WO2011123236A1 - Compositions de d-tagatose et de biguanide et procédés - Google Patents

Compositions de d-tagatose et de biguanide et procédés Download PDF

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Publication number
WO2011123236A1
WO2011123236A1 PCT/US2011/028305 US2011028305W WO2011123236A1 WO 2011123236 A1 WO2011123236 A1 WO 2011123236A1 US 2011028305 W US2011028305 W US 2011028305W WO 2011123236 A1 WO2011123236 A1 WO 2011123236A1
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Prior art keywords
pharmaceutical composition
mammal
effective amount
pharmaceutically effective
tag
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PCT/US2011/028305
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English (en)
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Robert A. Lodder
Lisa A. Cassis
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Biospherics, Inc.
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Publication of WO2011123236A1 publication Critical patent/WO2011123236A1/fr

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms

Definitions

  • the present invention relates generally to pharmaceutical compositions including a pharmaceutically effective amount of D-tagatose in combination with a pharmaceutically acceptable amount of a biguanide component, or a salt or derivative thereof. Also included are methods for the prevention or treatment of atherosclerosis, the metabolic syndrome, obesity, or diabetes, and combinations of the same, by administering a pharmaceutically effective amount of any of the above-noted compositions to a mammal.
  • TAG D-tagatose
  • 3S,4S,53 ⁇ 4-l,3,4,5,6-pentahydroxy-hexan-2-one or Naturlose® is a ketohexose, isomer of fructose and functional sweetener. It is a white anhydrous crystalline solid and has a molecular weight of 180.16 and empirical formula of C 6 Hi206. It is about 92% as sweet as sucrose and has been reported for use as a nutritive or low- calorie sweetener. Only about 25% of TAG ingested in humans is absorbed into the
  • TAG is a naturally occurring molecule found in heated dairy products, including sterilized and powdered cow's milk, hot cocoa, various cheeses and yogurt, although TAG can also be chemically manufactured.
  • heated dairy products including sterilized and powdered cow's milk, hot cocoa, various cheeses and yogurt, although TAG can also be chemically manufactured.
  • Various patents disclose information regarding TAG and its conventional uses.
  • U.S. Patent No. 6,991,923 discloses a process for manufacturing TAG that includes hydrolyzing lactose to galactose and glucose, isomerizing galactose to tagatose and then chromatographically separating the compounds and recycling any unconverted compounds.
  • TAG supplies 1.5 kcal/g of energy (as compared to 4 kcal/g from sucrose), in large part because TAG is incompletely absorbed by the small intestine.
  • Some uses of TAG include as a sweetener in diet beverages at concentrations up to 1%, light ice creams or yogurts at concentrations up to 3%, and regular or dietetic hard candies at levels up to 15%.
  • U.S. Patent No. 4,786,722 discloses a process for the preparation of a sweetened edible formulation in which the sweetening agent is less caloric than sucrose which includes the step of mixing a foodstuff with an amount sufficient to sweeten the foodstuff with TAG.
  • U.S. Patent No. 5,356,879 discloses a method for preventing the formation of advanced glycosylation end-products in a mammal including administering to said mammal an effective amount of TAG.
  • U.S. Patent No. 5,447,917 discloses TAG as an anti-hyperglycemic agent.
  • U.S. Patent No. 7,202,219 teaches a method for selectively inducing production of butyrate by bacteria in the colon of a human in need thereof by administering TAG. Butyrate is alleged to have a protective effect against colon cancer.
  • Biguanide otherwise known as diguanide or 2-carbamimidoylguanidine, refers to a type of molecule or class of drugs based on the biguanide structure. Biguanide has a basic empirical formula of C2H7N5 and a molecular weight of 101.11. Metformin, also known as N,N- dimethylimidodicarbonimidic diamide, and metformin hydrochloride are exemplary biguanides. Metformin has a molecular weight of 129.16 and an empirical formula of C4H11N5. Metformin hydrochloride is a white to off-white crystalline compound with a molecular weight of 165.62 and an empirical formula of C2H7N5 HCI.
  • Stilbenes and stilbenoids are diary lethenes, stilbenoids being hydroxylated derivatives of stilbenes. Stilbenes and stilbenoids can be found naturally in berries and in the heart wood of the Indian Kino tree, a known medicinal plant in India. Stilbenes have the basic empirical formula of C14H12. A common stilbenoid is resveratrol, also known as 3,5,4'-trihydroxystilbene, a natural component found in the skin of red grapes. Resveratrol is an off-white powdery substance when extracted with methanol and has a molecular weight of 228.24 and an empirical formula of C14H12O 3 .
  • Resveratrol has been reported to improve health and longevity of mice on high calorie diets under certain circumstances (Baur, J.A., et al., "Resveratrol improves health and survival of mice on high-calorie diet,” Nature, 444(7117):337-42 (2006)).
  • Pterostilbene also known as 3,5-dimethoxy-4'-hydroxystilbene, is chemically related to resveratrol and may possess many similar properties.
  • Pterostilbene is a white or off-white crystal powder and has a molecular weight of 256 and an empirical formula of C16H16O 3 .
  • Diabetes sometimes known as diabetes mellitus, is a group of disorders characterized by an insufficient amount of, or failure to respond properly to, insulin.
  • diabetes There are many forms of diabetes including: Type 1, which results from a failure to produce insulin; and Type 2 which results from insulin resistance; gestational diabetes which occurs in pregnant women who have high glucose levels; and various other types including congenital diabetes, steroid diabetes and monogenic diabetes.
  • Type 1 which results from a failure to produce insulin
  • Type 2 which results from insulin resistance
  • gestational diabetes which occurs in pregnant women who have high glucose levels
  • various other types including congenital diabetes, steroid diabetes and monogenic diabetes.
  • diabetics typically have
  • hyperglycemia and dyslipidemia are subject to acute and chromic complications such as ketoacidosis, and nonketotic hyperosmolar coma. Long-term complications include
  • cardiovascular disease chronic renal failure, retinal damage, nerve damage, microvascular damage and poor circulation and wound healing.
  • Treatment options currently include the use of insulin, diabetic and blood pressure medications, as well as diet and exercise.
  • Blood glucose monitoring is usually an essential part of treatment as hypoglycemia, or abnormally low blood glucose, can occur as a result of diabetes treatment and/or medications.
  • Atherosclerosis is a syndrome in which the walls of arterial blood vessels are thickened, usually as a result of a build-up of fatty materials such as cholesterol. This syndrome can be promoted by the presence of a high amount of low density lipoproteins ("LDLs”) as well as a low amount of high density lipoproteins (“HDLs”) and a high serum triglyceride concentration.
  • LDLs low density lipoproteins
  • HDLs high density lipoproteins
  • Atherosclerotic patients typically have plaques containing macrophage cells that have taken up oxidized LDLs, lipids such as cholesterol and fatty acids, calcium and fibrous connective tissue that build up along artery walls. Over time, narrowing or complete closure of arteries can result, decreasing the amount of blood supply to the organs and tissues the arteries feed.
