CN109394745A - A kind of composition comprising L-carnitine and beta-hydroxy-butanoic acid compound - Google Patents
A kind of composition comprising L-carnitine and beta-hydroxy-butanoic acid compound Download PDFInfo
- Publication number
- CN109394745A CN109394745A CN201710706672.8A CN201710706672A CN109394745A CN 109394745 A CN109394745 A CN 109394745A CN 201710706672 A CN201710706672 A CN 201710706672A CN 109394745 A CN109394745 A CN 109394745A
- Authority
- CN
- China
- Prior art keywords
- hydroxybutyrate
- carnitine
- composition
- compound
- hydroxybutanoic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 title claims abstract description 119
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 72
- 239000000203 mixture Substances 0.000 title claims abstract description 64
- -1 beta-hydroxy-butanoic acid compound Chemical class 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 239000002243 precursor Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 43
- 239000004475 Arginine Substances 0.000 claims description 16
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 16
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 15
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 15
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 15
- 229960003104 ornithine Drugs 0.000 claims description 15
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 11
- 208000007976 Ketosis Diseases 0.000 claims description 10
- 230000004140 ketosis Effects 0.000 claims description 10
- QYPPJABKJHAVHS-UHFFFAOYSA-N Agmatine Natural products NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 claims description 8
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 8
- QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical compound NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 claims description 8
- 235000015872 dietary supplement Nutrition 0.000 claims description 8
- 239000011777 magnesium Substances 0.000 claims description 8
- QPQMKNGFJFUJNY-JEDNCBNOSA-N (2s)-2,6-diaminohexanoic acid;3-hydroxybutanoic acid Chemical compound CC(O)CC(O)=O.NCCCC[C@H](N)C(O)=O QPQMKNGFJFUJNY-JEDNCBNOSA-N 0.000 claims description 7
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims description 7
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims description 7
- 108010077895 Sarcosine Proteins 0.000 claims description 7
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- OMSUIQOIVADKIM-UHFFFAOYSA-N ethyl 3-hydroxybutyrate Chemical compound CCOC(=O)CC(C)O OMSUIQOIVADKIM-UHFFFAOYSA-N 0.000 claims description 6
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- WHBMMWSBFZVSSR-UHFFFAOYSA-M 3-hydroxybutyrate Chemical compound CC(O)CC([O-])=O WHBMMWSBFZVSSR-UHFFFAOYSA-M 0.000 claims description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 5
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- MOSCXNXKSOHVSQ-UHFFFAOYSA-M sodium;2-hydroxybutanoate Chemical compound [Na+].CCC(O)C([O-])=O MOSCXNXKSOHVSQ-UHFFFAOYSA-M 0.000 claims description 3
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- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- 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
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- 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
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Abstract
The present invention provides a kind of composition comprising L-carnitine and beta-hydroxy-butanoic acid compound, specifically providing a kind of composition includes L-carnitine；With at least one beta-hydroxy-butanoic acid compound, the beta-hydroxy-butanoic acid compound includes beta-hydroxy-butanoic acid salt, beta-hydroxy-butanoic acid precursor or combinations thereof；It is preferred that L-carnitine and beta-hydroxy-butanoic acid amino acid exist in the form of molecule inner salt in the composition.The present invention also provides the L-carnitine-beta-hydroxy-butanoic acid salt preparation methods；Composition provided by the invention, stability is good, and bioavilability is high, fat-reducing effect and raw ketone significant effect；And preparation method provided by the invention is easy to operate.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a composition containing L-carnitine and β -hydroxybutyrate compound, and application of L-carnitine- β -hydroxybutyrate in preparation technology of medicines and food additives.
Background
Obesity has become a serious public health problem, and in recent years, the number of obesity patients worldwide is increasing, the number of fatness death people is only second to smoking every year, the international obesity will issue reports, and the number of fatness related diseases caused by obesity worldwide exceeds the number of fatness death people in the same period of the world. Obesity can also induce serious diabetes, cardiovascular diseases and other diseases, and is a big enemy of human health and longevity.
Therapeutic agents for obesity include: appetite suppressants, agents that increase energy expenditure, agents that inhibit digestive absorption in the gut, insulin sensitizers, biological peptides and agonists or inhibitors thereof, and the like. These drugs have many adverse reactions, such as heart valve damage, pulmonary hypertension and finger necrosis, elevated blood pressure, gastrointestinal dysfunction, respiratory tract infection, headache, menstrual disorder, anxiety, fatigue, intestinal flatulence, abdominal pain, diarrhea, etc., and individual patients may also have hypoglycemia, hepatotoxic reaction, etc.
The main physiological function of the L-carnitine is to promote fat to be converted into energy, and the L-carnitine can reduce body fat and weight without reducing water and muscle, so that the L-carnitine is considered as the most safe weight-reducing nutritional supplement without side effect by the international obesity health organization in 2003. L-carnitine is a key substance in the fat metabolism process and can promote fatty acid to enter mitochondria for oxidative decomposition. L-carnitine is a carrier for transporting fatty acids. In long-time heavy-intensity exercise, L-carnitine improves the oxidation rate of fat, reduces glycogen consumption and delays fatigue. Many weight-reducing products use L-carnitine as one of the main components for weight reduction.
