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WO2019034112A1 - COMPOSITION CONTENANT DE LA L-CARNITINE ET UN COMPOSÉ DE β-HYDROXYBUTYRATE - Google Patents

COMPOSITION CONTENANT DE LA L-CARNITINE ET UN COMPOSÉ DE β-HYDROXYBUTYRATE Download PDF

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Publication number
WO2019034112A1
WO2019034112A1 PCT/CN2018/100836 CN2018100836W WO2019034112A1 WO 2019034112 A1 WO2019034112 A1 WO 2019034112A1 CN 2018100836 W CN2018100836 W CN 2018100836W WO 2019034112 A1 WO2019034112 A1 WO 2019034112A1
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Prior art keywords
hydroxybutyrate
carnitine
hydroxybutyric acid
compound
composition
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Chinese (zh)
Inventor
袁建栋
孙占莉
丁海峰
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Brightgene Bio Medical Technology Co Ltd
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Brightgene Bio Medical Technology Co Ltd
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a composition comprising L-carnitine and ⁇ -hydroxybutyric acid compound, and the invention also relates to preparation of L-carnitine- ⁇ -hydroxybutyrate in medicine and food additive Application in technology.
  • Obesity has become a serious public health problem. In recent years, obesity patients are increasing all over the world. The number of deaths due to obesity is second only to smoking every year. The International Obesity Conference released a report on the number of deaths caused by obesity worldwide. The number of people who have starved to death in the world has been exceeded. Obesity can also cause severe diabetes, cardiovascular disease and other diseases, and is the enemy of human health and longevity.
  • Therapeutic drugs for obesity include: appetite suppressing drugs, drugs for increasing energy consumption, drugs for inhibiting intestinal digestion and absorption, insulin sensitizers, biological peptides, and agonists or inhibitors thereof. These drugs have many adverse reactions, such as heart valve damage, pulmonary hypertension and finger necrosis, elevated blood pressure, gastrointestinal dysfunction, respiratory infections, headache, menstrual disorders, anxiety, fatigue, flatulence, abdominal pain, diarrhea, etc. Individual patients may also have hypoglycemia and hepatotoxicity.
  • L-carnitine The main physiological function of L-carnitine is to promote the conversion of fat into energy. L-carnitine can reduce body fat and reduce body weight without reducing water and muscle. It was recognized as the safest and no side effect by the International Obesity Health Organization in 2003. Weight loss nutritional supplements. L-carnitine is a key substance in the process of fat metabolism, which can promote the oxidative decomposition of fatty acids into mitochondria. L-carnitine is a carrier for transporting fatty acids. In long-term high-intensity exercise, L-carnitine increases the rate of fat oxidation, reduces the consumption of glycogen, and also delays fatigue. Many weight loss products use L-carnitine as one of the main components of weight loss.
  • L-carnitine has been used in the fields of medicine, health care and food, and has been regulated as a legal multi-purpose nutrient by Switzerland, France, the United States and the World Health Organization.
  • China's food additive health standard GB2760-1996 stipulates that L-carnitine tartrate is a food nutrition fortifier, which can be applied to chewable tablets, drinking liquids, capsules, milk powder and milk drinks.
  • medical effects including cardiovascular disease, liver disease, kidney disease, hyperlipidemia, diabetes, neuromuscular diseases, etc. can be improved by taking L-carnitine and its products.
  • the pharmaceutically acceptable salt of L-carnitine has the same therapeutic or nutritional effect as its internal salt. And these pharmaceutically acceptable salts can improve the stability and moisture absorption of the inner salt, such as L-carnitine tartrate (US4602039) and L-fumarate (US2009281183A1), L-carnitine mucate commonly used in the market. (US5952379). It has also been reported that L-carnitine is combined with metal ions such as calcium and magnesium ions to form a salt which has good water solubility and is easily absorbed by the human body. For example, US Pat. No.
