancer efforts in the case of colon cancer. According to this comparison, the composition of the present invention demonstrates a cytotoxicity of 2.5 compared with known anticancer pharmaceuticals 5-fluorouracil, cis-platinum, adriamycin, vincristine and taxol demonstrating increasing cytotoxicy and nutraceuticals in the forms of alpha-lipoic acid, vitamins E and C, green tea, and grapeseed, which show decreasing cytoxicity.
Of concern to manufacturers is the production process itself. The manufacturing procedure of the formula is extremely dangerous as the oxidation process to create the various compounds causes the release of a highly toxic and acidic gas. The manufacturing method of known compositions also causes the release of hazardous nitrous peroxides into the atmosphere, causing pollution and possible ozone damage.
Experience has taught that the larger the volume of product being produced, the more dangerous the chemical reaction. So dangerous is the manufacturing procedure for known compositions that production on a large scale may lead to injury or death, which is the reason that previous manufacturing has been done on a small scale only.
Because of the level of pernicious nitric fumes generated, even protective wear that ' would ordinarily be effective (such as gas masks) fail to protect the operator.
Furthermore, experience has shown that stove wiring, fan motors, vacuum motors and general laboratory equipment must be renewed constantly and at considerable expense due to the presence of these acidic gases. In addition, laboratory cleanliness is all but impossible to maintain given the presence of these gases, resulting in stained walls, floors and furniture. So extreme is the problem that to maintain laboratory cleanliness at even the most rudimentary level the walls must be recoated with paint after the production of each batch. Given these problems, FDA or regulatory authority inspection compliance has been problematic.
Beyond the difficulties associated with the production of known compositions, the known compositions have a variety of demonstrable shortcomings. First, prior compositions fail to produce an optimum effect in that they do not utilize the most effective administration methods or dosages. Second, known compositions are unsafe to manufacture in any significant quantity. Third, known compositions have a black, tarry appearance and are unappealing to the user in appearance. Fourth, known compositions are unappealing to the user in taste.
Accordingly, an improved formulation that demonstrates high antioxidant characteristics, increased efficacy against cancer, autoimmune diseases and a broad array of viruses (including the virus that causes AIDS) while allowing safe manufacture and appeal to the user is desired.
SUMMARY OF THE INVENTION
The present invention overcomes the failings of known compositions and methods of disease treatments as set forth in the prior art by providing a composition that is high in antioxidants, is safe to produce and is adaptable to administration to a patient without the undesirable appeal problems associated with the prior art and is more efficacious against disease states.
The composition of the present invention generally includes a salt of rhodizonic acid and an OH anion-generating base (resulting in croconic acid), a non-toxic acid; a quinone, a salt-containing sulfite, catechol and, optionally, an acetogenin.
It may be characterized as a pharmaceutical, a nutraceutical, or a nutratherapeutical composition.
The composition of the present invention is a strong antioxidant. It is also effective against cancer, autoimmune diseases and viruses. The present composition has shown to be an effective antioxidant that works on all forms of the oxygen-related species of free radicals, including the peroxyl, hydroxyl and super oxide radicals. It is also believed that the composition of the present'invention may have utility in reducing the side effects of radiation therapy and chemotherapy as well as in radio-sensitizing tumors, thus improving the efficacy of radiation therapy.
The composition of the present invention also overcomes the problems discussed above that are commonly associated with its production by the effective elimination of the noxious fumes. This results in improved laboratory conditions and ease of maintenance of proper conditions.
-~ ---=--- --= ---- ._. ... ___ .
The present invention also improves the efficacy of the formula against tumors by providing chronic cytotoxic dosing of tumors and by providing a more consistent supply of antioxidants in the bloodstream, therefore providing a more effective in-vivo method of destroying the pernicious oxygen species of free radicals that are implicated in over 50 disease states.
As a further improvement over the art, the various compositions of the present invention achieve their efficacies without the use of such components as copper, potassium, triquinoyl, leuconic acid and rhodozonic acid. The absence of these components without compromising the effectiveness of the various compositions of the present invention is a testament to the unique approach taken herein. By avoiding such extra components both possible adverse patient reactions and cost may be reduced. -Other advantages and features of the present invention will become apparent from the following detailed description and appended claims.
DESCRIPTION OF THE DRAWINGS
FIG. I is a graph showing a comparison of the antioxidant effect of the formula of the present invention compared with antioxidants obtained from foods and pure vitamin sources.
FIG. 2 is a graph illustrating the time release kinetics of the composition according to the present invention.
FIG. 3 is a graph demonstrating pharmacokinetics of the levels of active ingredient after a single oral dose of the composition of the present invention.
FIG. 4 is a graph that shows the concentration and effect of the tumor-killing composition of the present invention over time.
FIG. 5 is a chart comparing the cytotoxicity of known anticancer pharmaceuticals and known nutraceuticals.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The composition and method of use of the present invention are set forth below.
However, it is envisioned that alternate compositions of the present invention may be adopted without deviating from the present invention. The preferred embodiments are set forth hereafter.
The Composition In general the composition consists of a salt of rhodizonic acid, an OH anion-generating base, a non-toxic acid, a quinone, a salt-containing sulfite, and catechol. An optional component is an acetogenin. The composition of the present invention provides significantly higher levels of antioxidants than the above-mentioned sources of vitamins E and C, broccoli, aipha-Lipoic acid, grapeseed and green tea extract, commonly accepted sources of antioxidants. The concentration of antioxidants of the present invention compared with these known sources is illustrated in Figure 1 in which equivalent amounts of the natural sources are indicated compared with a single dose of the composition of the present invention.