L-carnitine is currently used in medicine, health care and food and has been regulated by Swiss, France, the United states and the world health organization as a legal multi-purpose nutritional agent. The national food additive sanitary standard GB 2760-1996 stipulates that L-carnitine tartrate is a food nutrition enhancer and can be applied to chewable tablets, drinking liquid, capsules, milk powder, milk beverage and the like. In addition, the medical curative effects of the L-carnitine and the series products thereof comprise cardiovascular diseases, liver diseases, kidney diseases, hyperlipidemia, diabetes, neuromuscular diseases and the like, and the symptoms can be improved by taking the L-carnitine and the series products thereof.
It is also known that pharmaceutically acceptable salts of l-carnitine have the same therapeutic or nutritional effect as the inner salts thereof. And the pharmaceutically acceptable salts can improve the stability and moisture absorption of the inner salt, such as L-carnitine tartrate (US4602039), L-carnitine fumarate (US5703376) and L-carnitine mucate (US5952379) which are commonly used in the market at present. It has also been reported that L-carnitine combines with metal ions such as calcium and magnesium ions to form salts which have good water solubility and are easily absorbed by the human body, for example, US6051608 discloses L-carnitine magnesium fumarate and alkanoyl L-carnitine magnesium fumarate, WO 98/45250 discloses L-carnitine magnesium tartrate and alkanoyl L-carnitine magnesium citrate; there are also patents reporting calcium L-carnitine galactonate and calcium L-carnitine fumarate (WO 2008080287).
However, the existing L-carnitine pharmaceutically acceptable salts still have some problems and defects, such as the L-carnitine tartrate still has large moisture absorption, and the L-carnitine tartrate can be deliquesced when the relative humidity exceeds 60%; the salt formed by combining L-carnitine and metal ions such as calcium and magnesium ions also has some defects, such as fatigue caused by taking calcium lactate in large quantity; excessive calcium gluconate and calcium chloride are adverse to diabetes; in addition, the L-carnitine calcium galactarate has the risk of insufficient raw material supply in the preparation process and high cost, and because the lactobionic acid is not produced in large batch at home and is expensive; the preparation process of the L-carnitine calcium fumarate (CN101209975) needs to be frozen, which is inconvenient to operate in a large-scale production process and increases the production cost.
Studies have also shown that seeking weight loss through a ketogenic diet can result in loss of fat storage while maintaining and protecting muscle mass; several studies have also shown that the muscle protective properties of ketogenic diets lead to an increase in physical performance.
Nutritional or therapeutic ketosis is a physiological state resulting from ketogenic diet, calorie restriction, therapeutic fasting and/or supplementation with ketogenic precursors in elevated blood ketone levels (typically above 0.5 mmol/L.) the ketone bodies represent alternative energy substrates for peripheral tissues and the central nervous system, β -hydroxybutyrate and acetoacetate are the two most abundant and physiologically significant ketone bodies during fasting, extreme exercise and/or low carbohydrate consumption.
While pursuit of weight loss through ketogenic diets has many advantages, then, in pursuit and maintenance of ketogenic lifestyle, faces significant obstacles, such as difficulty in transitioning to the ketogenic state, most people being limited by their ability to gain difficulty in ketosis; the fastest way to lose glucose stores in the body is by a combination of fasting and exercise, while for people who get a pleasure from eating cake, candy, bread, etc., such dietary adjustments are emotionally demanding in the physical industry and have significant challenges; in the transition to ketosis, there are uncomfortable physiological and mental states such as drowsiness and dizziness.
While it has been reported that ketogenic medical foods or exogenous supplemental ketones can contribute to the transition to ketosis, ketogenic fats such as medium chain triglycerides (MCT oil) are generally not well tolerated by the gastrointestinal system in amounts necessary to contribute to ketosis induction, and β -hydroxybutyrate (β HB) and acetoacetate are expensive and ineffective in making persistent ketosis orally in their free acid forms, the use of sodium salts to buffer the free acid form of β HB, but this results in potentially harmful sodium overload and mineral balance disorders at the therapeutic level of ketosis.
The invention content is as follows:
it is an object of the present invention to overcome the above-mentioned deficiencies of the prior art by providing a novel composition comprising L-carnitine and at least one β -hydroxybutyrate compound, wherein said β -hydroxybutyrate compound comprises β -hydroxybutyrate, β -hydroxybutyrate precursor or a combination thereof
In another aspect of the present invention, there is provided a composition comprising L-carnitine and β -hydroxybutyrate in the form of an intramolecular salt;
in a third aspect, the invention provides a process for the preparation of said composition and the use of said composition.