  • an aneurysm may occur as a result of the artery enlarging to compensate for the blockage. This leads to an increased risk of rupture, which can result in a severe hemorrhage.
  • the plaque may rupture and cause the formation of a thrombus, which can rapidly decrease blood flow to an area.
  • Risk factors or symptoms include having high blood pressure, diabetes, dyslipidemia, dyslipoproteinemia, smoking, and high C-reactive protein concentrations in the blood.
  • Treatment options include the medicinal intake of statins, niacin, aspirin and cholesterol- lowering drugs as well as lifestyle modifications such as diet and exercise. Sometimes angioplasty is performed where stents may be inserted to expand narrowed arteries.
  • the Centers for Disease Control reports that about two-thirds of the adult population in the United States is classified as either overweight or obese, as defined by a body mass index (“BMI") of >25kg/m 2 or >30kg/m 2 , respectively.
  • BMI body mass index
  • Obesity and weight gain reportedly have many causes and symptoms including overeating, genetics, psychological factors, lifestyle, sex, age, medications, distribution of body fat and certain medical conditions including dyslipidemia, hyperthyroidism, Cushing syndrome, polycystic ovarian syndrome, and Prader- Willi syndrome.
  • Obesity has been reported to increase the likelihood of various diseases and health problems including heart disease, type 2 diabetes, hypertension, stroke, certain types of cancer including breast and colon, gallstones, gout, depression, sleep apnea and osteoarthritis. Treatment reportedly includes dieting, physical exercise, behavior modification and sometimes anti-obesity drugs such as appetite suppressants, and surgery such as malabsorptive procedures and restrictive procedures. Obesity is the second leading cause of preventable deaths in the United States. ("Overweight and Obesity," Centers for Disease Control and Prevention, available at: http://www.cdc.gov/obesity/index.html, (2009)).
  • the metabolic syndrome is characterized by a group of factors and lab test results, which have been alleged to include obesity, weight gain, athergenic dyslipidemia, especially lower than normal levels of high-density lipoprotein (HDL) cholesterol, hypertension, high serum triglyceride levels (>150 mg/dl), hypertension, insulin resistance or glucose intolerance and a proinflammatory state characterized by elevated C-reactive protein in the blood.
  • HDL high-density lipoprotein
  • Metabolic syndrome is also sometimes associated with liver and kidney problems as well as polycystic ovary syndrome and cognitive decline in the elderly. Reported treatment can consist of lifestyle changes including diet and exercise, as well as medication to treat the disease and the symptoms individually.
  • compositions and methods to prevent or treat the metabolic syndrome and its underlying causes, as well as atherosclerosis, obesity, and diabetes.
  • compositions as well as methods of employing them that may advantageously improve the prevention or treatment, or both, of the metabolic syndrome, atherosclerosis, obesity and diabetes, or any combination thereof.
  • the pharmaceutical composition includes a pharmaceutically effective amount of D-tagatose, or a pharmaceutically acceptable salt, sugar alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug thereof, or any combination thereof, and a pharmaceutically effective amount of a biguanide component, or a pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, polymorph, amide, derivative, analog, metabolite or prodrug thereof, or any combination thereof.
  • Preferred biguanide components may include metformin, phenformin, buformin, proguanil, or a combination thereof.
  • D-tagatose is present in a pharmaceutically effective amount of about 0.2 grams to about 50 grams.
  • the biguanide component is present in a pharmaceutically effective amount of about 5 milligrams to about 5,000 milligrams.
  • the pharmaceutical composition may be adapted for oral administration.
  • the pharmaceutical composition is an anti-metabolic syndrome composition that includes any of the compositions herein where the pharmaceutically effective amount of the composition is sufficient to prevent or treat the metabolic syndrome.
  • the pharmaceutical composition may be an anti-atherosclerosis
  • composition that includes any of the compositions herein where the pharmaceutically effective amount of the composition is sufficient to prevent or treat atherosclerosis.
  • the pharmaceutical composition may be an anti-obesity composition that includes any of the compositions herein where the pharmaceutically effective amount of the composition is sufficient to prevent or treat obesity.
  • the pharmaceutical composition may be an anti-diabetes composition that includes any of the compositions herein where the pharmaceutically effective amount of the composition is sufficient to prevent or treat diabetes.
  • the pharmaceutical composition including any of the pharmaceutical compositions described herein, are present in an amount sufficient to decrease the total serum triglyceride levels by about 1% to about 60%, preferably about 5% to about 50%, more preferably about 11% to about 40%.
  • the pharmaceutical compositions including any of the pharmaceutical compositions described herein, are present in an amount sufficient to decrease the concentration of low density lipoprotein (LDL) in blood by about 0.1% to about 30%, preferably about 4% to about 20%, more preferably about 6% to about 10%.
  • LDL low density lipoprotein
  • compositions including any of the
  • compositions described herein are present in an amount sufficient to decrease the plaque volume in arteries by about 0.1% to about 50%, preferably about 0.5% to about 40%, more preferably about 1% to about 30%.
  • pharmaceutical compositions, including any of the pharmaceutical compositions described herein are present in an amount sufficient to decrease lesion size by about 0.1% to about 95%, preferably about 0.5% to about 90%, more preferably by about 1% to about 70%.
  • the invention also encompasses methods for preventing or treating the metabolic syndrome in a mammal, which includes administering to the mammal a pharmaceutically effective amount of a composition including the pharmaceutical composition of any of the above-mentioned compositions discussed herein to prevent or treat the metabolic syndrome in the mammal.
  • the mammal is a human.
  • the pharmaceutical composition is adapted for oral administration and the methods include administering the pharmaceutical composition.
  • the invention further encompasses a method for preventing or treating atherosclerosis in a mammal, which includes administering to the mammal a pharmaceutically effective amount of a composition including any of the compositions described herein to prevent or treat the atherosclerosis in the mammal.
  • the mammal is a human.
  • the pharmaceutical composition is adapted for oral administration and the methods including orally administering the composition.
  • the invention includes methods for preventing or treating obesity in a mammal, which includes administering to the mammal a pharmaceutically effective amount of a composition, including any of the pharmaceutical compositions described herein, to prevent or treat obesity in the mammal.
  • the mammal is a human or domesticated pet, such as a dog or cat.
  • the pharmaceutical composition is adapted for oral administration and the methods include administering the pharmaceutical composition.
  • the invention includes methods for preventing or treating diabetes in a mammal, which includes administering to the mammal a pharmaceutically effective amount of a composition, including any of the pharmaceutical compositions described herein, to prevent or treat diabetes in the mammal.
  • the pharmaceutical compositions may be adapted for oral or nasal administration.
  • the compositions are adapted for oral administration and formed as a tablet.
  • the tablet may be formed by direct compression.