Catechol, its Analogs and Equivalents Catechol is a biologically significant organic phenol. It comprises two hydroxyl groups attached to a benzene ring. Catechol demonstrated significant anti-cancer activity in our studies. Catechol, its analogs and equivalents, as used herein may be characterized by the following.
Rs .' R3 Rs I ~ OR2 ORI
where Ri, R2, R3, R4 R5, R6 may be any combination of hydrogen, alkyl, alkenyl hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glyco-saccharide, amino acid, peptide, polypeptide, protein and any of the foregoing attached to a central carbon, nitrogen, oxygen, sulfur, phosphorus or silicon atom. In addition, Ri, R2, R3, R4, R5, R6 may be any of the R groups taken together will. form a C3 to C10 membered ring.
As an antioxidant catechol may include flavone, flavonol, flavanone, isoflavone and anthocyane. Specifically, this may include flavone having the generic structure shown below (as a specific example luteolin is also illustrated):
OH
OH
Nz. O
I / I HO ( NZ11 O
. / ~
O
OH O
luteolin As a flavonol it may have the generic structure shown below (as a specific example quercetin is also illustrated):
OH
OH
\o HO O
O OH
OH O
quercetin As a flavanone it may have the generic structure shown below (as specific examples naringenin and taxifolin are also illustrated):
OH OH
OH OH
HO ( O HO O ~ ~
OH
O
OH O OH O
naringenin taxffolin As an isoflavone it may have the generic structure shown below (as a specific example quercetin is also illustrated):
HO O
0 oH O OH
Genisfein Finally, as an anthocyane it may have the generic structure shown below (as a specific example cyanidin chloride is also illustrated):
OH
OH
X + CI-r HO ~ O . ~.
l oH
OH
cyanidin chloride Acetogenins Acetogenins are active compounds which act as anti-neoplastic agents. It is believed that acetogenins act against cancer by regulating the production of ATP in the mitochondria of unhealthy cells. In some of its embodiments the present invention combines the powerful effect of acetogenins with catechol. The addition of acetogenins in the present composition improve the effectiveness of the catechol by destroying both resistant and non-resistant cells that otherwise might not be destroyed by catechol or acetogenin alone. This is important in that even a small number of cells left intact after treatment can multiply geometrically in little time and can render either catechol or acetogenin useless. Importantly, acetogenins kill multiple drug-resistant cells (MDR
cells) which, in fact, may be resistant to catechol.
The Preferred Composition The preferred composition of the present invention includes the following essential ingredients. Other ingredients (for example, flavorings) may be added without deviating from the scope of the present invention.
= an antioxidant selected from the group consisting of catechol, its analogs and its equivalents in the amount of between 1 g and 10,000 g (10 kg), preferably between 150 g and 750 g = an anti-neoplastic agent selected from the group consisting of acetogenin, its analogs and its equivalents in the amount of between .1 mg and 2,000 g (2 kg) and preferably between 80 grams and 100 grams = an acid selected from the group consisting of croconic acid, its analogs and its equivalents and sulfites of croconic acid, their analogs and their equivalents in the amount of between I g and 1500 g (1.5 kg) and preferably between 15 g and 30g = a quinone selected from the group consisting of tetrahydroxyquinone, its analogs and its equivalents and sulfites of tetrahydroxyquinone, their analogs and their equivalents in the amount of between 1 g and 2,500 g (2.5 kg), preferably between 40 g and 80 g General Method for Making the Preferred Composition The composition of the present invention may be prepared by the foflowing general procedures:
Create a suspension of a salt of. rhodozonic acid (C6O6Na2) and any base that can generate OH anions by mixing both in a flask with water. (it should be noted that analogs and equivalents of rhodozonic acid could be substituted for rhodozonic acid.) The amount of the water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL and 1000 mL (1 L). The amount of the rhodozonic acid is preferably between I g and 7300 g (7.3 kg) and is more preferably between :100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg(OH)2, and Ca(OH)2. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all of the rhodizonic acid is dissolved and the solution becomes bright yellow. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC, 0.116 moles). Preferably the suspension is heated to between 25 C and 100 C. More preferably the suspension is heated to between 90 C and 100 C. The step of dissolving the rhodizonic acid takes about two hours. The new suspension demonstrates a pH of about 13Ø
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL
of water and more preferably to between 300 mL and 1000 mL of water to form a solution.
(It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Bring the pH of the solution formed in Step 2 (or the solution formed in the Alternative Step) to between preferably 7.0 and 10.0 and more preferably between 9.0 and 9.4.
STEP 4:
Add tetrahydroxy-1,4-quinone (C6H406) to the solution of Step 3, resulting in a black suspension. The tetrahydroxy-1,4-quinone is provided preferably in an amount of between I g and 2500 g (2.5 kg) and more preferably in an amount of between 40 g and 80 g. (Analogs and equivalents of tetrahydroxy-1,4-quinone may be substituted for tetrahydroxy-1,4-quinone.) STEP 5:
Add water and heat the suspension of Step 4 to completely dissolve all materials.
Preferably between I mL and 2000 mL of water is used, and more preferably between 1000 mL and 1500 mL of water is used. Heating is preferably between 70 C and and is more preferably between 85 C and 100 C. Dissolution of the materials preferably occurs between 1 and 180 minutes and rriore preferably occurs between 5 minutes'and 60 minutes.
