Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
  • A61K31/355—Tocopherols, e.g. vitamin E
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4415—Pyridoxine, i.e. Vitamin B6
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7135—Compounds containing heavy metals
  • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• • 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
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates generally to a dietary supplement, and more particularly, to an oral supplement.
• Cardiovascular disease is generally recognized to be the primary killer of men and women in developed countries globally. The cost of these premature deaths is great both to the individuals and their families and to the health care system of the country as a whole.
• the risk factors for cardiovascular disease are well-recognized and include: higher than average serum cholesterol, elevated levels of LDL; a low level of HDL in proportion to the LDL level; higher than average serum triglycerides; higher levels of lipid oxidation products creating plaques and streaks which cause blockages of coronary arteries.
• Another CND risk factor, high blood pressure is also a risk factor for strokes.
• statins are cholesterol-lowing drugs, which work by blocking an enzyme the liver needs for cholesterol production. There are at least a half-dozen statins available on the market, from a number of different manufacturers. These statins vary somewhat in their potency and ability to lower LDL cholesterol.
• vitamin E is the major lipid- soluble antioxidant in the human body [L. Mosca, et al, "Antioxidant nutrient supplementation reduces the susceptibility of low density lipoprotein to oxidation in patients with coronary artery disease," J Am Coll CardioL 30:392-9 (1997)].
• Vitamin C is another well-known anti-oxidant. See A. Bendich, L. Langseth, "The health effects of vitamin C supplementation: A Review" J. Am. Coll. Nutr. 14:124- 36 (1995), [published en-ata appear in J Am Coll Nutr Jun:14(3):218 (1995) and Aug:14(4):398 (1995)].
• High blood pressure is another important risk factor for cardiovascular disease [D. A. McCarron and M.E. Reusser, "Finding consensus in the dietary calcium-blood pressure debate,” J. Am. Coll Nutr., !8:398S-405S (1999)].
• the present invention provides a novel composition, which may be incorporated into an orally administered dietary supplement for the reduction of risk factors associated with CND.
• the composition of the invention represents a unique combination of one or more statins with active dietary factors (essential nutrients and non-essential food components) that have never before been developed into a single supplement. This combination is surprisingly effective in the treatment of a variety of risk factors which have been linked to heart attacks, particularly reduction of overall serum cholesterol levels, reductions in high blood pressure, increase in the HDL:LDL ratio, reduction of triglycerides and homocysteine levels, and prevention of lipid oxidation and the formation of plaques and streaks.
• the composition of this invention comprises the following components: statins; vitamin E; vitamin C; docasahexanoic acid "DHA"; folic acid; vitamin B6 and vitamin B12, and calcium.
• statins for CVD, work synergistically to reduce the risk of CND more effectively than any of these components taken alone.
• all of the components have wide safety margins, therefore it is expected that the combination of all of these active components will require a lower concentration of each component alone, and therefore, enhance the safety of the combination of these dietary factors.
• the invention provides a pharmaceutical and/ or dietary composition containing the formulation described above in admixture with pharmaceutically acceptable base, and optionally containing other known agents including, but not limited to stabilizer agents, preservatives and emulsifiers.
• compositions, according to this invention may be presented in different embodiments, including but not limited to tablets, powders, chews, bars, and shakes or similar formulations.
• a method for preparing the novel dietary compositions described herein and incorporating the same into orally administrated pharmaceutical compositions.
• this invention provides a process for treating individuals to reduce the risk factors for CVD comprising orally administering a pharmaceutical composition as described above.
• the present invention provides novel compositions comprised of combinations of selected mixtures of one or more statins with active dietary factors, including certain vitamins and other components, which are surprisingly effective in their ability to reduce the risk factors of CVD and promote improved cardiovascular health.
• the oral administration of these compositions acts to reduce serum cholesterol levels and blood pressure, increase HDL levels in proportion to LDL levels, to protect lipids from oxidation thereby preventing the formation of plaques and streaks which block coronary arteries, and to lower both triglyceride levels and homocysteine levels.