Most preferably, the present invention provides a composition comprising L-carnitine and at least one β -hydroxybutyrate compound, wherein the β -hydroxybutyrate compound comprises β -hydroxybutyrate, β -hydroxybutyrate precursors, or a combination thereof.
Wherein the at least one β -hydroxybutyrate compound includes one or more of sodium β -hydroxybutyrate, potassium β -hydroxybutyrate, calcium β -hydroxybutyrate, magnesium β -hydroxybutyrate, lithium β -hydroxybutyrate, or mixtures thereof;
β -hydroxybutyrate arginine, β -hydroxybutyrate lysine, β -hydroxybutyrate histidine, β -hydroxybutyrate ornithine, β -hydroxybutyrate sarcosine, β -hydroxybutyrate agmatine or β -hydroxybutyrate citrulline;
1, 3-butanediol, ethyl acetoacetate or β -hydroxybutyric acid ethyl ester, or,
β -hydroxybutyrate in combination with 1, 3-butanediol, ethyl acetoacetate or ethyl β -hydroxybutyrate, or,
β -hydroxybutyrate mixture in combination with 1, 3-butanediol, ethyl acetoacetate or ethyl β -hydroxybutyrate.
Further preferably, the at least one β -hydroxybutyric acid compound comprises
(1) β sodium hydroxybutyrate, β arginine hydroxybutyrate, or combinations thereof, or
(2) β -hydroxybutanoic acid sodium salt in combination with β -hydroxybutanoic acid potassium salt, or
(3) β -hydroxybutanoic acid histidine, β -hydroxybutanoic acid ornithine, β -hydroxybutanoic acid sarcosine, β -hydroxybutanoic acid agmatine or β -hydroxybutanoic acid citrulline.
Wherein the at least one β -hydroxybutyrate compound is racemic DL- β -hydroxybutyrate or the single isomer R- β -hydroxybutyrate.
Preferably, in the composition, the molar ratio of the β -hydroxybutyrate compound to the L-carnitine is 20: 1-1: 1.
In addition, the invention also provides a composition containing the compound AmBnWherein A is L-carnitine, B is β -hydroxybutyrate arginine, β -hydroxybutyrate lysine, β -hydroxybutyrate histidine, β -hydroxybutyrate ornithine, β -hydroxybutyrate sarcosine, β -hydroxybutyrate agmatine or β -hydroxybutyrate citrulline, m, n are independently selected from 1-4Preferably B is β -hydroxybutyrate arginine, β -hydroxybutyrate lysine, β -hydroxybutyrate histidine, or β -hydroxybutyrate ornithine, and preferably m is 1 or 2 and n is 2 or 1.
In another preferred embodiment of the present invention, there is provided a composition comprising L-carnitine- β -hydroxybutyrate and wherein the L-carnitine and β -hydroxybutyrate are present as intramolecular salts having the structure:
wherein M is Na, K or Li, and the value ratio of M to n is 0.8: 10 to 10:0.8, preferably 1:4 to 4:1, more preferably 1:1, most preferably both m and n are 1, or,
wherein M is Ca or Mg, and the value ratio of M to n is 0.8: 10-10: 0.8, preferably 1: 4-4: 1, more preferably 1:1, and most preferably both m and n are 1.
Further, preferably the composition comprises L-carnitine- β -hydroxybutyrate in a combination with one or more of the following:
wherein the value ratio of m to n is 0.8: 10-10: 0.8, preferably 1: 4-4: 1, more preferably 1:1, and most preferably both m and n are 1.
In another preferred embodiment of the present invention, there is provided a composition comprising L-carnitine- β -hydroxybutyrate which is a mixture of compound (Ia) and compound (Ib),
wherein the value ratio of m to n is 1: 4-4: 1, preferably 1: 1; more preferably, m and n in the compounds Ia and Ib are both 1.
In another preferred embodiment of the present invention, there is provided a composition comprising one or more compounds AmBnAnd/or compound I and/or compound II. Preferably, for example, the composition comprises one or more compounds AmBnAnd one or more compounds I; the composition comprises one or more compounds AmBnAnd one or more compounds III; the composition comprises one or more compounds AmBnAnd one or more compounds I and one or more compounds III;
wherein compound I is:
wherein M is Na, K or Li, and the value ratio of M to n is 0.8: 10-10: 0.8, preferably 1: 4-4: 1, and more preferably m and n are both 1;
the compound II is:
wherein M is Ca or Mg, and the value ratio of M to n is 0.8: 10-10: 0.8, preferably 1: 4-4: 1, and more preferably both m and n are 1.
In a second aspect of the invention there is also provided the use of a composition as described above for the preparation of a medicament for promoting lactation in a mammalUse of ketotropic drugs// nutritional supplements, preferably in said composition l-carnitine, and at least one β -hydroxybutyrate compound as active ingredients, or compound amBnAnd/or compound I and/or compound II as active ingredients.