STEP 6:
Dissolve a salt containing a sulfite (S03 2) in water and add to the flask of the solution of Step 5. The salt used in Step 6 is preferably taken from the group consisting of Na2SO3, Li2SO3, K2S03, MgSO3, and Ca2SO3. The amount of sulfite used in this step is preferably between I g and 10,000 g (10 kg) and is more preferably between 1000 g (1 kg) and 3000 g (3 kg). The amount of water used in this step is preferably between 9 mL and 20,000 mL and more preferably is in the range of between 5000 mL and mL.
As an alternative to the addition of a salt containing a sulfite a sulfurous acid may be added to the base to generate sodium sulfite in situ.
STEP 7:
Adjust the pH of the solution formed in Step 6 to preferably between 5.0 and 7.9 and more preferably to between 6.5 and 6.9.
STEP 8:
Heat the mixture of Step 7 first to preferably between 60 C and 100 C and more preferably between 90 C and 100 C for preferably between 1 minute and 60 minutes and more preferably between 5 and 10 minutes.
STEP 9:
Heat the mixture of Step 8 first to preferably between 0 C and 100 C and more preferably between 85 C and 95 C for preferably between 1 minute and 180 minutes and more preferably between 45 and 60 minutes. A black precipitate solution will form.
STEP 10:
Allow the solution of Step 9 to cool to preferably between 0 C and 60 C and more preferably to between 20-25 C.
STEP 11:
Dissolve between 1 g and 10,000 g (10 kg) and preferably between 150 g and 750 g of catechol (C6H602) in water and add to the solution of Step 10. The amount of water used in this step is preferably between I mL and 5000 mL and more preferably is in the range of between 1000 mL and 2000 ml. (Analogs and equivalents of catechol may be substituted for catechol.) STEP 12:
Adjust the pH of the suspension of Step 11 to preferably between 1.0 and 12.0 and more preferably to between 7.0 and 7.5.
STEP 13 (OPTIONAL):
An acetogenin (including its analogs and equivalents) may be added to the composition of Step 12 preferably in the amount of between 0.1 mg to 2000 g (2 kg) and, more preferably, in the amount of between 80 g and 100 g. The addition of an acetogenin would enhance the cancerous cell-killing potency of the composition, and particularly on drug-resistant (MDR) cells.
STEP 14:
Increase the final volume of the solution of Step 11 by adding water preferably in ~
the amount of between 5 L and 100 L and more preferably in the amount of between 10 Land 15L.
Additional Component - Time Release Mechanism In vitro studies have verified that the above-mentioned Cantron has anti-cancer activity. However, chronic dosing is required in order for this composition to be effective. The half-life of the Cantron formula was thought, at one time, to be between six and eight hours. Importantly, recent studies undertaken by the inventor of the present composition and its method of formulation have shown, surprisingly, that the biomarker for Cantron only stays in the bloodstream for a maximum of two hours and only stays in tumors for one hour.
According to the present invention, the delivery system has been altered by providing a time release formulation to obtain optimum anti-cancer effects by delivering a constant supply of the active ingredients into the bloodstream. It is this chronic exposure to tumors which obtains full efficacy of the present composition.
To effect a time release mechanism in the various compositions of the present invention, once the liquid material is produced as set forth above, the liquid is converted to a dry powder form by techniques such as lypholization, spray or by vacuum drying.
The powder is then coated to produce time release beads or pellets. Capsules (gelatin or non-gelatin) are then filled with the beads or pellets. (The time release beads may be used in animal food such as animal treats as weli.) A description of the time release process may be found in U.S. Patent No. 5,292,461, "Process for the Production of Pellets."
The time release formulation provides significant advantages over the prior art by sustaining an effective amount of the composition in the user's bloodstream at all times while medicated. Effectiveness of the time release formulation of the present composition is addressed below with respect to Figure 2.
Example - Method of Making the Preferred Composition The following is a non-limiting example of a method of producing the preferred composition of the present invention.
A suspension of rhodizonic acid disodium salt (C6O6Na2, 124 g, 0.58 moles) and KOH (2N, 168 g 1, 0.5 L, pH = 12.4) was created by mixing the two components together in a 10 L flask. This suspension was heated for approximately two hours to reflux until all of the rhodizonic acid disodium salt was dissolved and the solution became bright yellow. HCL (2N, 200 ml) was then added to the solution to bring the pH
of the solution formed to 9.2. (It should be noted that while an acid was added to the solution to adjust the pH to its desired level, it may be required in the alternative to use a base to make the same adjustment in a different expe(ment.) Tetrahydroxy-1,4-quinone (C6H406, 50.4 g, 7.1 moles) was added to the solution to achieve a black suspension. Water was next added (1.3 L). The suspension was heated to 90 C
for 10 minutes to completely dissolve all of the materials. Sodium sulfite (Na2SO3, 1490 g, 11.8 moles) was dissolved in 6 L of water and was added to the 10 L flask of the solution. HCI was then added to bring the pH of the solution to 6.5-6.9.
The resulting mixture was heated first to 100 C for 10 minutes and Was then heated again to 90 C for 50 minutes, resulting in the formation of a black precipitate solution. This solution was allowed to cool to room temperature (20-25 C). An amount of Catechol (C6H602, 365 g, 3.12 moles) was dissolved in 2 L of water. This was added to the solution. The pH of this suspension was adjusted to between 7.0-7.5.
The final volume of the solution thus achieved was increased to 13 L by adding water.
Variants of the Preferred Composition While the preferred composition has been set forth above, a number of variations of this composition have demonstrated characteristics that are similar to those of the preferred composition. These variants were prepared according to the following 1. VARIANTS WITH CATECHOL
A. Catechol Plus Acetogenins Catechol (C6H602) in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 150 g and 750 g is combined with an acetogenin preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in Ihe amount of between 80 g and 100 g. There are over 1000 different types of this compound plus extracts from source plants. This powder is then made into pill form or formulated as time release and made into pill form.