  • any of the pharmaceutical compositions herein are used in the prevention or treatment of the metabolic syndrome; in the prevention or treatment of atherosclerosis; in the prevention or treatment of obesity; or in the prevention or treatment of diabetes; or a combination thereof.
  • the pharmaceutical compositions are for use as a medicament.
  • the pharmaceutical compositions are for use as a medicament for preventing or treating the metabolic syndrome; as a medicament for preventing or treating atherosclerosis; as a medicament for preventing or treating obesity; or as a medicament for preventing or treating diabetes; or a combination thereof.
  • the invention encompasses the use of any of the pharmaceutical compositions mentioned herein in the manufacture of a medicament for the prevention or treatment of one or more symptoms of the metabolic syndrome; in the manufacture of a medicament for the treatment or ameliorating one or more symptoms of atherosclerosis; in the manufacture of a medicament for the treatment or ameliorating one or more symptoms of obesity; in the manufacture of a medicament for the treatment or ameliorating one or more symptoms of diabetes; or a combination thereof.
  • the use of a pharmaceutically effective amount of the pharmaceutical compositions herein is in the manufacture of a medicament for the prevention or treatment of one or more symptoms of dyslipidemia, hypertension, hypertriglyceridemia, hyperglycemia, hypercholesterolemia, or a combination thereof.
  • a preferred embodiment is the use of a pharmaceutically effective amount of a composition discussed herein to prepare a medicament for the prevention or treatment of hyperglycemia symptom(s).
  • the invention encompasses the use of any or all of the pharmaceutical compositions herein or the use of any or all of the pharmaceutical compositions herein in the manufacture of a medicament for use in therapy. In some embodiments, the invention encompasses the use of any or all of the pharmaceutical compositions herein or the use of any or all of the pharmaceutical compositions herein in the manufacture of a medicament for use in therapy of a human that has, is suspected of having, or is at risk for developing metabolic syndrome, atherosclerosis, obesity, or diabetes, or a combination thereof.
  • the second pharmaceutically active drug includes both a biguanide component and a stilbene or stilbenoid component; or any pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug thereof; or any combination thereof.
  • the stilbene or stilbenoid component includes one or more of piceatannol, pinosylvin, pterostilbene, resveratrol, viniferins, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, gnetin H, hemsleyanol D, hopeaphenol, trans -diptoindonesin B, vaticanol B, astringin, piceids, and diptoindonesin A, or any combination thereof.
  • compositions and methods herein may find broad applicability in a variety of treatment/prophylaxis regimens, including other diseases and syndromes. It should also be understood that each of the embodiments described herein may typically be used in connection with any of the other embodiments described herein.
  • the pharmaceutical compositions further include a pharmaceutically acceptable carrier of one or more pharmaceutically acceptable excipients.
  • compositions including a pharmaceutically effective amount of D-tagatose, or a pharmaceutically acceptable salt, sugar alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug thereof; in combination with a pharmaceutically effective amount of at least a second pharmaceutically active drug, or a pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug thereof; have surprising and unexpected prophylactic or therapeutic effect in mammals, preferably humans.
  • the compositions involve a combination of pharmaceutically effective amounts of D- tagatose and at least a second pharmaceutically active drug, and may also contain a
  • the second pharmaceutically active drug includes a biguanide component, or both a biguanide component and a stilbene or stilbenoid component; or any pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug thereof; or any combination thereof.
  • TAG D- tagatose
  • TAG can be used in any state, including as a salt, sugar alcohol, hydrate, solvate, ester, polymorph, amide, derivative, analog, metabolite, or prodrug thereof, it is preferably included as an active ingredient in its natural state, i.e., not in the form of a salt, sugar alcohol, hydrate, solvate, ester, polymorph, amide, derivative, analog, metabolite, or prodrug thereof.
  • TAG includes the active agent itself, or an active metabolite, pharmaceutically acceptable salt, sugar alcohol, hydrate, solvate, ester, polymorph, amide, derivative, polymorph, analog, metabolite, or prodrug thereof, or any combination thereof.
  • Salt and the other forms noted herein in connection with TAG and any other pharmaceutically active drug component herein refers to pharmaceutically acceptable forms in pharmaceutical compositions and food products. These same forms may be included in the compositions and methods with reference to the second pharmaceutically active drug for any of the
  • the present invention relates to a pharmaceutical composition including
  • the biguanide component preferably includes metformin, buformin, phenformin, proguanil, or a pharmaceutically acceptable salt or derivative thereof, or any combination thereof.
  • a preferred biguanide component includes metformin.
  • the biguanide component is typically present in a human dosage amount from about 5 mg to about 5,000 mg a day, preferably from about 50 mg to 2,550 mg a day, more preferably from about 100 mg to about 2,000 mg per day.
  • the second active drug component may further include a stilbene or stilbenoid component (i.e., one or more stilbenes, stilbenoids, or a combination thereof) in any form, including but not limited to any pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, polymorph, amide, derivative, polymorph, analog, metabolite, or prodrug form, or any combination thereof, along with the biguanide component and D-TAG.
  • a stilbene or stilbenoid component i.e., one or more stilbenes, stilbenoids, or a combination thereof
  • stilbene or stilbenoid component means one or more stilbenes, one or more stilbenoids, or any combination thereof in any of the forms noted herein. These stilbene and stilbenoid compounds may be obtained by any suitable technique available to those of ordinary skill in the art, including but not limited to chemical synthesis or by extraction and optional isolation or purification from a plant. The stilbene compounds can be formed into pharmaceutically acceptable acid-addition salts and salts with bases.
  • the stilbene and stilbenoid component preferably includes one or more of: piceatannol, pinosylvin, pterostilbene, resveratrol, viniferins, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, gnetin H, hemsleyanol D, hopeaphenol, trans-diptoindonesin B, vaticanol B, astringin, piceids, and diptoindonesin A, or any combination thereof.
  • a preferred stilbenoid may be one or more of resveratrol and derivative(s) thereof.
  • Resveratrol can be synthesized via the phenylalanine/polymalonate pathway in plants and is found in the skin of red grapes.
  • Resveratrol is a fat-soluble compound that occurs in both cis- and trans- configurations, each of which can form one or more glucosides.
  • Resveratrol may also be obtained by chemical isolation from plant-derived compositions or synthesized. It has been reported that about 70% of resveratrol dosed orally is absorbed by the human body. Due to its rapid metabolism by the small intestine and liver, which lowers its bio-availability, higher doses of resveratrol may be preferred.
  • the stilbenoid When included in the second active drug component, the stilbenoid preferably includes one or more resveratrol-derived components, including, but not limited to one or more resveratrol dimers, more preferably resveratrol fraws-dehydrodimer, resveratrol (E)-dehydrodimer ⁇ - ⁇ - ⁇ -D-glucopyranoside, resveratrol (E)-dehydrodimer l l-0- ⁇ - D-glucopyranoside and viniferins, or an isomer thereof, or any combination thereof.