The composition provided by the invention can also be used for preparing weight-reducing medicines or health-care foods, diet/nutritional supplements, veterinary products or feeds, and preferably, the composition contains L-carnitine and at least one β -hydroxybutyric acid compound as active ingredients, or the compound AmBnAnd/or compound I and/or compound II as active ingredients.
Preliminary studies have found that the compositions provided by the present invention are also beneficial in treating hyperglycemia or type II diabetes, and improve the general health of the user in a short period of time. It can also be used as a brain tonic, for enhancing athlete performance, helping to prevent diseases associated with metabolic dysfunction, mitochondrial defects, and insulin resistance, as an adjunct to ketogenic diets, as an anti-aging supplement, and for other uses associated with enhanced metabolic health.
When the composition is applied, the composition can be prepared into an oral dosage form, which comprises the following components: tablet, capsule, granule, pill, and oral liquid. The composition, which may also contain one or more pharmaceutically acceptable or edible excipients, is formulated as a powder mix, as a ready-to-drink liquid, as a hard or soft capsule, tablet, concentrated gel, or any other suitable dosage form known to those skilled in the art.
In use, the compositions of the present invention may be combined with optional pharmacologically acceptable excipients. According to the primary measurement and calculation, the composition is used as a weight-losing medicine or health-care food, wherein the unit dose of the composition is equivalent to 20-2000 Mg/day, or 50-1000 Mg/day, or 40-800 Mg/day by weight. As a dietary/nutritional supplement, the composition is characterized in that the unit dose of L-carnitine is 50-3000mg/kg, or 100-1000 mg/kg; as a booster of ketosisThe amount of β -hydroxybutyrate in a unit dose of 1g to 50g, alternatively 2g to 30g, alternatively 2g to 10g, alternatively 5g to 8g the preferred frequency of use and the particular amount of formulation may vary depending on factors such as the susceptibility of the individual, the age, sex and weight of the individual, the specific response of the individual and the like, the optimisation of which may be determined as required by the skilled personmBnA preparation method of the compound I and the compound II;
AmBnthe preparation method can be adopted, wherein the values of m and n are 1: 4-4: 1, and 1 is preferably selected: 1:
adding a small amount of water into an organic solvent such as acetone, isopropanol and the like, feeding β -hydroxybutyrate amino acid salt and L-carnitine (preferably according to a molar ratio of 1-1.2:. 1) for reaction, more preferably, dissolving the L-carnitine into a small amount of pure water, then slowly dropwise adding an equimolar alkali such as sodium hydroxide or potassium hydroxide, and then adding the prepared L-carnitine solution into the organic solvent of β -hydroxybutyrate amino acid salt for reaction, after the reaction is finished, removing the solvent from the reaction solution in a water bath at 40 ℃ under reduced pressure, adding the organic solvent such as acetone, isopropanol and the like into a flask, stirring, precipitating a solid, filtering, and drying in vacuum to obtain the product.
Compound I and compound II can be prepared by the following method:
dissolving 3-hydroxybutyrate in an organic solvent such as acetone, isopropanol or dichloromethane to give a solution of 3-hydroxybutyrate, additionally dissolving L-carnitine in purified water, adding an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or magnesium hydroxide to the solution, slowly dropping the formulated L-carnitine solution into the solution of 3-hydroxybutyrate, then removing the solvent from the combined reaction solution under reduced pressure in a water bath at 35 ℃ to 45 ℃, preferably 40 ℃, adding the corresponding organic solvent such as acetone, isopropanol or dichloromethane to the residue, stirring for crystallization, filtering, washing the filter cake with the organic solvent such as acetone, isopropanol or dichloromethane, and drying under vacuum to give the corresponding compound I, compound II, wherein the organic solvent is preferably acetone, the base used is selected on the basis of the corresponding metal in compound I, compound II, e.g. when M in compound I is Na, preferably the base used is strong sodium oxide, the provided composition comprises L-carnitine, and at least one compound β -hydroxybutyrate, the composition of 56-hydroxybutyrate is capable of accelerating the metabolism of the individual and accelerating the blood glucose metabolism of the individual and the individual's glucose metabolism, the composition is capable of accelerating the blood glucose metabolism and of accelerating the blood glucose metabolism of the individual through the conventional glucose metabolism.
The invention provides a pharmaceutical composition comprising one or more compounds AmBnAnd/or compound I and/or compound II, have the further significant advantage that these compounds in the form of intramolecular salts:
most preferably, compound A is administered to humans when these compositions comprising L-carnitine and β -hydroxybutyrate are administeredmBnThe β -hydroxybutyrate precursor or β -hydroxybutyrate moiety of the structures of compounds I and II does not accumulate in humans and instead acts as a ketone supplement, allowing patients to quickly establish ketosis and maintain ketosis with little or no perception of the patient's physiological and psychological comfort, whereas ketone bodies supplemented in this form do not find a reduction in High Density Lipoprotein (HDL) levels.