  • 6,051,608 discloses magnesium levoth fumarate and alkanoyl L-carnitine magnesium fumarate
  • WO 98/45250 discloses L-carnitine magnesium tartrate and alkanoyl L-carnitine magnesium citrate
  • L-carnitine tartrate still has a large moisture absorption, relative humidity above 60% will deliquesce; and L-carnitine and metal ions such as Salts formed by the combination of calcium and magnesium ions also have some defects.
  • L-carnitine and metal ions such as Salts formed by the combination of calcium and magnesium ions also have some defects.
  • a large amount of calcium lactate may cause fatigue; excessive calcium gluconate and calcium chloride are unfavorable for diabetes; in addition, L-carnitine calcium galactate is in the preparation process.
  • Nutritional or therapeutic ketosis is a physiological condition caused by a ketogenic diet, calorie restriction, therapeutic fasting, and/or supplementation with ketogenic precursors resulting in elevated blood ketone levels (typically above 0.5 mmol/L).
  • Ketone bodies represent alternative energy substrates for peripheral tissues and the central nervous system. Beta-hydroxybutyrate and acetoacetate are the two most abundant and physiologically significant ketone bodies. Glucose storage in the body is quickly used and becomes rapidly depleted during fasting, extreme sports, and/or low carbohydrate consumption. Failure to replenish glucose storage as they become depleted causes the body to resort to alternative methods to produce energy by making ketone bodies.
  • Ketone bodies can be used as an alternative fuel by every cell in the body to meet the body's energy needs, including the needs of the brain.
  • blood ketone levels will increase up to 2 mmol/L or 3 mmol/L.
  • ketone bodies ⁇ -hydroxybutyric acid and acetoacetic acid
  • This state is called Ketoacidosis or "nutritional ketosis”.
  • ketosis the body burns fat essentially, so once in ketosis, one can induce body fat loss by reducing dietary fat intake and adjusting carbohydrate intake to a low enough to maintain ketosis.
  • ketogenic fats such as medium chain triglycerides (MCT oils) are usually not required by the gastrointestinal system to help induce ketosis.
  • MCT oils medium chain triglycerides
  • ⁇ HB beta-hydroxybutyrate
  • acetoacetate in its free acid form is expensive and ineffective in the manufacture of persistent ketosis.
  • the sodium salt is used to buffer the free acid form of [beta]HB, but this causes potentially harmful sodium overload and mineral balance imbalance at the therapeutic level of ketosis.
  • the ketogenic diet raises concerns about increasing total cholesterol and triglycerides while lowering high-density lipoprotein (HDL) levels, leading to cardiovascular disease.
  • HDL high-density lipoprotein
  • the object of the present invention is to overcome the above-mentioned deficiencies of the prior art, to provide a novel composition comprising L-carnitine; and at least one ⁇ -hydroxybutyric acid compound comprising ⁇ -hydroxyl groups Butyrate, beta-hydroxybutyrate precursor or a combination thereof.
  • Another aspect of the present invention also provides a composition comprising L-carnitine and a ⁇ -hydroxybutyric acid compound in the form of an intramolecular salt.
  • a third aspect of the invention provides a process for the preparation of the composition and the use of the composition.
  • the present invention provides a composition comprising L-carnitine; and at least one ⁇ -hydroxybutyric acid compound comprising ⁇ -hydroxybutyrate, ⁇ -hydroxybutyric acid Precursor or a combination thereof.
  • the at least one ⁇ -hydroxybutyric acid compound comprises one or more of the following: sodium ⁇ -hydroxybutyrate, potassium ⁇ -hydroxybutyrate, calcium ⁇ -hydroxybutyrate, magnesium ⁇ -hydroxybutyrate , lithium beta-hydroxybutyrate, or a mixture thereof;
  • the at least one ⁇ -hydroxybutyric acid compound comprises
  • the at least one ⁇ -hydroxybutyric acid compound is racemic DL- ⁇ -hydroxybutyric acid or the single isomer R- ⁇ -hydroxybutyric acid.