  • resveratrol-derived components including, but not limited to one or more resveratrol dimers, more preferably resveratrol fraws-dehydrodimer, resveratrol (E)-dehydrodimer ⁇ - ⁇ - ⁇ -D-glucopyranoside, resveratrol (E)-dehydrodimer l
  • Resveratrol fraws-dehydrodimer also known as resveratrol (E)-dehydrodimer
  • E resveratrol
  • Resveratrol (E)-dehydrodimer ⁇ - ⁇ - ⁇ -D-glucopyranoside also known as (2S,3R,4S,5S,6R)-2- (3- ⁇ (E)-2-[(2S,3S)-3 ⁇ 3,5-Dihydroxy ⁇ henyl)-2-(4-hydroxy-phenyl)-2,3-dihydro-benzofuran-5- yl]-vinyl ⁇ -5-hydroxy-phenoxy)-6-hydroxymethyl-tetrahydropyran-3,4,5-triol, is heterocyclic, has an empirical formula of C 3 4H 3 2O11 and a molecular weight of 616.62.
  • Viniferins are glycosylated and polymerized derivatives of resveratrol.
  • a preferred component of the second active ingredient is epsilon viniferin ( ⁇ -viniferin), which is a cyclic dimer of resveratrol and can be extracted from Vitis vinifera. This compound is typically formed through the peroxidase-mediated oxidative dimerization of resveratrol.
  • ⁇ - viniferin also known as 5- ⁇ 6-hydroxy-2-(4-hydroxyphenyl)-4-[2-(4-hydroxyphenyl)vinyl]-2,3- dihydroxybenzofuran-3-yl ⁇ benzene-l,3-diol
  • 5- ⁇ 6-hydroxy-2-(4-hydroxyphenyl)-4-[2-(4-hydroxyphenyl)vinyl]-2,3- dihydroxybenzofuran-3-yl ⁇ benzene-l,3-diol is heterocyclic and has an empirical formula of C2 8 H22O6 and a molecular weight of 454.48.
  • the stilbenoid may preferably include one or more piceids.
  • Resveratrol can conjugate to sugars, which can form one or more glucosides such as trans- and cz ' s-piceid, the 3- ⁇ - ⁇ - ⁇ - resveratrol glucoside.
  • a preferred second active drug component includes trans-(14C6)piceid.
  • Trans-(14C6)piceid is heterocyclic, has an empirical formula of C2 0 H22O 8 and a molecular weight of 402.32.
  • a prophylactic or therapeutic dose of the compositions of the invention in the acute or chronic management of disease will vary depending on the subject to which it is being administered, the severity of the condition to be treated, and the route and manner of administration, and may be determined by one of ordinary skill in the art with reference to the guidance provided herein.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient based on the guidance herein.
  • the total daily dose range, for the conditions described herein is from about 0.01 grams to about 240 grams, preferably about 0.1 grams to 200 grams, and more preferably about 0.5 grams to 100 grams of TAG.
  • the pharmaceutically effective amount of TAG may include about 0.75 grams to 90 grams, about 1 gram to 80 grams, or even about 1.5 grams to 75 grams, or any whole number in between. In a preferred embodiment, the pharmaceutically effective amount of TAG is about 2 grams, about 2.5 grams, about 5 grams, about 7.5 grams, about 15 grams, about 25 grams, or about 50 grams. In general, the total daily dose range for the conditions described herein is about 500 mg to about 2600 mg, preferably about 1,000 mg to 2,500 mg, of biguanide component.
  • the total daily dose range for the conditions described herein is about 0.0001 grams to about 1.5 grams, preferably about 0.001 grams to about 0.75 grams, and more preferably about 0.005 grams to about 0.5 grams of the stilbene or stilbenoid component.
  • An exemplary amount of stilbene or stilbenoid component is about 0.01 grams to about 0.1 grams, when included.
  • the compositions can be administered in single or divided doses, preferably with the total daily dose divided into equal dosages taken over the course of a day. Preferably, only one dose per day will be required. In one embodiment, the composition that is administered will be taken with food and drink (e.g. , within about 2 hours of eating, preferably within about one hour of eating) so as to eliminate any potential gastrointestinal distress.
  • compositions may be administered without regard to eating, while in another the TAG will be included in a food product and administered as a food product while the biguanide component is separately pharmaceutically administered.
  • the biguanide component may be administered concurrently or sequentially, and in the latter event, at different times compared to the TAG.
  • compositions discussed herein including TAG and optionally a second active drug component, which may independently be prophylactic, therapeutic, or help manage, e.g., the condition or disease or its symptoms, may be administered in any dosage form(s) suitable to administer a measured amount of the pharmaceutical composition to achieve the desired prophylactic or therapeutic effect based at least on the guidance herein.
  • dosage forms include, for example, solid dosage forms, such as tablets, capsules, powders, and cachets, or liquid dosage forms, such as suspensions, syrups, solutions, and elixirs.
  • the second drug component may be combined with the TAG composition or may be administered in a separate dosage form, but preferably is in an oral dosage form, more preferably a tablet form.
  • the tablet can be any suitable tablet, such as an orally disintegrating tablet, uncoated tablet, coated tablet, sustained-release or controlled-release tablet, or the like.
  • the dosage form containing the second active drug component will, in any event, contain a quantity of the additional active drug(s) in an amount effective to alleviate or manage the symptoms or condition of the subject being treated or to provide a prophylactic effect.
  • the selection of the specific second active drug component will depend upon the specific disease state being treated, some of which are described in detail herein.
  • all active ingredients will be in an oral form, e.g. , an oral composition or tablet, capsule, powder, and/or cachets, more preferably in a combined form to facilitate patient compliance.
  • a preferred oral daily dose range can include from about 0.1 g to about 20 g of TAG, preferably about 1 g to about 15 g of TAG, and in one exemplary embodiment, from about 2 g to 10 g of TAG, and an amount of about 250 mg to 1,500 mg of a biguanide component, preferably about 500 mg to 1,000 mg of a biguanide component.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of the compositions according to the methods of the present invention.
  • oral, rectal, parenteral, intravenous, topical, transdermal, subcutaneous, intramuscular, and like forms of administration may be employed.
  • Oral, topical, transdermal, or locally by inhalation dosage forms are preferred.
  • Non-limiting exemplary dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
  • a preferred dosage form includes tablets, in one embodiment, preferably directly compressed tablets.
  • compositions for use in the methods of the present invention include compositions such as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets), with the oral solid preparations being preferred over the oral liquid preparations.
  • oral solid preparations such as powders, capsules, and tablets
  • the most preferred oral solid preparations are tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet may be prepared by direct compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound optionally moistened with an inert liquid diluent. Desirably, each tablet contains a single dose of the pharmaceutical composition(s) as discussed herein.
  • the second active drug component can be formed as an immediate release formulation and may be incorporated into a single dosage form with the TAG dosage, for example without limitation, by coating onto the membrane by conventional methods.
  • the second active drug component may be incorporated or combined by any pharmaceutically acceptable method into a single dosage form with the first active drug.