Secondly, AmBnAfter the compound I and the compound II enter the body, the L-carnitine part of the compound I and the compound II promotes the oxidation of ketone body supplements (such as β -hydroxybutyrate compound, β -hydroxybutyrate or β -hydroxybutyrate precursor) while promoting the decomposition of fatThereby playing a promoting role in the utilization and elimination of the ketone bodies and reducing the metabolic toxicity caused by the accumulation of acyl groups in the utilization process of the ketone bodies; in particular AmBnThe values of m and n in the compound I and the compound II are 1: 4-4: 1, especially when m and n are simultaneously 1, the ketogenesis and weight-reducing effects are optimal;
thirdly, in the medicine composition, the L-carnitine and the β -hydroxybutyrate compound are in the form of intramolecular salt compound AmBnThe compound I and the compound II exist in a form, so that the compound I and the compound II have more stable properties, are not easy to absorb moisture and have higher bioavailability in vivo.
Fourth, when the composition of the present invention comprises Compound AmBnAnd when B is β -hydroxybutyrate amino acid (such as β -hydroxybutyrate arginine, β -hydroxybutyrate lysine, β -hydroxybutyrate histidine, β -hydroxybutyrate ornithine, β -hydroxybutyrate sarcosine, β -hydroxybutyrate agmatine or β -hydroxybutyrate citrulline) when the composition is used, the supplement of amino acid in a human body is increased, which is very beneficial for users needing weight loss or ketogenesis.
Fifth, the composition comprises Compound AmBnAnd when B is β -hydroxybutyric acid amino acid, on the other hand, the risk that β -hydroxybutyric acid in the form of mineral salt may cause potential mineral salt overload, such as sodium salt overload, calcium salt influence on the cardiovascular system, is also solved.
Sixth, the composition provided by the invention has the advantages of simple and reasonable production process, reaction under normal pressure, mild reaction conditions and suitability for industrial mass production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The advantages of the technical solutions of the present invention are specifically explained below with reference to specific examples, and it should be understood that these examples are only illustrative and not intended to limit the present invention.
The ' β -hydroxybutyrate ' and the ' 3-hydroxybutyrate ' are the same compound and can be replaced mutually, the ' L-carnitine- β -hydroxybutyrate ' refers to an inner salt formed by L-carnitine and a β -hydroxybutyrate compound, the ' β -hydroxybutyrate ' refers to a metal salt of β -hydroxybutyrate, such as a sodium salt, a potassium salt, a calcium salt and a magnesium salt, and a salt formed by β -hydroxybutyrate and an amino acid, and the ' β -hydroxybutyrate amino acid salt "refers to a salt formed by β -hydroxybutyrate and the amino acid.
Example 1, preparation of compound (Iaa):
a100 mL round-bottom flask was charged with 1.04g (10mmol) of 3-hydroxybutyric acid and 8mL of acetone. 1.61g (10mmol) of L-carnitine was dissolved in 3mL of pure water, and 1mL of 10N (10mmol) aqueous sodium hydroxide solution was added to the solution. Slowly dripping the prepared L-carnitine solution into a reaction bottle, reacting for 5 minutes after dripping, decompressing the reaction solution in a water bath at 40 ℃ to remove the solvent to obtain colorless oily substances, adding 80mL of acetone into the flask, stirring for crystallization, filtering, washing a filter cake with acetone, and drying in vacuum to obtain 2.58g of white solid with the yield of 90%.
Chemical Formula:C11H22NO6Na；1HNMR(D2O):δ1.12(3H,d),2.12～2.41(4H,m),3.14(9H,s),3.34(2H,dd),4.04～4.09(1H,m),4.47～4.50(1H,m)。
Example 2: preparation of Compound (IIaa) of the formula
A100 mL round-bottom flask was charged with 1.04g (10mmol) of 3-hydroxybutyric acid and 16mL of acetone. Dissolving 1.61g (10mmol) of L-carnitine in 16mL of pure water, adding 0.37g (5mmol) of calcium hydroxide powder into the solution, stirring and heating to 80 ℃ for 2 hours, then dropping the suspended L-carnitine solution into a reaction bottle, heating to 60 ℃ and stirring for 2 hours, dissolving to be clear, removing the solvent from the reaction solution in a water bath at 40 ℃ under reduced pressure to obtain milky oily matter, adding 80mL of acetone into the flask, stirring and crystallizing, filtering, washing a filter cake with acetone, and drying in vacuum to obtain 1.76g of white product with the yield of 86%.