  • the molar ratio of the ⁇ -hydroxybutyric acid compound to the L-carnitine is from 20:1 to 1:1.
  • the present invention provides a composition
  • A is L-carnitine
  • B is ⁇ -hydroxybutyrate arginine, ⁇ -hydroxybutyrate lysine, ⁇ -hydroxyl Butyric acid histidine, ⁇ -hydroxybutyrate ornithine, ⁇ -hydroxybutyrate sarcosine, ⁇ -hydroxybutyrate decyl butylamine or ⁇ -hydroxybutyrate citrulline
  • m, n independently selected from An integer of from 1 to 4; preferably B is ⁇ -hydroxybutyrate arginine, ⁇ -hydroxybutyrate lysine, ⁇ -hydroxybutyrate histidine, or ⁇ -hydroxybutyrate ornithine, and preferably m is 1 or 2, and n is 2 or 1.
  • composition comprising L-carnitine- ⁇ -hydroxybutyrate, and wherein the L-carnitine and the ⁇ -hydroxybutyric acid compound are intramolecular salts.
  • the form exists and has the following structure:
  • M is Na, K or Li
  • the ratio of m to n is from 0.8:10 to 10:0.8, preferably from 1:4 to 4:1, more preferably 1:1, most preferably m and n are both 1, or ,
  • M is Ca or Mg
  • the ratio of m to n is from 0.8:10 to 10:0.8, preferably from 1:4 to 4:1, more preferably 1:1, and most preferably m and n are both 1.
  • the composition comprises L-carnitine- ⁇ -hydroxybutyrate, and the L-carnitine- ⁇ -hydroxybutyrate is a combination of one or more of the following:
  • the ratio of values of m to n is from 0.8:10 to 10:0.8, preferably from 1:4 to 4:1, more preferably 1:1, and most preferably m and n are both 1.
  • composition comprising L-carnitine- ⁇ -hydroxybutyrate, the L-carnitine- ⁇ -hydroxybutyrate being the following compound ( a mixture of Ia) and compound (Ib),
  • ratio of m to n is 1:4 to 4:1, preferably 1:1; more preferably, m and n are 1 in the compounds Ia and Ib.
  • a composition comprising one or more compounds A m B n and/or compound I and/or compound II.
  • the composition comprises one or more compounds A m B n and one or more compounds I; the composition comprising one or more compounds A m B n and one or more Compound II; the composition comprising one or more compounds A m B n and one or more compounds I and one or more compounds II;
  • M is Na, K or Li
  • the ratio of m to n is from 0.8:10 to 10:0.8, preferably from 1:4 to 4:1, more preferably both m and n are 1;
  • M is Ca or Mg
  • the ratio of m to n is from 0.8:10 to 10:0.8, preferably from 1:4 to 4:1, more preferably both m and n are 1.
  • compositions for the preparation of a medicament for the promotion of ketosis in a mammal, preferably a L-carnitine, and at least one of the compositions
  • the ⁇ -hydroxybutyric acid compound is used as an active ingredient, or the compound A m B n and/or the compound I and/or the compound II are used as an active ingredient.
  • composition provided by the present invention may also be used for the preparation of a slimming or health food, a diet/nutrition supplement, a veterinary product or a feed, preferably, the composition has L-carnitine, and at least one ⁇ -hydroxyl group.
  • a butyric acid compound is used as an active ingredient, or a compound A m B n and/or a compound I and/or a compound II as an active ingredient.
  • compositions provided by the present invention are also advantageous for treating hyperglycemia or type II diabetes and improving the general health of the user in a short period of time. It can also be used as a brain-enhancing medicine to improve athlete performance, to prevent diseases associated with metabolic disorders, mitochondrial defects and insulin resistance, as an adjunct to the ketogenic diet, as an anti-aging supplement, and for Other uses associated with increased metabolic health.