B. Catechol plus THQ
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is combined with catechol (C6H602) preferably in the amount of between 1 g and 10,000 g (10 kg) and more preferably in the amount of between 150 g and 750 g. This powder is then made into pill form or formulated as time release and made into pill form.
C. Catechol plus THQ Sulfite STEP 1:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between 1 g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in 3 liters of water and heated at 90 C for 10 minutes to compietely dissolve all materials.
STEP 2:
Dissolve a sulfite-containing salt preferably in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g(3 kg) in 6 L of water and add to the solution created in Step 1.
STEP 3:
Adjust the pH of the solution of Step 2 to 6.5-6.9.
STEP 4:
Heat the mixture of Step 3 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 5:
Catechol (in ranges along the lines set forth above with respect to the preferred embodiment of the present invention) is added and the mixture is stirred to dissolve the catechol. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
D. Catechol plus Croconic Acid STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between 1 g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between I g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step 9 to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt -(C505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS 1 AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 7.4 (6.9-7.9).
STEP 4:
Catechol (in ranges along the lines set forth above with respect to the preferred embodiment of the present invention) was added and the mixture is stirred to dissolve catechol. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
E. Catechol plus Croconic Acid Sulfite STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the -water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between I g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2.. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C5505K2, yield = 20% by HPLC). (Note that as an altemative to forming croconic acid in the suspension croconic acid may be added directly. If this option is selected, preferably between 1 g and 1500g (1.5 kg) and more preferably between 15g and 30g of croconic acid may be added preferably to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution.) ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) ,to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.2 (9.0-9.4).
STEP 4:
-,. - - ----- = --- ---- =- = -- -__ .
Dissolve a sulfite-containing salt preferably in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 3.
STEP 5:
Adjust the pH of the solution of Step 4 to 6.5-6.9.
STEP 6:
Heat the mixture of Step 5 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 7:
Catechol (in ranges along the lines set forth above with respect to the preferred embodiment of the present invention) was added and the mixture was stirred to dissolve catechol. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
II. VARIANTS WITH ACETOGENINS
A. Acetogenin plus THQ
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably. between 40 g and 80 g is niixed with an acetogenin preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g. The components were mixed as solids and were made into pill form or formulated as time release and made into pill form.
B. Acetogenin plus THQ Sulfite STEP 1:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in 3 liters of water and heated at 90 C for 10 minutes to completely dissolve all materials.
STEP 2:
Dissolve a sulfite-containing salt preferably in the amount of between 1 g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 1.
STEP 3:
Adjust the pH of the solution of Step 2 to 6.5-6.9.
STEP 4:
Heat the mixture of Step 3 first (at sub-step (a)) to 4 00 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 5:
This solution is freeze dried to a powder.
STEP 6:
An acetogenin, preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g, is added to the powder in Step 5 The materials are then blended. This blended material is made into pill form or formulated as time release and made into pill form.
C. Acetogenin plus Croconic Acid STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between I mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between I g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between I g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between I g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (It should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 7.4 (6.9-7.9) STEP 4:
This solution is freeze dried to a powder.
STEP 5:
An acetogenin in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g is added to the powder from Step 4. This mixture was made into pill form or formulated as time release and made into pill form.
D. Acetogenin plus Croconic Acid Sulfite STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between 1 mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between 1 g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g. ::
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt IC505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between I g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C505K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (it should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.0-9.4.
STEP 4:
Dissolve a sulfite-containing salt preferably in the amount of between I g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 3.
STEP 5:
Adjust the pH of the solution of Step 4 to 6.5-6.9.
STEP 6:
Heat the mixture of Step 5 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes.
STEP 7:
The solution is freeze dried to a powder.
STEP 8:
An acetogenin preferably in the amount of between 0.1 mg and 2000 g (2 kg) and more preferably in the amount of between 80 g and 100 g is added to the powder from Step 7. This mixture may be made into pill form or formulated as time release and made into pill form.
Ill. VARIANTS WITH THQ
. A. THQ Sulfite pius Croconic Acid Sulfite STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between I mL and 10,000 mL (10 L) and more preferably between 300 mL
and 1000 mL (1 L). The amount of the, rhodozonic acid is preferably between I
g and 7300 g (7.3 kg) and is more preferably between 100 g and 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between 1 g and 500 g and is more preferably between 100 g and 200 g.
STEP2:
Heat the suspension created in Step 1 to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC).
STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.0-9.4.
STEP 4:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in the solution of Step 3, resulting in a black suspension.
STEP 5:
Add water (1.3 L) and heat the suspension of Step 4 to 90 C for 10 minutes to completely dissolve all materials.
STEP 6:
Dissolve a sulfite-containing salt preferably in the amount of between 1 g and 10,000 g (10 kg) and more preferably in the amount of between 1000 kg (1 kg) and 3000 g (3 kg) in 6 L of water and add to the solution created in Step 5.
STEP 7:
Adjust the pH of the solution of Step 6 to 6.5-6.9.
STEP 8:
Heat the mixture of Step 7 first (at sub-step (a)) to 100 C for 10 minutes followed second by heating (at sub-step (b)) to 90 C for 50 minutes, resulting in the formation of a black precipitate solution.
STEP 9:
Allow the solution of Step 8 to cool to room temperature (20-25 C).
STEP 10:
Adjust the pH of the suspension of Step 90 to 7.0-7.5.