Chemical Formula:C22H44N2O12Ca；1HNMR(D2O):δ1.13(3H,d),2.11～2.40(8H,m),3.15(18H,s),3.36(4H,dd),4.05～4.13(2H,m),4.47～4.51(2H,m)。
Example 3 preparation of L-carnitine- β -hydroxybutyrate arginine (wherein the molar ratio of L-carnitine to β -hydroxybutyrate arginine is 1: 1). to a 100mL round-bottomed flask, 2.78g (11mmol) of β -hydroxybutyrate arginine, 10mL of acetone and 3mL of purified water were added, 1.61g (10mmol) of L-carnitine was dissolved in 3mL of purified water, 1mL of 10N (10mmol) sodium hydroxide solution was added to the solution, the prepared L-carnitine solution was slowly dropped into a reaction flask, after dropping, the reaction was carried out for 5 minutes, the reaction solution was depressurized in a water bath at 40 ℃ to remove the solvent, a colorless oily substance was obtained, 80mL of acetone was added to the flask, stirring was carried out for 20 minutes, a white solid was precipitated, filtering was carried out, the filter cake was washed with acetone and vacuum-dried to obtain 3.92g of a white product, and the yield was 89%.
Example 4 preparation of L-carnitine- β -hydroxybutyrate lysine (wherein the molar ratio of L-carnitine to β -hydroxybutyrate lysine is 1: 1). Add 11mmol of β -hydroxybutyrate lysine to a 100mL round-bottomed flask, add 10mL of acetone and 3mL of purified water, dissolve 10mmol of L-carnitine in 3mL of purified water, add 1mL of 10N (10mmol) of NaOH solution to the solution, slowly drop the prepared L-carnitine solution into a reaction flask, after the dropping, react for 5 minutes, remove the solvent in a water bath at 40 ℃ under reduced pressure to obtain colorless oil, add 80mL of acetone to the flask, stir for 20 minutes, precipitate a white solid, filter, and vacuum-dry the filter cake with acetone to obtain 3.92g of white product with a yield of 87%.
Example 5 preparation of L-Carnitine- β -Hydroxybutanoic acid ornithine (wherein the molar ratio of L-Carnitine to β -Hydroxybutanoic acid ornithine is 1:1) to a 100mL round-bottomed flask was added 11mmol of β -Hydroxybutanoic acid ornithine, 10mL of acetone and 3mL of purified water, 10mmol of L-Carnitine was dissolved in 3mL of purified water, 1mL of 10N (10mmol) of sodium hydroxide solution was added to the solution, the prepared L-Carnitine solution was slowly dropped into a reaction flask, after dropping, the reaction was carried out for 5 minutes, the solvent was removed from the reaction solution in a water bath at 40 ℃ under reduced pressure to give a colorless oil, 80mL of acetone was added to the flask, stirring was carried out for 20 minutes to precipitate a white solid, filtering was carried out, and the filter cake was washed with acetone and dried under vacuum to give 3.92g of a white product in 83%.
Example 6 preparation of L-Carnitine- β -Hydroxybutylguanidinobutylamine (wherein the molar ratio of L-Carnitine to β -Hydroxyguanidinobutylamine is 2:1)
Adding 10.5mmol of β -hydroxybutyric agmatine into a 100mL round-bottom flask, adding 10mL of acetone and 3mL of purified water, dissolving 10mmol of L-carnitine into 3mL of purified water, adding 1mL of 10N (10mmol) sodium hydroxide solution into the solution, slowly dripping the prepared L-carnitine solution into a reaction bottle, reacting for 5 minutes after dripping, removing the solvent from the reaction solution in a water bath at 40 ℃ under reduced pressure, adding 80mL of acetone into the flask, stirring for 20 minutes, precipitating a white solid, filtering, washing a filter cake with acetone, and performing vacuum drying to obtain 3.92g of a white product with the yield of 80%.
EXAMPLE 8 preparation of L-Carnitine- β -Hydroxybutyric acid histidine (wherein the molar ratio of L-Carnitine to β -Hydroxybutyric acid histidine is 1:2) 11mmol of β -Hydroxybutyric acid histidine, 10mL of acetone and 3mL of purified water were added to a 100mL round-bottomed flask, 10mmol of L-Carnitine was dissolved in 3mL of purified water, 1mL of 10N (10mmol) sodium hydroxide solution was added to the solution, the prepared L-Carnitine solution was slowly dropped into a reaction flask, after dropping, the reaction was carried out for 5 minutes, the solvent was removed from the reaction solution in a water bath at 40 ℃ under reduced pressure, 80mL of acetone was added to the flask, stirring was carried out for 20 minutes to precipitate a white solid, filtering was carried out, the filter cake was washed with acetone and vacuum dried to obtain 3.92g of a white product, the yield was 85
Example 9, study of weight loss effect, ketogenesis effect and influence of lipid profile:
54 male SD rats of SPF grade, purchased from Shanghaisi Leke laboratory animals Limited company, the laboratory animals were housed in SPF animal rooms well ventilated, equipped with air-conditioning, kept at a temperature of 20-25 ℃, kept at a humidity of 40-70%, ventilated for 10-15 times/h, illuminated with light and dark for 12 hours each, and the experimental animals were fed with water and water freely, each rat was labeled with ear tags.8 rats in the blank group were fed with normal diet, 48 rats in the molding group were fed with high-fat high-cholesterol diet (Nantong Polarophila science Co., Ltd.) for 60 days to establish an obesity model.48 rats in the molding success were randomly divided into six groups according to body weight, model group, model + exercise group, composition (Iaa + exercise group prepared in example 1), physical mixture (L-carnitine and sodium hydroxybutyrate molar ratio 1:1 mix) + exercise group, L-carnitine + exercise group and β -hydroxybutyrate + exercise group, 8 rats/group, model group, left-carnitine + exercise group and rat group were fed with conventional group only, no other rats, after the animal group was fed with daily exercise group, the test results were measured for half an hour, the animal serum concentration of L-hydroxybutyrate protein (TG), the test period: 10 kg), the test period of L-serum concentration of L-hydroxybutyrate + L-1 + L-hydroxybutyrate + L-hydroxybutyrate + L-1 + L-hydroxybutyrate + L-butyrate + L.