  • the combination of the TAG and second active drug component and any optional prophylactic or therapeutic agent and pharmaceutically acceptable carrier, as selected, may be performed by, but is not limited to, processes such as drug layering, coating, lamination, dry compression, deposition and printing.
  • the TAG, second active component e.g.
  • a combination of D-tagatose and a biguanide component can be prepared in controlled or sustained release form, for example without limitation, in association with a gel, matrix, capsule, or resin material, or any combination of controlled release, sustained release, or delivery device technology available to those of ordinary skill in the art as an alternative or in addition to the common dosage forms set out above, such as those described in, for example without limitation, U.S. Patent Nos.
  • compositions for use in the methods of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with a pharmaceutically carrier.
  • compositions of the invention can be entirely free of additional pharmaceutically acceptable carriers, given that the TAG itself can function as a diluent permitting tableting without any additional carrier.
  • a carrier if a carrier is used, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • the components of a solid composition according to the invention are blended and compressed directly from a powder mixture without need for pretreatment of the powder blend by wet or dry granulation procedure.
  • Substantially all the components preferably have a substantially or entirely uniform particle size and preferably are substantially free or entirely free of air entrapped in the tablets during direct compression.
  • the composition(s) of the present invention be at least substantially free, preferably entirely free, of large particulates or other impurities. Due to the nature and physical properties of TAG, in one embodiment it is preferred that no binders or other cohesive substances be used during direct compression of the tablets.
  • the exemplary tablets may be manufactured by other granulation procedures that are available in the art. Additionally, other excipients such as lubricants, pigments or dyes may also be employed in the formulation of the subject invention.
  • the components may be dissolved into a liquid solution that is to be taken orally or by intramuscular, subcutaneous, or intradermal injection.
  • an excipient, a binder, a disintegrant, a lubricant, a colorant, a corrigent and the like can be added thereto as required, and the resulting mixture formed into tablets, coated tablets, granules, capsules or the like.
  • a pH adjuster, a buffer, a stabilizer, an antiseptic and the like can be added. Injections can be made in a conventional manner as known to those of ordinary skill in the art. Due to the comparatively low absorption rate of TAG when taken orally, adjustment to dosage amount would be necessary if injected into the bloodstream.
  • the active drug components of the pharmaceutical compositions can be obtained by any chemical isolation, chemical synthesis or a combination thereof available to those of ordinary skill in the art.
  • the components of the pharmaceutical composition are at least substantially pure, and more preferably are pure with no more than trace amounts of impurities. Any suitable purification techniques can be carried out in association with the compositions of the invention using suitable processes generally available to those of ordinary skill in the art, such as, but not limited to, filtration, extraction, distillation, fractionation, and crystallization.
  • the components of the pharmaceutical composition are at least substantially or essentially free of, preferably entirely free of, detectable amounts of other material that normally accompany the material as it is found in its native state.
  • preparations should meet sterility, pyrogenicity, and the general safety and purity standards as required by the FDA Office of Biologies standards.
  • phrases "pharmaceutically” in connection with the effective amount includes that amount of the one of more other active ingredient(s), that either acts as a prophylactic and inhibits or prevents the development of and/or provides a prophylactic or therapeutic benefit in the treatment or management of symptoms or conditions associated with the treatment of the metabolic syndrome, atherosclerosis, obesity or diabetes, or a combination thereof, including, but not limited to, the symptoms thereof.
  • Such symptoms include, without limitation, dyslipidemia, hypertension, high glycated hemoglobin levels in the blood, high blood pressure, dyslipoproteinemia, hypertriglyceridemia, high C-reactive protein concentrations in the blood, or high concentrations of LDLs as well as low concentrations of high density lipoproteins HDLs, or one or more other conditions or symptoms associated therewith.
  • the pharmaceutical compositions described herein are administered in an amount sufficient to lower or decrease the total serum triglyceride levels by about 1% to about 60%, preferably about 5% to about 50%, more preferably about 11% to about 40%.
  • Lowering serum triglyceride levels can be an important aspect of reducing the risk or severity of the metabolic syndrome, atherosclerosis, obesity or diabetes in a mammal, particularly a human.
  • the pharmaceutical compositions described herein are administered in an amount sufficient to lower or decrease the concentration of LDL in the blood by about 0.1% to about 30%, preferably about 4% to about 20%, more preferably about 6% to about 10%.
  • Lowering LDL concentrations in the blood can also be advantageous in reducing the risk or severity of the metabolic syndrome, atherosclerosis, obesity or diabetes in a mammal, particularly a human.
  • the pharmaceutical compositions described herein are administered in an amount sufficient to lower or decrease the plaque volume in arteries by about 0.1% to about 50%, preferably about 0.5% to about 40%, more preferably about 1% to about 30%.
  • plaque includes any deposit on, or thickening of, the arterial lining exceeding about 0.5mm. Lowering the plaque volume in arteries is an important aspect of reducing the risk or severity of the metabolic syndrome, atherosclerosis, obesity or diabetes in a mammal, particularly a human. This can also advantageously minimize lesion formation.
  • the pharmaceutical compositions, including any of the pharmaceutical compositions described herein can be administered in an amount sufficient to decrease lesion size by about 0.1% to about 95%, preferably about 0.5% to about 90%, more preferably by about 1% to about 70%.
  • the present invention also provides methods of treating symptoms or conditions associated with the metabolic syndrome, atherosclerosis, obesity or diabetes mellitus, or a combination thereof, including one or more of: dyslipidemia, hypertension, high glycated hemoglobin levels in the blood, high blood pressure, dyslipoproteinemia, hypertriglyceridemia, high C-reactive protein concentrations in the blood, or high concentrations of LDLs as well as low concentrations of high density lipoproteins HDLs, or one or more other conditions or symptoms associated therewith, for example, preferably in a mammal, more preferably in a human.
  • T he methods of the invention include administering to a patient, preferably a mammal, more preferably a human, an effective amount of a TAG and biguanide composition of the invention.
  • a pharmaceutically effective amount of TAG in an oral tablet form is a concentration of about 2.5 grams, wherein the tablet is administered from about one to about three times daily, such as with meals.
  • the dosage form is , e.g.
  • the pharmaceutically effective amount of D-tagatose can include amounts of about 0.67 grams, about 0.83 grams, about 1.67 grams, about 5 grams, about 7.5 grams, about 8.3 grams, about 10 grams, about 12.5 grams, about 15 grams and about 16.67 grams per dose.
  • the pharmaceutically effective amount of TAG can be co-administered with a pharmaceutically effective amount of at least a second active drug.
  • dosing of about 0.05 to about 50 mg per kg of body weight may be preferred, with dosing of about 0.1 to about 10 mg per kg of body weight especially preferred, although there can be significant dosing variation outside of this range to achieve the desired therapeutic or prophylactic effect according to the invention, which may depend on the amount of TAG present in the composition.