  • composition of the present invention When the above composition of the present invention is applied, it can be formulated into an oral dosage form including: a tablet, a capsule, a granule, a pill, and an oral solution.
  • the composition further comprises one or more pharmaceutically acceptable or edible excipients, which are formed into a powder mixture, as a ready-to-drink liquid, into hard or soft capsules, tablets, concentrated gels or in the field. Any other suitable dosage form known to the skilled person.
  • compositions described herein and optional pharmacologically acceptable excipients can be combined.
  • the composition is equivalent to 20-2000 mg/day, or 50 mg to 1000 mg, or 40-800 mg/day, per unit weight of L-carnitine.
  • the composition comprises, by weight, L-carnitine in a unit dose equivalent to 50-3000 mg/kg, or 100-1000 mg/kg; as a drug for promoting ketosis, the composition is by weight
  • the ⁇ -hydroxybutyric acid in a unit dose corresponds to 1 g to 50 g, or 2 g to 30 g, or 2 g to 10 g, or 5 g to 8 g.
  • the frequency of use and the specific amount of the preferred preparation may vary depending on various factors such as the degree of susceptibility of the individual, the age, sex and weight of the individual, the specific reaction of the individual, etc., and optimization of these factors can be determined by those skilled in the art as needed.
  • Another aspect of the present invention provides a method for preparing the compound A m B n , the compound I, and the compound II in the composition;
  • a m B n can be prepared by the following method, wherein m and n have a value of 1:4 to 4:1, preferably 1:1.
  • L-carnitine preferably in a molar ratio of 1 to 1.2:1
  • an equimolar amount of a base such as sodium hydroxide or potassium hydroxide is slowly added dropwise, and then the prepared L-carnitine solution is added to the above-mentioned organic compound of the ⁇ -hydroxybutyric acid amino acid salt.
  • the reaction is carried out in a solvent.
  • the organic solvent is preferably acetone; the base used is selected according to the corresponding metal in the compound I or the compound II. For example, when M in the compound I is Na, the base used is preferably sodium hydroxide.
  • the present invention provides L-carnitine; and at least one ⁇ -hydroxybutyric acid compound comprising ⁇ -hydroxybutyrate, ⁇ -hydroxybutyrate precursor or a combination thereof
  • the composition is capable of significantly promoting fat metabolism, and synergistically promotes a fat loss effect by significantly increasing blood ketone and lowering blood sugar level, and the use of the composition does not adversely affect the lipid mass spectrum, by using the composition,
  • the rapid initiation of ketosis and the rate at which ketone adaptation is accelerated is beneficial to avoid the symptoms of glucose withdrawal that are routinely experienced by individuals who initiate a ketogenic diet. It is more easily accepted by the human body than the existing L-carnitine salt, and is more likely to participate in physiological metabolism of the human body, and has stronger nutrition and therapeutic effects.
  • the human body takes these compositions containing L-carnitine and ⁇ -hydroxybutyric acid compounds, the compound A m B n , the ⁇ -hydroxybutyric acid precursor or the ⁇ -hydroxybutyrate in the compound I and the compound II structure. Part of it will not accumulate in the human body, but can be used as a ketone supplement to enable patients to quickly establish ketosis and maintain ketosis with little or no perception of the patient's physical and psychological comfort; The ketone body also did not find a decrease in high-density lipoprotein (HDL) levels.
  • HDL high-density lipoprotein
  • the L-carnitine part promotes the decomposition of the fat while promoting the ketone body supplement (such as ⁇ -hydroxybutyric acid compound, ⁇ -hydroxybutyrate or Oxidation of ⁇ -hydroxybutyric acid precursors, thereby promoting the utilization and elimination of these ketone bodies, reducing metabolic toxicity caused by acyl accumulation during ketone body utilization; in particular, A m B n , Compound I
  • the values of m and n are 1:4 to 4:1, especially when m and n are simultaneously 1, the ketogenic and weight loss effects are the best;
  • L-carnitine and ⁇ -hydroxybutyric acid compound are present in the form of intramolecular salt compounds A m B n , Compound I and Compound II, which are more stable in nature, are not hygroscopic, and are bioavailable in vivo. Higher degrees.