STEP 11:
Increase the final volume of the solution of Step 11 to 13 L by adding the requisite amount of water. This mixture was freeze dried to a powder and made into pill form or formulated as time release and made into pill form.
C. THQ plus Croconic Acid STEP 1:
Create a suspension of a salt of rhodozonic acid and any base that can generate OH anions by mixing both in a 10 L flask with water. The amount of the water is preferably between I mL and 10,000 mL (10 L) and more preferably between 300 mL in 1000 mL (1 L). The amount of the rhodozonic acid is preferably between 1 g and g (7.3 kg) and is more preferably between 100 g in 150 g. The base is taken from the group consisting of KOH, LiOH, NaOH, Mg (OH)2, and Ca (OH)2. The amount of base is preferably between I g and 500 g and is more preferably between 100 g and 200 g.
STEP 2:
Heat the suspension created in Step I to reflux until all rhodizonic acid disodium salt is dissolved and the solution becomes bright yellow, approximately 2 hours. The yellow color is indicative of the formation of croconic acid dipotassium salt (C505K2, yield = 20% by HPLC).
ALTERNATIVE INITIAL STEP (ALTERNATIVE TO STEPS I AND 2):
Create a solution by adding between 1 g and 1500 g (1.5 kg) and preferably between 15 g and 30 g of croconic acid (C5O5K2) to between I mL and 10,000 mL of water and more preferably to between 300 mL and 1000 mL of water to form a solution. (it should be noted that analogs and equivalents of croconic acid could be substituted for croconic acid.) STEP 3:
Adjust the pH of the solution formed in Step 2 to 9.0-9.4.
STEP 4:
Tetrahydroxy-1,4-quinone (C6H406) preferably in the amount of between I g to 2500 g (2.5 kg) and more preferably between 40 g and 80 g is suspended in the solution of Step 3, resulting in a black suspension.
STEP 5:
Add water (1.3 L) and heat the suspension of Step 4 to 90 C for 10 minutes to completely dissolve all materials.
STEP 6:
Allow the solution of Step 5 to cool to room temperature (20-25 C).
STEP 7:
Adjust the pH of the suspension of Step 6 to 7.0-7.5.
STEP 8:
Increase the final volume of the solution of Step 7 to 13 L by adding the requisite amount of water. This mixture was freeze dried to a powder and made into pill 'form or formulated as time release and made into pill form.
Individual Component Compositions Many of the positive effects may be delivered by treatment using individual components. Specifically, catechol (between I g - 10,000 g), tetrahydroxyquinone (in its free and sulfited forms) (between I g - 2500 g), and croconic acid (in its free and sulfited forms) (between I g - 1500 g) may be individually delivered in the forms discussed herein, including both tablet (in both time release and non-time release forms), a powder, a gel capsule, an intravenous liquid, and transdermally.
Administration of the Composition Regardless of the selected composition, the formulation of the present invention may be administered in any one of a variety of methods. A combination of these methods may also be used. These methods include liquid, powder or gel forms.
The composition may be administered externally by transdermal delivery. Regardless of the form of the composition the objective is to achieve and maintain an effective amount of the composition in the patient's blood stream and at the tumor site. The forms of delivery discussed hereafter eliminate the negative appeal of the dark black liquid of earlier compositions while improving dosage compliance, optimum efficiency, and eliminate the staining of teeth and clothing that was an inherent characteristic of these earlier compositions.
Intravenous Administration When administered in liquid form, the composition may be introduced via intravenous delivery. Intravenous administration particularly assures that an effective amount of the composition can be maintained in the patient's bloodstream at all times.
As a further variant of the intravenous form of administration the composition of the present invention may be injected directly into the patient.
Oral Administration When administered in liquid form, the composition may also be introduced orally.
An optional approach for oral administration for the iiquid composition is administrative by way of a gel capsule.
As set forth above, an altemative to the liquid form of the composition is to convert the liquid composition form to a dry powder form. The dry powder may then be tabletized and conveniently administered as a tablet (including sublinqual tablets) or may be coated with a time release agent then encapsulated as discussed above.
Oral forms of the composition of the present invention as described above :should be taken every two hours during waking hours in either one or two tablets or capsules. ;.
The patient is given a double dose before retiring for the night. No more than six hours should elapse between doses. Transdermal Administration As an alternative to the intravenous and oral techniques for administering the composition of the present invention, the composition may be delivered transdermally by use of a patch or a transdermal gel. If administered as a patch, a single patch is attached to the patient's pulse point and is replaced every four to twelve hours. In either event, the transdermal delivery mechanism provides a constant supply of the active ingredients of the present invention to the patient's bloodstream.
Effectiveness of the Composition The time-release kinetics of the composition of the present invention are set forth in Figure 2 which shows percentage release along the Y-axis and time along the X-axis.
As shown, release exceeds 90% after 12 hours. Release of 100% is achieved after13 hours. Figure 3 illustrates the levels of active ingredient after a single oral ingestion of the composition of the present invention. Concentration is shown on the Y-axis and time (in hours) is shown on the X-axis.
In addition to its high-antioxidant concentration, the composition of the present invention has demonstrated significant anti-cancer effects. The composition provides a tumor-killing approach to resolution of a broad variety of cancers. The concentration of the tumor-killing composition over time is shown in Figure 4. According to this graph, the surviving fraction of cancer cells (shown in the Y-axis) versus concentration (shown in the X-axis) is illustrated. The exposure is generally ineffective over two hours but begins to provide maximum effect over twenty-four hours. The concentration is clearly effective at seven days.