  • Recommended dosages of the biguanide component can be administered as stated in the Physician's Desk Reference, with starting doses of about 500 mg being administered twice a day and gradually increasing the dosage to about 1000 mg, or even up to about 1,275 mg, two times a day.
  • the effective amount of the biguanide component will vary depending on the subject being treated, the severity of the disease state and the manner of administration, and may be determined by one of ordinary skill in the art with reference to the guidance herein. It may be necessary to use dosages outside the above ranges in some cases, as will be apparent to those of ordinary skill in the art. Further, it is noted that the clinician or treating physician will know the appropriate daily dose, and how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
  • the invention relates to a method of treating the metabolic syndrome in a mammal by administering to the mammal a prophylactically or therapeutically effective amount of a composition of TAG and at least one second pharmaceutical drug component.
  • the invention relates to a method of treating atherosclerosis in a mammal by administering to the mammal a prophylactically or therapeutically effective amount of a composition of TAG and at least one second pharmaceutical drug component.
  • the invention relates to a method of preventing the metabolic syndrome in a mammal by administering to the mammal a prophylactically effective amount of a composition of TAG and at least one second pharmaceutical drug component.
  • the invention relates to a method of preventing atherosclerosis in a mammal by administering to the mammal a prophylactically effective amount of a composition of TAG and at least one second pharmaceutical drug component.
  • the methods administer pharmaceutically effective compositions including TAG compositions along with a second pharmaceutical drug component including a biguanide component to provide an additive, more complete, or synergistic effect in preventing, treating, or managing a condition or disease, or its symptoms, as discussed herein, or any other disease or condition for which the same patient may require prevention, treatment, or management thereof.
  • an unexpected, beneficial synergistic effect may occur as a result of the application of a combination of TAG and a second active drug component including the biguanide component or a combination of the biguanide component and a stilbene or stilbenoid component, in the pharmaceutical compositions discussed herein.
  • a lower dose of the second active drug component in combination with the TAG component can be used to achieve the effect expected by a significantly larger dose of the second active drug component alone.
  • a lower dose of TAG can be used in combination with a second active drug to achieve the effect expected by a significantly larger dose of TAG alone.
  • preparations of pharmaceutical compositions herein could render a 500 mg dose of biguanide component in combination with an effective amount of TAG more effective in preventing, treating or managing a condition or disease discussed herein, or its symptoms, compared to a 500 mg or greater dose of biguanide component alone that is at least substantially or entirely free of TAG.
  • compositions may be administered to prevent, treat, or manage obesity; diabetes; atherosclerosis; the metabolic syndrome; or one or more conditions associated with the symptoms or disease state of the metabolic syndrome; any symptom(s) thereof; or a combination of any of the foregoing diseases, symptoms, or conditions.
  • a method of preventing, treating, or managing a disease in a mammal includes administering to the patient a pharmaceutically effective amount of an oral tablet including a composition of a
  • compositions of the present invention can be administered in connection with combination therapy regimens, e.g. , for preventing, treating, or managing the symptoms of the metabolic syndrome, atherosclerosis, obesity, or diabetes, or a combination thereof.
  • combination therapy regimens e.g. , for preventing, treating, or managing the symptoms of the metabolic syndrome, atherosclerosis, obesity, or diabetes, or a combination thereof.
  • additional prophylactic or therapeutic agents may include, for instance, one or more effective agents such as diuretics, ACE inhibitors and cholesterol-lowering drugs or any combination thereof.
  • compositions may also include one or more other classes of pharmaceutically active agents for the prevention, treatment, or management of other conditions, as deemed necessary or desired by a physician. Such other conditions may occur, for example, in patients that are also suffering from one or more related conditions. Other conditions may include, but are not limited to, for example, gout, polycystic ovarian syndrome and endothelial dysfunction.
  • the invention provides for a composition for use in preventing, treating or ameliorating the symptoms of the metabolic syndrome in a mammal.
  • the invention provides for a composition for use in preventing, treating or ameliorating the symptoms of atherosclerosis in a mammal.
  • the invention provides for a composition for use in preventing, treating or ameliorating the symptoms of obesity in a mammal.
  • the invention provides for a composition for use in preventing, treating or ameliorating the symptoms of diabetes in a mammal.
  • an advantage may be achieved by formulating the composition to include two active drugs, for example, TAG and a biguanide component each or both present in the composition in an amount effective to treat, prevent or lessen the symptoms of the metabolic syndrome, in the individual.
  • the invention also provides for the use of TAG and biguanide -based compounds in the manufacture of one or more medicaments for treating, preventing, or ameliorating one or more clinical symptoms of the metabolic syndrome in general as well as atherosclerosis, obesity and diabetes.
  • Such compositions may also include one or more pharmaceutically acceptable carriers useful in the preparation of medicaments suitable for systemic or local administration to a mammal having, suspected of having, or at risk for developing the metabolic syndrome, as well as atherosclerosis, obesity and diabetes.
  • the invention provides for the use of TAG and biguanide-based compounds in the manufacture of one or more medicaments for treating, preventing, or ameliorating one or more clinical symptoms of the metabolic syndrome in general as well as atherosclerosis, obesity and diabetes.
  • a composition including at least TAG and a second active drug preferably a biguanide component, or optionally both a stilbene or a stilbenoid component and a biguanide component, or any pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, polymorph, amide, derivative, analog, metabolite, or prodrug thereof, or any combination thereof, formulated for administration to the mammal in the manufacture of a medicament for preventing, treating or ameliorating the symptoms of the metabolic syndrome, atherosclerosis, obesity, diabetes, or a combination thereof, are also provided herein.
  • the present invention discloses composition and methods for the prevention, treatment, amelioration of symptoms of the metabolic syndrome, atherosclerosis, obesity, and diabetes including, but not limited to dyslipidemia, hypertension,
  • hypertriglyceridemia hyperglycemia, hypercholesterolemia, or a combination thereof.
  • compositions disclosed herein, and compositions that include, consist essentially of, or consist of them, have been shown to be effective in lowering LDL, serum triglyceride, HbAlc levels, as well as the number of atherosclerotic lesions present in susceptible individuals, and can thus be used as either as a monotherapy, or alternatively in combination with one or more known prophylactic or therapeutic agent(s) to provide regimen(s) that cure or significantly diminish the dynamics of the development of the metabolic syndrome, atherosclerosis, obesity or diabetes in vivo.
  • the determination of individual dose size, duration of therapy, the need for concomitant co-therapy using additional compounds, as well as all other dosing considerations is considered to be well within the purview of the ordinary skilled medical practitioner carrying out the methods of the invention.
  • the invention is also particularly contemplated to be useful in persons who are placed at a higher risk for developing the metabolic syndrome, atherosclerosis, obesity and diabetes, such as those individuals currently with dyslipidemia, hypertension, hypertriglyceridemia, hyperglycemia, hypercholesterolemia, or a combination thereof.