  • composition of the present invention comprises the compound A m B n and when B is a ⁇ -hydroxybutyric acid amino acid (such as ⁇ -hydroxybutyrate arginine, ⁇ -hydroxybutyrate lysine, ⁇ - when using hydroxybutyrate histidine, beta-hydroxybutyrate ornithine, beta-hydroxybutyrate sarcosine, beta-hydroxybutyrate decylamine or beta-hydroxybutyrate citrulline, etc.
  • ⁇ -hydroxybutyric acid amino acid such as ⁇ -hydroxybutyrate arginine, ⁇ -hydroxybutyrate lysine, ⁇ - when using hydroxybutyrate histidine, beta-hydroxybutyrate ornithine, beta-hydroxybutyrate sarcosine, beta-hydroxybutyrate decylamine or beta-hydroxybutyrate citrulline, etc.
  • ⁇ -hydroxybutyric acid amino acid such as ⁇ -hydroxybutyrate arginine, ⁇ -hydroxybut
  • composition comprising the compound A m B n and when B is the above-mentioned ⁇ -hydroxybutyric acid amino acid, on the other hand, also solves the possibility that the presence of ⁇ -hydroxybutyric acid in the form of a mineral salt may cause potential Mineral salt overload, such as sodium salt overload, the risk of cardiovascular effects of calcium salts.
  • composition provided by the invention has simple and reasonable production process, and reacts under normal pressure, mild reaction conditions, and is suitable for industrial large-scale production.
  • the " ⁇ -hydroxybutyric acid” and the “3-hydroxybutyrate” described in the present invention are the same compound and are mutually replaceable.
  • the "L-carnitine- ⁇ -hydroxybutyrate” refers to an internal salt formed by L-carnitine and a ⁇ -hydroxybutyric acid compound; and the “ ⁇ -hydroxybutyrate” refers to ⁇ -hydroxybutyric acid.
  • a metal salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt, and a salt of ⁇ -hydroxybutyric acid and an amino acid;
  • the “ ⁇ -hydroxybutyric acid amino acid salt” refers to a ⁇ -hydroxybutyric acid and an amino acid. salt.
  • Example 3 Preparation of L-carnitine- ⁇ -hydroxybutyrate arginine (in which the molar ratio of L-carnitine to ⁇ -hydroxybutyrate arginine is 1:1):
  • Example 4 Preparation of L-carnitine- ⁇ -hydroxybutyrate lysine (in which the molar ratio of L-carnitine to ⁇ -hydroxybutyrate lysine is 1:1):
  • Example 5 Preparation of L-carnitine- ⁇ -hydroxybutyrate ornithine (in which the molar ratio of L-carnitine to ⁇ -hydroxybutyrate ornithine is 1:1):
  • Example 6 Preparation of L-carnitine- ⁇ -hydroxybutyrate amdecylamine (in which the molar ratio of L-carnitine to ⁇ -hydroxybutyrate is 2:1)
  • Example 8 Preparation of L-carnitine- ⁇ -hydroxybutyrate histidine (in which the molar ratio of L-carnitine to ⁇ -hydroxybutyrate histidine is 1:2)
  • Example 9 Study on weight loss effect, ketogenic effect and lipid mass spectrometry:
  • SPF male SD rats were purchased from Shanghai Slack Laboratory Animals Co., Ltd.
  • the experimental animals were kept in the SPF animal room.
  • the animal room was well ventilated and equipped with air conditioning.
  • the temperature was kept at 20-25 °C
  • the humidity was kept at 40%-70%
  • the air exchange times were 10-15 times/h
  • the light and dark lighting was 12 hours each.