• oral administration of the compositions of this invention acts to reduce the risk of stroke, as well as heart attack, in human adults.
• compositions of this invention include those dietary admixtures in which the formulations are swallowed in any acceptable form.
• Conventional forms for this purpose include but are not limited to liquids, tablets, effervescent tablets, pills, powders, chews, bars, wafers or premixed shakes. See Remington's Practice of Pharmacy. 11 th Edition, (1956).
• the novel compositions of the present invention are comprised of the following vitamins and dietary factors, which in combination provide a surprising result in reducing the risk factors of CVD.
• the combination of dietary factors and vitamins work synergistically to improve cardiovascular health to a great degree than expected.
• the essential components of the compositions are a statin or a combination of statins, docosahexaenoic acid "DHA", vitamin E, vitamin C, folic acid, vitamin B6, vitamin B12, and calcium.
• Statins are a class of cholesterol-lowering drugs.
• the statin selected for the composition of the invention is simvastatin [available commercially from Merck as ZocorTM].
• statins including, without limitation, lovastatin [available commercially as MevacorTM from Merck], fluvastatin [available commerically from Novartis as LescolTM], pravastatin [available commercially from Bristol-Meyers Squibb as PravacholTM].
• atorvastatin available commercially from Parke-Davis/Pfizer as LipitorTM
• cerivastatin available commercially from Bayer as BaycolTM
• the statins are included in the composition to assist in the reduction of serum cholesterol levels. Used alone, simvastatin has been shown to reduce LDL cholesterol levels by about 38% and total cholesterol by about 28% in individuals with moderately elevated or high serum cholesterol and triglyceride levels.
• the composition of the invention contains about 1 mg to about 30 mg simvastatin, and preferably, 10 mg to 20 mg.
• other statins may be readily utilized; mixtures of statins may also be utilized.
• the concentration of the selected statin(s) may be within the range of about 1 ⁇ g to about 120 mg, and more preferably, about 10 ⁇ g to about 60 mg, and most preferably, about 1000 ⁇ g to about 30 mg of the selected statin, per dose.
• the composition of the invention further includes vitamin E, which may be in any suitable form.
• Natural vitamin E can be isolated from vegetable oils, including corn, cottonseed, rapeseed, peanut, sunflower and soybean oil, or obtained from a variety of commercial sources. Natural vitamin E may be in the form d- alpha-tocopherol (RRR-alpha-tocopherol), or the acetate [d-alpha-tocopheryl acetate (RRR-alpha-tocopheryl acetate)] or succinate salt thereof [d-alpha-tocopheryl acid succinate (RRR-alpha-tocopheryl acid succinate)], or may be in the form of natural mixed tocopherols [d-alpha-, d-beta-, d-gamma and d-delta-tocopherol].
• synthetic vitamin E may be produced from petrochemicals in the form of dl-alpha-tocopherol ( all-rac-alpha-tocopherol), or the acetate [dl-alpha- tocopheryl acetate, (all-rac-alpha-tocopheryl acetate)] or succinate salt thereof [dl- alpha-tocopheryl acid succinate (all-rac-alpha-tocopheryl acid succinate), or mixtures thereof.
• any of the natural or synthetic forms of the vitamin may be used, or combinations thereof.
• Vitamin E prevents the blockage of coronary arteries and other vessels within the body that result when oxidized lipids are permitted to form [S.B.
• vitamin E is a useful as an antioxidant [Jeng et al, Am. J. Clin. Nutr.. 64:960-5 (1996); F.M. Steinberg and A. Chait, Am. J. Clin. Nutr.. 68:319-27 (1998), [publ. erratum appears in Am J Clin Nutr.. Jun: 69(6): 1293 (1999)].
• the composition of the invention contains about 50 IU to about 800 IU of vitamin E, and most preferably, about 100 IU.