The composition of the present invention demonstrates high cytotoxicity when compared with anticancer pharmaceuticals and nutraceuticals. This comparison is shown in Figure 5 in anticancer efforts in the case of colon cancer. According to this comparison, the composition of the present invention demonstrates a cytotoxicity of 2.5 compared with known anticancer pharmaceuticals 5-fluorouracil, cis-platinum, adriamycin, vincristine and taxol demonstrating increasing cytotoxicy and nutraceuticals in the forms of alpha-lipoic acid, vitamins E and C, green tea, and grapeseed, which show decreasing cytoxicity.
Claims (65)
- Claim 1. A method of preparing a therapeutic composition comprising the steps of:
creating a first solution;
adjusting the pH of said first solution;
adding tetrahydroxy-1,4-quinone to said first solution to create a second suspension;
adding water and heating said second suspension to dissolve the components to create a third solution;
dissolve a sulfite-containing salt to create a fourth solution;
adjust the pH of said fourth solution;
heating said fourth solution;
allowing said fourth solution to cool;
dissolving catechol in water to create a catechol-water solution;
adding said catechol-water solution to said fourth solution to create a fifth solution;
adding a non-toxic acid to said fifth solution to increase the pH of said fifth solution; and adding water to said fifth solution to create a sixth solution. - Claim 2. The method of Claim 1 wherein the step of creating said first solution includes the steps of:
combining a salt of rhodizonic acid and any base that can generate OH anions to create a first suspension;
heating said first suspension to reflux until all of the rhodizonic acid is dissolved to create a first solution; - Claim 3. The method of Claim 2 wherein the amount of said rhodizonic acid is between 1.0 g and 7300 g (7.3 kg).
- Claim 4. The method of Claim 2 wherein the amount of said rhodizonic acid is between 100 g and 150 g.
- Claim 5. The method of Claim 2 wherein said base is selected from the group consisting of KOH, LiOH, NaOH, Mg(OH)2, and Ca(OH)2.
- Claim 6. The method of Claim 2 wherein said base is in the amount of between 1 g and 500 g.
- Claim 7. The method of Claim 2 wherein said base is in the amount of between 100 g and 200 g.
- Claim 8. The method of Claim 1 wherein the step of creating said first solution includes the steps of adding between I g and 1500g (1.5 kg) of croconic acid to between 1 mL and 10,000 mL of water.
- Claim 9. The method of Claim 1 wherein the step of creating said first solution includes the steps of adding between 15g and 30g of croconic acid to between 300 mL and 1000 mL of water.
- Claim 10. The method of Claim I wherein the said first suspension is heated to between 25°C and 100°C.
- Claim 11. The method of Claim 1 wherein said first suspension is heated to between 90°C and 100°C.
- Claim 12. The method of Claim 1 wherein the pH of the first solution is adjusted to between 7.0 and 10Ø
- Claim 13. The method of Claim 1 wherein the pH of the first solution is adjusted to between 9.0 and 9.4.
- Claim 14. The method of Claim I wherein said tetrahydroxy-1,4-quinone is added in an amount of between 1 g and 2500 g (2.5 kg).
- Claim 15. The method of Claim I wherein said tetrahydroxy-1,4-quinone is added in an amount of between 40g and 80g.
- Claim 16. The method of Claim 1 wherein between 1 mL and 2000 mL of water is added to said second solution to create said third solution.
- Claim 17. The method of Claim 1 wherein between 1000 mL and 1500 mL of water is added to said second solution to create said third solution.
- Claim 18. The method of Claim 1 wherein said third solution is heated to between 70°C and 100°C for between about 1 and 180 minutes.
- Claim 19. The method of Claim 1 wherein said third solution is heated to between 85°C and 100°C for between about 1 and 180 minutes.
- Claim 20. The method of Claim 1 wherein said sulfite-containing salt is selected from the group consisting of Na2SO3, Li2SO3, K2SO3, Mg2SO3, and Ca2SO3.
- Claim 21. The method of Claim I wherein said sulfite-containing salt is provided in an amount of between 1 g and 10,000 g (10 kg) and is dissolved in between 1 mL and 20,000 mL of water.
- Claim 22. The method of Claim 1 wherein said sulfite-containing salt is provided in an amount of between 1000 g (1 kg) and 3000 g (3 kg) and is dissolved in between 1 mL and 20,000 mL of water.
- Claim 23. The method of Claim 1 including the step of adjusting the pH of said fourth solution to between 5.0 and 7.9.
- Claim 24. The method of Claim 1 including the step of adjusting the pH of said fourth solution to between 6.5 and 6.9.
- Claim 25. The method of Claim 1 wherein said step of heating said fourth solution includes the steps of heating said fourth solution a first time, allowing the heated solution to cool, then heating the cooled solution a second time.
- Claim 26. The method of Claim 25 wherein said first heating includes heating said fourth solution to between 0°C and 100°C.
- Claim 27. The method of Claim 25 wherein said first heating includes heating said fourth solution to between 90°C and 100°C.
- Claim 28. The method of Claim 25 wherein said first heating includes heating said fourth solution for between 1 minute and 60 minutes.
- Claim 29. The method of Claim 25 wherein said first heating includes heating said fourth solution for between 5 minutes and 10 minutes.
- Claim 30. The method of Claim 25 wherein said second heating includes heating said fourth solution to between 70°C and 100°C.
- Claim 31. The method of Claim 25 wherein said second heating includes heating said fourth solution to between 85°C and 100°C.
- Claim 32. The method of Claim 25 wherein said second heating includes heating said fourth solution for between 1 minute and 180 minutes.
- Claim 33. The method of Claim 25 wherein said second heating includes heating said fourth solution for between 45 minutes and 60 minutes.