  • Experimental animals were given free access to food and water, and each rat was labeled with an ear tag.
  • Eight blank rats were fed normal diet, and 48 model rats were fed a high-fat and high-cholesterol diet (Nantong Trophy Feed Technology Co., Ltd.) for 60 days to establish an obesity model.
  • mice were randomly divided into six groups: model group, model + exercise group, composition (compound prepared in Example 1 (Iaa)) + exercise group, physical mixing (L-carnitine and ⁇ - Sodium hydroxybutyrate molar ratio 1:1 mixed) + exercise group, L-carnitine + exercise group and ⁇ -hydroxybutyrate + exercise group, 8 / group.
  • the blank control group and the model group were only routinely reared, and there was no other intervention.
  • the rats in the exercise group were forced to exercise for half an hour every day. Rats in the blank control group, model group and model + exercise group were given normal saline, 10 mL/kg once a day for 4 weeks.
  • Composition (Compound (Iaa) prepared in Example 1) + exercise group, physical mixing (mixed L-carnitine with ⁇ -hydroxybutyrate molar ratio 1:1) + exercise group, L-carnitine + exercise group and ⁇ - The hydroxybutyrate + exercise group was intragastrically administered with 15 mmol/kg of the composition, physical mixture, L-carnitine and ⁇ -hydroxybutyric acid once a day for 4 weeks.
  • the body weight of the animals was measured four weeks after the administration, and the ketone body level was measured using a Yicheng T-1 blood ketone body tester 4 hours after the last administration, and serum triglyceride (TG) and cholesterol (TCHO) were determined by blood separation serum. , low density lipoprotein (LDL) and high density lipoprotein (HDL) levels.
  • Table 1 The experimental results are shown in Table 1 below.
  • L-carnitine- ⁇ -hydroxybutyrate arginine prepared in Example 3 L-carnitine- ⁇ -hydroxybutyrate ornithine prepared in Example 5 was substituted for the above compound (Iaa), and the corresponding L-carnitine was used.
  • L-carnitine- ⁇ -hydroxybutyrate arginine or L-carnitine- ⁇ -hydroxybutyrate ornithine + exercise group had the best weight loss effect, and the ketogenic effect was the most significant and increased to some extent.
  • HDL; L-carnitine and ⁇ -hydroxybutyrate (such as ⁇ -hydroxybutyrate ornithine, ⁇ -hydroxybutyrate arginine) + exercise group weight loss and ketone effect is also significantly higher than the use of left-handed meat alone In the base + exercise group or the ⁇ -hydroxybutyrate + exercise group, it was found that the ⁇ -hydroxybutyrate + exercise group reduced HDL to a certain extent.
  • SPF male SD rats were purchased from Shanghai Slack Laboratory Animals Co., Ltd.
  • the experimental animals were kept in the SPF animal room.
  • the animal room was well ventilated and equipped with air conditioning.
  • the temperature was kept at 20-25 °C, the humidity was kept at 40%-70%, the air exchange times were 10-15 times/h, and the light and dark lighting was 12 hours each.
  • Experimental animals were given free access to food and water, and each rat was labeled with an ear tag. Animals before the administration were fasted overnight, and were randomly divided into 4 groups and 3 groups/group according to body weight.
  • Three rats were given 1 mg/kg L-carnitine intravenously, 3 rats were given 5 mg/kg L-carnitine- ⁇ -hydroxybutyrate, and 3 rats were given 5 mg/kg L-carnitine and ⁇ -.
  • Physical mixture of hydroxybutyrate, 3 rats were intragastrically administered with 5 mg/kg L-carnitine, before the administration and 5, 15, 30, 1, 2, 4, 8, 12 and 24 h after the completion of the bolus, by the neck 0.2 mL of venous blood was collected and placed in a test tube containing K2-EDTA anticoagulant. The whole blood sample collected was placed on ice before centrifugation. The whole blood sample collected at the same time point was centrifuged within half an hour after the collection was completed.