  • the present invention relates to a food product including a first active ingredient of TAG, which can be eaten in conjunction with the at least one biguanide component, or a salt, isomer, alcohol, hydrate, solvate, ester, polymorph, amide, derivative, polymorph, analog, metabolite, or prodrug thereof; optionally including an additional pharmaceutically active agent.
  • a food product includes gum and anything edible by a mammal, including liquid, that has nutritional content, such as without limitation, a fortified food supplemented with the composition of the invention, a nutritional supplement including the composition of the invention, or the like.
  • “food product” refers to an edible product.
  • the term “in conjunction with” means that the food product is ingested any time before, during or after the second active ingredient is administered.
  • the preferred additional pharmaceutically active agent is a stilbene or stilbenoid component, or a pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug forms.
  • the compounds of the present invention can be formed as described above. TAG may be incorporated into any food product by any means known to those of ordinary skill in the art.
  • compositions such as food products or any other form prepared for administration, are at least substantially free, or entirely free, of any sweetener or bulking agents aside from the TAG.
  • sweeteners and bulking agents that could be included, but in one embodiment are preferably minimized or avoided, include without limitation:
  • compositions are at least substantially free, or entirely free, of any other diluent.
  • active agent in some cases with the term “component” are used interchangeably herein to refer to one or more chemical materials or compounds which, when administered to a mammal, induce(s) a desired pharmacological, prophylactic, or therapeutic effect. Included are any pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug forms, of those compounds or classes of compounds, particularly those specifically mentioned, that also induce the desired pharmacological, prophylactic, or therapeutic effect.
  • the term “amount” includes both a dry quantity of an agent, compound, or component, such as a quantity that is measured or given in gram (g) or milligram (mg) units, as well as a quantity of an agent, compound, or component that is dissolved or otherwise present in a particular volume of a solvent or other liquid reagent and expressed in terms of a concentration, such as mg/dl.
  • the term “effective amount” or “pharmaceutically effective amount” includes an amount of an active pharmaceutical agent that is required to obtain prophylactic or therapeutic efficacy against a disease or condition, or a symptom thereof, or to manage a disease or condition, or a symptom thereof.
  • an "effective amount” or “pharmaceutically effective amount” of any portion of the compositions described herein, as well as each entire composition, are encompassed by the frequency and dosage amounts described herein.
  • an effective amount of TAG includes an amount of TAG, or a salt, sugar alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug thereof, that is required to obtain efficacy to prevent, treat, or manage the metabolic syndrome condition, or the formation or retention thereof, or the symptoms or conditions associated with the metabolic syndrome condition.
  • the term "manage” includes any action that results, for instance, in the amelioration of a disease or condition, or other therapeutic effect that improves the health or well-being of a patient such as the prevention or reduction of its symptoms without necessarily completely curing the disease or condition.
  • mammal is meant the class of warm-blooded vertebrate animals that have, in the female, milk-secreting organs for feeding the young. Mammals include, without limitation, humans; apes; various four-legged animals such as cows, horses, pets such as dogs and cats; whales; dolphins; and bats.
  • pharmaceutically acceptable salt(s) or "a pharmaceutically acceptable salt thereof refers to salt(s) prepared from pharmaceutically acceptable non-toxic acid or bases including inorganic acids and bases and organic acids or bases.
  • the pharmaceutically acceptable salts used in the present invention may be amphoteric, may be present in the form of internal salts, or both. Although any available salt made by any method available to those of ordinary skill in the art may be used, a few exemplary acids and bases are described without limitation.
  • Exemplary inorganic acids that can be used to form such salts include one or more mineral acids such as hydrochloric, hydroiodic, hydrobromic, sulfuric or phosphoric acid.
  • organic acids may be selected, for example without limitation, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, glucuronic acid, furoic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid, stearic acid, sulfanilic acid, algenic acid, galacturonic acid, oxalic acid, fumaric acid, maleic acid, malic acid, citric acid, tartaric acid, glutamic acid, or a combination thereof.
  • organic acids may be selected, for example without limitation, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic acid, ace
  • salts derived from organic bases include, for example, one or more salts of primary, secondary and tertiary amines, substituted amines including naturally- occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, tripropylamine, ethanolamine, 2-dimethyl aminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, fumarate, maleate, succinate, acetate, N,N-dibenz
  • the term “prevent,” “preventing” or “prevention” covers preventing the specified disease and/or its symptoms in a mammal, more preferably a human, and includes: (i) preventing the disease or its symptoms from occurring in a subject that may be predisposed to the disease but has not yet been diagnosed as having it; and (ii) inhibiting the disease or its symptoms, i.e., arresting its development before or after it afflicts a patient, or both. It should be understood that symptoms of any disease are also encompassed within the terms “prevent,” “preventing” or “prevention” such that inhibiting symptoms of the metabolic syndrome, for example, may address some or all of the symptoms thereof with or without actually affecting the underlying disease itself.
  • substantially means, e.g. , not entirely complete, or not entirely absolute. Typically, “substantially” should be understood to refer to at least about 90 percent, preferably at least about 95 percent, and more preferably at least about 99 percent. In one more preferred embodiment, “substantially” can refer to at least about 99.5 percent or 99.9 percent.
  • a composition that is "substantially stable,” such as a formulation of TAG having substantial stability encompasses a solution that may not necessarily exhibit absolute or 100% stability over a defined period of time; instead, the composition may exhibit nearly total stability, such as greater than about 97% stability or 99.8% stability, over a particular period of time under ambient conditions (unless specified otherwise).
  • substantially free means, e.g. , almost entirely devoid of the referenced characteristic.
  • substantially free should be understood to refer to less than about 5 percent, preferably less than about 1 percent, and more preferably less than about 0.1 percent. In a more preferred embodiment, it refers to less than about 0.05 percent, or less than about 0.01 percent. In one most preferred embodiment, the term refers to less than an analytically detectable amount.
  • the term “treat,” “treating” or “treatment” covers treating or managing the specified disease and/or its symptoms in a mammal, more preferably a human, and includes: (i) relieving the disease or its symptoms, i.e., causing regression of the disease; (ii) monitoring the disease or its symptoms, i.e. , adjustment of the drug delivery cycle to optimum levels. It should also be understood that symptoms of any disease are also encompassed within the terms “treat,” “treating,” or “treatment” such that managing symptoms of the metabolic syndrome, for example, may address some or all of the symptoms thereof with or without actually affecting the underlying disease itself.
  • the invention is further defined by reference to the following illustrative (non- limiting) examples, describing in detail specific excipients, indications, combinations, dosage amounts, and the like, that may be used to help one of ordinary skill in the art prepare or administer the compositions and carry out the methods of the present invention.
  • Example 1 Comparison of Body Weight, Adipocyte Characteristics, Blood Cholesterol Concentrations, Hyperglycemia, and Atherosclerotic Lesions in Control, TAG-Fed and Sucrose- Fed Hypercholesterolemic Mice According to the Invention
  • LDLr " _ Low-density lipoprotein receptor male and female mice
  • sucrose and TAG were introduced to the experimental mice gradually over a three week period, using an increasing ratio of sucrose or TAG diet to the standard murine diet.