- Claim 34. The method of Claim I wherein said fourth solution is cooled to between 0°C and 50°C during said cooling step.
- Claim 35. The method of Claim 1 wherein said fourth solution is cooled to between 20°C and 25°C during said cooling step.
- Claim 36. The method of Claim 1 wherein between 1 g and 10,000 g (10 kg) of catechol is used.
- Claim 37. The method of Claim 1 wherein between 150 g and 750 g of catechol is used.
- Claim 38. The method of Claim 1 wherein between 1 mL and 5000 mL of water is used to create the catechol-water solution.
- Claim 39. The method of Claim 1 wherein between 1000 mL and 2000 mL of water is used to create the catechol-water solution.
- Claim 40. The method of Claim 1 including the step of adjusting the pH of said fifth solution to between 1.0 and 12Ø
- Claim 41. The method of Claim 1 including the step of adjusting the pH of said fifth solution to between 7.0 and 7.5.
- Claim 42. The method of Claim 1 wherein between 5 L and 100 L of water is added to said fifth solution to create said sixth solution.
- Claim 43. The method of Claim 1 wherein between 10 L and 15 L of water is added to said fifth solution to create said sixth solution.
- Claim 44. The method of Claim 1, further including adding an anti-neoplastic agent selected from the group consisting of an acetogenin, its analogs and its equivalents in the amount of between 0.1 mg and 2000 g.
- Claim 45. The method of Claim 1, further including adding an anti-neoplastic agent selected from the group consisting of an acetogenin, its analogs and its equivalents in the amount of between 80 g and 100g.
- Claim 46. A composition for the treatment of disease consisting essentially of therapeutically effective amounts of:
an antioxidant selected from the group consisting of catechol, its analogs and its equivalents;
an anti-neoplastic selected from the group consisting of acetogenin, its analogs and its equivalents;
an acid selected from the group consisting of croconic acid, its analogs and its equivalents and sulfites of croconic acid, their analogs and their equivalents; and a quinone selected from the group consisting of tetrahydroxyquinone, its analogs and its equivalents and sulfites of tetrahydroxyquinone, their analogs and their equivalents. - Claim 47. The composition of Claim 46, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 48. A composition for the treatment of disease consisting essentially of therapeutically effective amounts of:
an antioxidant selected from the group consisting of catechol, its analogs and equivalents; and an anti-neoplastic selected from the group consisting of acetogenin, its analogs and equivalents. - 49 Claim 49. The composition of Claim 48, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 50. A composition for the treatment of disease consisting essentially of therapeutically effective amounts of:
an antioxidant selected from the group consisting of catechol and its analogs;
and a quinone selected from the group consisting of tetrahydroxyquinone and its analogs and sulfites of tetrahydroxyquinone and their analogs. - Claim 51. The composition of Claim 50, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 52. A composition for the treatment of disease consisting essentially of therapeutically effective amounts of:
an antioxidant selected from the group consisting of catechol and its analogs;
and an acid selected from the group consisting of croconic acid and its analogs and sulfites of croconic acid and their analogs. - Claim 53. The composition of Claim 52, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 54. A composition for the treatment of disease consisting essentially of therapeutically effective amounts of:
an anti-neoplastic selected from the group consisting of acetogenin, its analogs and its equivalents; and a quinone selected from the group consisting of tetrahydroxyquinone, its analogs and its equivalents and sulfites of tetrahydroxyquinone, their analogs and their equivalents. - Claim 55. The composition of Claim 54, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 56. A composition for the treatment of disease consisting essentially of therapeutically effective amounts of:
an anti-neoplastic selected from the group consisting of acetogenin, its analogs and its equivalents; and an acid selected from the group consisting of croconic acid and its analogs and sulfites of croconic acid and their analogs. - Claim 57. The composition of Claim 56, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 58. A composition for the treatment of disease consisting essentially of therapeutically effective amounts of:
a quinone selected from the group consisting of tetrahydroxyquinone, its analogs and its equivalents and sulfites of tetrahydroxyquinone, their analogs and their equivalents; and an anti-neoplastic selected from the group consisting of acetogenin, its analogs and its equivalents. - Claim 59. The composition of Claim 58, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 60. A composition to quench the oxygen related species of free radicals consisting essentially of therapeutically effective amounts of:
a quinone selected from the group consisting of tetrahydroxyquinone, its analogs and its equivalents and sulfites of tetrahydroxyquinone, their analogs and their equivalents; and an acid selected from the group consisting of croconic acid and its analogs and sulfites of croconic acid and their analogs. - Claim 61. The composition of Claim 60, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 62. A composition for the treatment of disease consisting essentially of catechol in an amount of between 1 g - 10,000 g, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 63. A composition for use as an antioxidant consisting essentially of catechol in an amount of between 1 g - 10,000 g, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 64. A composition for the treatment of disease consisting essentially of croconic acid in an amount of between I g - 1500 g, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