  • L-carnitine- ⁇ -hydroxybutyrate prepared in Examples 3 to 8 of the present invention was physically mixed with L-carnitine and its corresponding ⁇ -hydroxybutyrate to carry out the above bioavailability study, and the experimental results showed similar to Table 2
  • the trend is that L-carnitine- ⁇ -hydroxybutyrate has the highest bioavailability, followed by a physical mixture, which is more bioavailable than L-carnitine alone.
  • the compound (Iab), the compound (IIaa), and the L-carnitine- ⁇ -hydroxybutyric acid prepared in Examples 3 to 8 were tested according to the Guiding Principles of Drug Hygroscopicity (Chinese Pharmacopoeia 2015 Edition, Part 4, 9103). Salt, and the corresponding physical mixture of L-carnitine and ⁇ -hydroxybutyrate, and L-carnitine-calcium fumarate, the hygroscopicity results are shown in Table 3.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Polymers & Plastics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Food Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Zoology (AREA)
  • Obesity (AREA)
  • Animal Husbandry (AREA)
  • Biochemistry (AREA)
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  • Endocrinology (AREA)
  • Toxicology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition contenant de la L-carnitine et au moins un composé de β-hydroxybutyrate. Ledit composé de β-hydroxybutyrate contient du β-hydroxybutyrate et un précurseur de β-hydroxybutyrate ou une combinaison de ceux-ci. La L-carnitine et le β-hydroxybutyrate présents dans ladite composition se présentent, de préférence, sous la forme d'un sel intramoléculaire. L'invention concerne également un procédé de préparation de L-carnitine-β-hydroxybutyrate. La composition, qui présente un effet cétogène, se révèle efficace à des fins de perte de poids.
PCT/CN2018/100836 2017-08-17 2018-08-16 COMPOSITION CONTENANT DE LA L-CARNITINE ET UN COMPOSÉ DE β-HYDROXYBUTYRATE Ceased WO2019034112A1 (fr)

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CN201710706672.8A CN109394745A (zh) 2017-08-17 2017-08-17 一种包含左旋肉碱和β-羟基丁酸化合物的组合物

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CN112341331B (zh) * 2019-08-07 2023-04-07 辽宁科硕营养科技股份有限公司 一种3-羟基丁酸盐及其制备方法与应用
WO2022170677A1 (fr) * 2021-02-09 2022-08-18 Nanjing Nutrabuilding Bio-Tech Co., Ltd. Granulés de sel de bêta-hydroxybutyrate et leurs procédés de production
CA3159208A1 (fr) * 2021-02-09 2022-08-09 Nanjing Nutrabuilding Bio-Tech Co., Ltd. Granule de sel de beta-hydroxybutyrate et methodes de production
CN115518059A (zh) * 2022-09-24 2022-12-27 新乡医学院 β-羟基丁酸的医药新用途

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CN101062025A (zh) * 2007-06-01 2007-10-31 中山市尤利卡天然药物有限公司 用于减肥、降脂、降糖、降压、防治骨质疏松的复方制剂
CN102048884A (zh) * 2010-12-16 2011-05-11 北京康比特体育科技股份有限公司 一种含瓜拉那提取物的减肥组合物
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CN105050594A (zh) * 2013-03-19 2015-11-11 南佛罗里达大学 用于产生升高和持久的酮症的组合物和方法

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GB201304467D0 (en) * 2013-03-12 2013-04-24 Tdeltas Ltd Compound for use in protecting skin
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CN102309049A (zh) * 2010-07-02 2012-01-11 北京康比特体育科技股份有限公司 一种能量控制饮料
CN102048884A (zh) * 2010-12-16 2011-05-11 北京康比特体育科技股份有限公司 一种含瓜拉那提取物的减肥组合物
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