• Vitamin C is another component of the composition of the invention.
• Vitamin C is an anti-oxidant that works synergistically with Vitamin E to protect cellular components from oxidative damage leading to cardiovascular disease.
• Vitamin C optimizes the effects of Vitamin E to reduce the oxidation of lipids.
• Vitamin C taken alone has been linked with a decreased risk of CVD as well as CVD mortality, possibly because of the reduction in systolic and diastolic blood pressure seen in those individuals taking large does of the vitamin [S.J. Duffy et al, "Treatment of hypertension with ascorbic acid", Lancet. 354:2048-9 (1999); P. Weber et al, "Vitamin C and human health - a review of recent data relevant to human requirements", Int.
• vitamin C is in the form of ascorbate or ascorbic acid, and is present in an amount of about 60 mg to about 1000 mg, or about 100 to about 500 mg.
• the present invention further includes an omega-3 fatty acid which is known to cause reduction in triglycerides and increase in HDL levels. Most preferably, this omega-3 fatty acid is in the form of docasahexaenoic acid "DHA", which may be extracted from algae using known methods or purchased commercially. DHA is the longest omega-3 fatty acid and is known to be important in the functioning of every cell membrane in the body. It is found in especially high concentration in the human brain and retina.
• DHA docasahexaenoic acid
• the composition of the invention contains about 125 mg to about 500 mg, and preferably about 230 to about 250 mg DHA.
• another omega-3 oil may be included in the composition of the invention.
• Folic acid (or a pharmaceutically acceptable salt thereof), vitamin B6 and vitamin B 12 are all involved in normal amino acid metabolism. Specifically, these vitamins have been known to significantly reduce elevated homocysteine levels that have been linked to an increased risk of CVD, as well as stroke, peripheral vascular disease and dementia.
• the composition of the invention contains about 400 ⁇ g to about 1000 ⁇ g folic acid (or folate); about 2 mg to about 50 mg vitamin B6, preferably about 10 to 25 mg vitamin B6; and about 6 ⁇ g to about 1 mg vitamin B 12.
• composition of this invention contains about 200 to about 100 mg of elemental calcium, which may be in the form of pharmaceutically acceptable salt thereof. In one desirable embodiment, calcium is present in the composition of the form of calcium carbonate.
• the active components discussed above may be admixed with other active ingredients.
• these components are the only active ingredients in the composition of the invention.
• Example 1 One particularly desirable embodiment of the composition of the invention is provided in Example 1 below.
• the invention is not limited by this formulation, or by the ranges provided herein, which are intended for guidance only.
• One of skill in the art can readily select other ranges, depending upon the delivery form (e.g., effervescent tablet vs. tablet), the age, and condition of the patient, among other factors.
• a composition of the formulation of the invention may be used orally to treat and/or prevent risk factors of CVD and stroke, including reduction of high blood pressure and overall serum cholesterol.
• compositions work by acting at different sites and aspects of cardiovascular disease.
• High cholesterol, high LDL, elevated triglycerides, high blood pressure, low HDL, high homocysteine levels and oxidized lipids are all attacked by one or more of the dietary factors present in the oral formulation and act synergistically to reduce the risk factors of CVD.
• CVD risk factors By affecting CVD risk factors at several sites and by different mechanisms of action, there is an enhancement of the effects of the supplement that is greater than the additive effect of the dietary factors.
• the dietary supplement contains active ingredients that are safe, efficacious and cost-effective in lowering CVD risk factors.
• compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
• unit dosage forms such as tablets, capsules, pills, powders, granules, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
• oral administration either solid or fluid unit dosage forms can be prepared.
• Powders are prepared quite simply by comminuting the active ingredient(s) to a suitably fine size and mixing with a similarly comminuted diluent.
• the diluent can be an edible carbohydrate material such as lactose or starch.