Table 1: the research results of the influence of the weight-losing effect, the ketogenesis effect and the lipid profile are as follows:
the same operation was performed by substituting the compound (Iaa) with the l-carnitine- β -hydroxybutyrate arginine prepared in example 3 and the l-carnitine- β -hydroxybutyrate ornithine prepared in example 5, respectively, and by substituting the physical mixture with the l-carnitine- β 0-hydroxybutyrate arginine molar ratio of 1:1 and the l-carnitine- β -hydroxybutyrate ornithine molar ratio of 1:1, respectively, and the physical mixture with the l-carnitine- β -hydroxybutyrate arginine or the l-carnitine- β -hydroxybutyrate ornithine + the exercise group, wherein the effects of l-carnitine- β -hydroxybutyrate arginine or l-carnitine- β -hydroxybutyrate + the exercise group were the best and the ketogenic effect was the most significant, and the effect of increasing HDL, l-carnitine and β -hydroxybutyrate (e.g., β -hydroxybutyrate ornithine, β -hydroxybutyrate arginine) + the exercise group was also significantly higher than that of the l-carnitine + the exercise group or β -hydroxybutyrate + the exercise group alone was used, and it was found that β -hydroxybutyrate + the exercise group reduced HDL to some extent.
Example 10 in vivo bioavailability study
12 male SD rats of SPF grade purchased from Shanghai Lyike laboratory animal Limited liability company, the laboratory animals are raised in an SPF animal room, the animal room is well ventilated, air-conditioned, the temperature is kept at 20-25 ℃, the humidity is kept at 40-70%, the ventilation frequency is 10-15 times/h, the laboratory animals are free to eat and drink water after 12 hours of light and dark illumination, each rat is marked with an ear tag, the animals are randomly divided into 4 groups according to the body weight after overnight fasting before administration, 3 rats are given 1mg/kg of L-carnitine by intravenous injection, 3 rats are given 5mg/kg of L-carnitine- β -hydroxybutyrate by gastric lavage, 5mg/kg of L-carnitine and β -hydroxybutyrate physical mixture are given to 3 rats by gastric lavage, 5mg/kg of L-carnitine are given to 3 rats before administration and after completion of bolus injection, 5, 15, 30min, 1, 2, 4, 8, 12 and 24 hours before the blood collection and after completion of bolus injection, the collection of blood plasma samples is carried out by a blood collection test tube with a centrifugal test tube (NonLC-70 rpm), the blood plasma concentration is calculated by using a NonLC-MS test tube, and the non-NonLC (NonLC) is calculated and the blood plasma concentration is calculated after the blood collection time is calculated after the blood collection.
Table 2: bioavailability of
The bioavailability studies described above were conducted by physically mixing the l-carnitine- β -hydroxybutyrate prepared in examples 3-8 of the present invention with l-carnitine and β -hydroxybutyrate, and the experimental results showed a trend similar to that in table 2, wherein the bioavailability of l-carnitine- β -hydroxybutyrate was the highest, and the bioavailability of the physical mixture was higher than that of l-carnitine alone.
Example 11 stability study
The compound (Iab), the compound (Iba), the compound (IIaa), L-carnitine- β -hydroxybutyrate prepared in examples 3 to 8, a physical mixture of L-carnitine and β -hydroxybutyrate, and L-carnitine-calcium fumarate provided by the present invention were tested according to the guidelines on drug hygroscopicity (the four parts 9103 of the 2015 th edition of Chinese pharmacopoeia), and the hygroscopicity results are shown in Table 3.
TABLE 3 hygroscopicity results
Claims (11)
1. A composition comprising l-carnitine, and at least one β -hydroxybutyrate compound, said β -hydroxybutyrate compound comprising β -hydroxybutyrate, β -hydroxybutyrate precursors, or a combination thereof.