  • mice fed a diet enriched with sucrose exhibited a marked increase in body weight (40+2 g for males; 31+1 g for females) compared to the mice fed a diet enriched with TAG (27+0 g for males; 24+1 g for females) and the control (30+0 g for males; 24+1 g for females) mice.
  • the body weights of mice fed a TAG enriched diet were comparable to the body weights of the control mice.
  • adipose tissue mass was increased in both male and female mice fed the diet enriched with sucrose when compared to mice fed murine or TAG-enriched diets.
  • adipose tissue sections were deparrafinized and stained using hematoxylin and eosin and then analyzed using Image Pro Plus 5.1 (Media Cybernetics, Silver Spring, MD).
  • mice fed the sucrose-enriched diet exhibited increased adipocyte size (83+3 ⁇ for males; 50+1 ⁇ for females) when compared to TAG-fed (79+3 ⁇ for males; 31+1 ⁇ for females) and control (74+3 ⁇ for males; 30+1 ⁇ for females) mice.
  • Macrophage positive F4/80 immunostaining was detected in adipose section from mice fed a sucrose-enriched diet but not in those fed standard murine or TAG-enriched diets. Results from this study indicate that a sucrose-enriched diet promotes the development of obesity, while TAG surprisingly did not promote substantial weight gain, enhanced adiposity or adipocyte hypertrophy.
  • mice fed sucrose-enriched diets had markedly increased total serum triglyceride (822+148 mg/dl for males; 326+37 mg/dl for females) concentrations compared to male and female mice fed standard murine (110+20 mg/dl for males; 79+16 mg/dl for females) and TAG (162+29 mg/dl for males; 54+8 mg/dl for females) diets.
  • Male and female mice fed sucrose-enriched diets had markedly increased total serum cholesterol concentrations compared to male and female mice fed standard murine and TAG diets.
  • male and female mice fed sucrose-enriched diets had significantly elevated concentrations of very low density lipoprotein and LDL cholesterol.
  • mice fed TAG- enriched diets had only slightly elevated concentrations of very low density lipoprotein and LDL cholesterol compared to male and female control mice.
  • Total serum cholesterol levels were surprisingly and unexpectedly decreased in both male and female TAG-fed mice as compared to sucrose-fed mice.
  • mice were exsanguinated by perfusion through the left ventricle.
  • Aortic tissues from the heart to the ileal bifurcation were dissected and fixed overnight in 4% paraformaldehyde made with phosphate buffered solution ("PBS”) and then stored in PBS.
  • PBS phosphate buffered solution
  • Atherosclerosis was quantified by en face analysis of lesion surface area as detailed in
  • Macrophage infiltration into atherosclerotic areas was assessed using immunohistochemistry staining.
  • Sucrose-fed mice exhibited a larger degree of macrophage infiltration and larger lesions in aortic roots when compared to TAG-fed mice.
  • Infrared microscopy was then performed on the aortic lesions and atherosclerotic lesions of the sucrose-fed mice had the highest concentration of lipids compared to the lesions in TAG-fed and control mice.
  • TAG-fed mice had an intermediate amount of lipids but Gomori Trichome staining of the lesions revealed that there was a higher concentration of collagen in the atherosclerotic lesions of the TAG-fed mice compared to the lesions in the sucrose-fed mice.
  • Collagen may strengthen the fibrous caps in lipid-filled atheromas, preventing rupture.
  • both male and female sucrose-fed mice exhibited a surprisingly greater number and size of atherosclerotic lesions in aortic roots when compared to TAG-fed mice.
  • Example 2 Serum Triglyceride and Cholesterol Level Variance with TAG
  • the patients in the 7.5 g group experienced an average reduction of 0.3% in HbAlc from the HbAlc of the 2.5 g group.
  • the 5 g group experienced an average reduction of 0.05% in HbAlc from the HbAlc of the 2.5 g group.
  • TAG also surprisingly decreased the average serum triglycerides of the TAG-consuming patients by about 59 mg/dl by the end of the first month on the therapy, a decrease from baseline that remained at about 41 mg/dl by the end of the six months of the experiment.
  • the patients in the 2.5 g group surprisingly experienced an average reduction of 22.2 mg/dl
  • the patients in the 5 g group surprisingly experienced an average reduction of 96.8 mg/dl
  • the patients in the 7.5 g group surprisingly experienced an average reduction of 2.8 mg/dl.
  • TAG also decreased the serum LDL by an average of about 13 mg/dl by the end of the first month on the therapy, while serum HDL was essentially unchanged.
  • LDL levels in patients in the 2.5 g group surprisingly decreased by about 12.3 mg/dl and in the 5 g group surprisingly by about 23.8 mg/dl by the end of the first month of therapy.
  • the LDL:HDL ratio was unexpectedly improved for two of the three dose groups (i.e., the 2.5 g and 5 g groups) by an average of 0.3.
  • Example 3 TAG Tablet Formation According to the Invention
  • TAG composition tablet by direct compression is exemplified by the following, although different second active drug compositions can be used.
  • TAG is passed through a 40 mesh stainless steel screen and blended with metformin HC1 granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches (plain lower punch, upper punch with an approximately 1 mm indentation pin).
  • the orifice may be formed by any means commonly employed in the pharmaceutical industry.

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Abstract

L'invention concerne des compositions pharmaceutiques comprenant du D-tagatose associé à au moins un composant biguanide, ou l'un de ses sels ou dérivés, comprenant éventuellement un autre agent pharmaceutiquement actif. Elle concerne des procédés de prophylaxie et de thérapie par administration à un mammifère de quantités pharmaceutiquement efficaces de D-tagatose en combinaison avec un composant biguanide, ou l'un de ses sels ou dérivés pharmaceutiquement acceptable, en vue de prévenir ou de traiter l'athérosclérose, le syndrome métabolique, l'obésité ou le diabète ou une de leurs combinaisons.
PCT/US2011/028305 2010-04-01 2011-03-14 Compositions de d-tagatose et de biguanide et procédés WO2011123236A1 (fr)

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US20080031964A1 (en) * 2005-02-15 2008-02-07 Jallal Messadek Combination therapeutic compositions and method of use
US20080107787A1 (en) * 2006-11-02 2008-05-08 The Coca-Cola Company Anti-Diabetic Composition with High-Potency Sweetener
WO2009080025A1 (fr) * 2007-12-20 2009-07-02 Fertin Pharma A/S Chewing-gum comprimé comprenant un mimétique de la metformine
WO2009080033A1 (fr) * 2007-12-20 2009-07-02 Fertin Pharma A/S Chewing-gum comprimé comprenant de la metformine
JP2009286703A (ja) * 2008-05-27 2009-12-10 Matsutani Chem Ind Ltd Ｄ−タガトースを有効成分とする体脂肪蓄積改善剤およびメタボリックシンドローム改善剤

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