• a sweetening agent or sugar is present as well as a flavoring oil. Additional pharmaceutically acceptable binders, lubricants, colouring agents, and sweeteners, well known in the art may be added as necessary.
• Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths.
• a lubricant such as a talc, magnesium stearate, and the like is added to the powder mixture before the filling operation.
• Soft gelatin capsules are prepared by machine encapsulation of a slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride. Tablets, chews and bars are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets, chews, or bars.
• the powder mixture is prepared by mixing an active ingredient, suitably comminuted, with a diluent or base such as starch, lactose, kaolin, dicalcium phosphate and the like.
• the powder mixture can be granulated by wetting with a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage and forcing through a screen.
• the powder mixture can be slugged, e.g., run through the tablet, bar or chew, machine and the resulting imperfectly formed tablets broken into pieces (slugs).
• the slugs can be lubricated to prevent sticking to the shape-forming dies by means of the addition of stearic acid, a stearic salt, talc or mineral oil.
• the lubricated mixture is then compressed into tablets, chews or bars, as desired.
• a tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac, a coating of sugar and methylcellulose and polish coating of carnauba wax.
• chews and bars may be mixing with a variety of flavorings, sweetening agents, or the like.
• Fluid unit dosage forms for oral administration such as syrups, elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount of active ingredient for administration.
• the water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup.
• An elixir is prepared by using a hydroalcoholic vehicle with suitable sweeteners together with a flavoring agent.
• Suspensions can be prepared on the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
• the invention provides a method of using the composition to improve the health of the heart and to reduce risk factors associated with cardiovascular disease by delivering to an individual the composition of the invention.
• delivery of the composition of the invention e.g., by oral administration, is useful for preventing oxidation of low density lipoprotein (LDL), increasing high density lipoprotein (HDL), and for reducing total cholesterol.
• Delivery of the composition of the invention is also useful for reducing triglycerides and reducing homocysteine.
• the compositions of the invention are formulated such that an effective amount is delivered by two tablets (or other suitable formulation) a day.
• these doses may be taken with meals, mixed into feed, or taken on an empty stomach.
• the compositions of the invention may be delivered daily in a suitable form (e.g., a chew or bar) for a limited period of time, e.g., six to eight weeks.
• suitable dosage regimens may be readily developed by one of skill in the art. Such dosage regimens are not a limitation of the invention.
• Several factors have been observed to interfere with the positive effects of dietary supplementation with the compositions of the invention, including smoking, eating a high fat diet, omitting dietary fibers or roughage from a daily diet and maintaining an essentially sedentary lifestyle.
• compositions of the present invention in addition to their use in treating CVD in humans, may also be useful in treating non-human animals, particularly mammals.
• these dietary supplements may be useful for companion animals such as dogs and cats, for cattle, horses, and pigs, among other animals.
• compositions of the invention for illustrative purposes only and does not limit the scope of the invention.
• the compositions of this invention are anticipated to produce surprisingly good results in reducing a variety of risk factors associated with impaired cardiovascular conditions.
• the compositions of the invention have advantages over the prior art in safely lowering CVD risk factors in a cost effective manner.
• the components listed below were combined into a tablet, using simple mixing procedures.
• Vitamin C 60 mg Folic Acid 400 ⁇ g
• Wet granulated (Wet Granulation Process- WGP) with well recognized tableting aid(s)/filler(s), granulating agent(s), disintegrant (s) and lubricant(s) as necessary or desired to form a blend that it can be directly compressed into tablets.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
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• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Coloring Foods And Improving Nutritive Qualities (AREA)

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• 2001
  • 2001-11-29 MX MXPA03004818A patent/MXPA03004818A/es unknown
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  • 2001-11-29 WO PCT/US2001/044734 patent/WO2002043659A2/en not_active Application Discontinuation
  • 2001-11-29 EP EP01986043A patent/EP1339429A4/en not_active Withdrawn
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