2. The composition of claim 1, wherein the at least one β -hydroxybutyrate compound comprises one or more of sodium β -hydroxybutyrate, potassium β 0-hydroxybutyrate, calcium β 1-hydroxybutyrate, magnesium β 2-hydroxybutyrate, lithium β 3-hydroxybutyrate, or mixtures thereof, arginine β 4-hydroxybutyrate, lysine β 5-hydroxybutyrate, histidine β 6-hydroxybutyrate, ornithine β 7-hydroxybutyrate, sarcosine β -hydroxybutyrate, agmatine β -hydroxybutyrate, or citrulline β -hydroxybutyrate, 1, 3-butanediol, ethyl acetoacetate, or ethyl β -hydroxybutyrate, or a combination of β -hydroxybutyrate with 1, 3-butanediol, ethyl acetoacetate, or ethyl β -hydroxybutyrate, or a combination of a mixture of β -hydroxybutyrate with 1, 3-butanediol, ethyl acetoacetate, or ethyl β -hydroxybutyrate.
3. The composition according to claim 1, wherein said at least one β -hydroxybutanoic acid compound comprises
(1) β sodium hydroxybutyrate, β arginine hydroxybutyrate, or combinations thereof, or
(2) β -hydroxybutanoic acid sodium salt in combination with β -hydroxybutanoic acid potassium salt, or
(3) β -hydroxybutanoic acid histidine, β -hydroxybutanoic acid ornithine, β -hydroxybutanoic acid sarcosine, β -hydroxybutanoic acid agmatine or β -hydroxybutanoic acid citrulline.
4. The composition according to claim 1, wherein said at least one β -hydroxybutyrate compound is racemic DL- β -hydroxybutyrate or the single isomer R- β -hydroxybutyrate.
5. The composition of any one of claims 1 to 4, wherein the molar ratio of β -hydroxybutyrate compound to L-carnitine in the composition is 1:4 to 4: 1.
6. A composition comprising compound amBnWherein A is L-carnitine, B is β -hydroxybutyrate arginine, β -hydroxybutyrate lysine, β -hydroxybutyrate histidine, β -hydroxybutyrate ornithine, β -hydroxybutyrate sarcosine, β -hydroxybutyrate agmatine or β -hydroxybutyrate citrulline, and the values of m and n are 1: 4-4: 1.
7. The composition of claim 6, wherein m and n are both 1.
8. The composition of claim 7, further comprising a compound of formula I or II:
wherein M is Na, K or Li, and the value ratio of M to n is 1: 4-4: 1; or,
wherein M is Ca or Mg, and the value ratio of M to n is 1: 4-4: 1.
9. Use of a composition according to any one of claims 1 to 8 for the manufacture of a medicament// nutritional supplement for promoting ketosis in a mammal.
10. Use of a composition according to any one of claims 1 to 8 for the preparation of a slimming medicament or a health food, a dietary/nutritional supplement, a veterinary product or a feed.
11. Use of a composition according to any one of claims 9 to 10, wherein the composition is formulated as an oral dosage form comprising: tablet, capsule, granule, pill, and oral liquid.
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| PCT/CN2018/100836 WO2019034112A1 (en) | 2017-08-17 | 2018-08-16 | COMPOSITION CONTAINING L-CARNITINE AND β-HYDROXYBUTYRATE COMPOUND |
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| WO2022170677A1 (en) * | 2021-02-09 | 2022-08-18 | Nanjing Nutrabuilding Bio-Tech Co., Ltd. | Beta-hydroxybutyrate salt granule and methods for producing it |
| CN115210212A (en) * | 2021-02-09 | 2022-10-18 | 南京纽邦生物科技有限公司 | Beta-hydroxybutyrate granules and preparation method thereof |
| CN115518059A (en) * | 2022-09-24 | 2022-12-27 | 新乡医学院 | New medical application of β-hydroxybutyric acid |
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| CN102911067A (en) * | 2011-08-04 | 2013-02-06 | 广州市奥海生物科技有限公司 | L-carnitine pyruvate, and preparation method and application thereof |
| US20160030314A1 (en) * | 2013-03-12 | 2016-02-04 | Tdeltas Limited | Compound for use in protecting skin |
| CN105050594A (en) * | 2013-03-19 | 2015-11-11 | 南佛罗里达大学 | Compositions and methods for producing elevated and sustained ketosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112341331A (en) * | 2019-08-07 | 2021-02-09 | 辽宁科硕营养科技股份有限公司 | 3-hydroxybutyrate and preparation method and application thereof |
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| WO2022170677A1 (en) * | 2021-02-09 | 2022-08-18 | Nanjing Nutrabuilding Bio-Tech Co., Ltd. | Beta-hydroxybutyrate salt granule and methods for producing it |
| CN115210212A (en) * | 2021-02-09 | 2022-10-18 | 南京纽邦生物科技有限公司 | Beta-hydroxybutyrate granules and preparation method thereof |
| CN115210212B (en) * | 2021-02-09 | 2023-08-25 | 南京纽邦生物科技有限公司 | Beta-hydroxybutyrate particles and preparation method thereof |
| CN115518059A (en) * | 2022-09-24 | 2022-12-27 | 新乡医学院 | New medical application of β-hydroxybutyric acid |
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