- Claim 65. A composition for the treatment of disease consisting essentially of tetrahydroxyquinone in an amount of between 1 g - 2500 g, said composition being prepared for administration to a patient in a form taken from the group consisting of a tablet of the time-release or non-time release variety, a liquid in the form of a gel capsule, a liquid for intravenous administration, a transdermal patch, and a transdermal gel.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/317,534 US7537774B2 (en) | 2005-12-23 | 2005-12-23 | Therapeutic formulation |
| US11/317,534 | 2005-12-23 | ||
| PCT/US2006/061999 WO2007076266A2 (en) | 2005-12-23 | 2006-12-13 | Therapeutic formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2634931A1 true CA2634931A1 (en) | 2007-07-05 |
| CA2634931C CA2634931C (en) | 2015-06-16 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2634931A Expired - Fee Related CA2634931C (en) | 2005-12-23 | 2006-12-13 | Nutraceutical therapeutic formulation |
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|---|---|
| US (2) | US7537774B2 (en) |
| CA (1) | CA2634931C (en) |
| WO (1) | WO2007076266A2 (en) |
Families Citing this family (1)
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| US8273384B2 (en) * | 2007-07-02 | 2012-09-25 | Stephen Ray Wurzberger | Process for the preparation of a non-corrosive base solution and methods of using same |
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| US2875769A (en) * | 1957-08-20 | 1959-03-03 | Apod Corp | Keratinaceous fiber dye of hydroquinone and either dihydroxyphenylalanine or dihydroxyphenylglycine and method of its use |
| EP0031237B1 (en) | 1979-12-19 | 1984-10-17 | National Research Development Corporation | Quinazoline derivatives, processes for their preparation, compositions containing them and their use as anti-cancer agents |
| US4283342A (en) | 1980-01-31 | 1981-08-11 | University Of Delaware | Anticancer agents and methods of manufacture |
| NZ222192A (en) | 1986-10-20 | 1991-03-26 | Kanto Ishi Pharma Co Ltd | Glycolipid containing n-glycolylneuraminic acid, and preparation thereof |
| GB8708927D0 (en) | 1987-04-14 | 1987-05-20 | Erba Farmitalia | Chiral synthesis of anthracyclines |
| US5157049A (en) | 1988-03-07 | 1992-10-20 | The United States Of America As Represented By The Department Of Health & Human Services | Method of treating cancers sensitive to treatment with water soluble derivatives of taxol |
| US5229419A (en) * | 1989-04-11 | 1993-07-20 | Purdue Research Foundation | Chemotherapeutically active acetogenins |
| GB9103075D0 (en) * | 1991-02-13 | 1991-03-27 | Washington Odur Ayuko | Trinitrobenzene derivatives and their therapeutic use |
| KR960703901A (en) | 1993-08-19 | 1996-08-31 | 로즈 암스트롱 | Substituted 2 (5H) furanone, 2 (5H) thiophenone and 2 (5H) pyrrolone derivatives, methods for their preparation and their use as endothelin antagonists (Substituted 2 (5H) Furanone, 2 (5H) Thiophenone and 2 (5H) Pyrrolone Derivatives, Their Preparation and Their Use as Endothelin antagonists) |
| US5536848A (en) * | 1994-06-14 | 1996-07-16 | Purdue Research Foundation | Bioactive acetogenins and derivatives |
| US5563143A (en) | 1994-09-21 | 1996-10-08 | Pfizer Inc. | Catechol diether compounds as inhibitors of TNF release |
| JP3290834B2 (en) | 1994-11-25 | 2002-06-10 | 昌俊 中野 | Antiviral agent and method for producing the same |
| US5607673A (en) * | 1995-04-20 | 1997-03-04 | C.S.S.A.H.A., Inc. | Purified extract of uvaria brevistipitata and a process for obtaining the purified extract therefor |
| ES2184893T3 (en) | 1995-11-17 | 2003-04-16 | Warner Lambert Co | SULFONAMIDE INHIBITORS OF LASD METALOPROTEINASES MATRICALES. |
| EP0967984A1 (en) | 1997-03-04 | 2000-01-05 | Peregrine Pharmaceutical, Inc. | Composition and method for treating cancer and immunological disorders resulting in chronic conditions |
| US6207648B1 (en) | 1997-07-24 | 2001-03-27 | Trustees Of Boston University | Methods of using cytochrome P450 reductase for the enhancement of P450-based anti-cancer gene therapy |
| US6576660B1 (en) * | 1997-10-31 | 2003-06-10 | Arch Development Corporation | Methods and compositions for regulation of 5-α-reductase activity |
| DE19809304A1 (en) * | 1998-03-05 | 1999-09-09 | Merck Patent Gmbh | Formulations with an antiviral effect |
| US6482943B1 (en) | 1999-04-30 | 2002-11-19 | Slil Biomedical Corporation | Quinones as disease therapies |
| US6569857B1 (en) * | 1999-05-03 | 2003-05-27 | Drugtech Corporation | Dietary supplement |
| NZ519069A (en) * | 1999-11-29 | 2004-06-25 | Lohmann Therapie Syst Lts | Transdermal therapeutic systems having improved stability and their production |
| US6555677B2 (en) | 2000-10-31 | 2003-04-29 | Merck & Co., Inc. | Phase transfer catalyzed glycosidation of an indolocarbazole |
| US6888014B2 (en) | 2001-07-24 | 2005-05-03 | Panagin Pharmaceuticals Inc. | Dammarane sapogenins, their use as anti-cancer agents, and a process for producing same |
| US20040101584A1 (en) * | 2002-11-22 | 2004-05-27 | Mclaughlin Jerry Loren | Control of cancer with annonaceous extracts |
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- 2006-12-13 CA CA2634931A patent/CA2634931C/en not_active Expired - Fee Related
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2008
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Also Published As
| Publication number | Publication date |
|---|---|
| US8501820B2 (en) | 2013-08-06 |
| US20070149623A1 (en) | 2007-06-28 |
| US20090042995A1 (en) | 2009-02-12 |
| WO2007076266A3 (en) | 2007-11-15 |
| CA2634931C (en) | 2015-06-16 |
| WO2007076266A2 (en) | 2007-07-05 |
| US7537774B2 (en) | 2009-05-26 |
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| EEER | Examination request | ||
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