CN114272383A - Thermal protective agent of HMB and application thereof, HMB derivative and application thereof - Google Patents
Thermal protective agent of HMB and application thereof, HMB derivative and application thereof Download PDFInfo
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- CN114272383A CN114272383A CN202111631920.XA CN202111631920A CN114272383A CN 114272383 A CN114272383 A CN 114272383A CN 202111631920 A CN202111631920 A CN 202111631920A CN 114272383 A CN114272383 A CN 114272383A
- Authority
- CN
- China
- Prior art keywords
- beta
- hydroxy
- methylbutyrate
- malate
- hmb
- Prior art date
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Links
- 239000003223 protective agent Substances 0.000 title claims abstract description 22
- AXFYFNCPONWUHW-UHFFFAOYSA-N 3-hydroxyisovaleric acid Chemical compound CC(C)(O)CC(O)=O AXFYFNCPONWUHW-UHFFFAOYSA-N 0.000 claims abstract description 97
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 27
- 235000011090 malic acid Nutrition 0.000 claims abstract description 24
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 16
- 239000001630 malic acid Substances 0.000 claims abstract description 15
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000001530 fumaric acid Substances 0.000 claims abstract description 8
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 8
- 239000011975 tartaric acid Substances 0.000 claims abstract description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 38
- 239000008187 granular material Substances 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 21
- 235000019359 magnesium stearate Nutrition 0.000 claims description 19
- 239000002994 raw material Substances 0.000 claims description 19
- 229940099690 malic acid Drugs 0.000 claims description 14
- 239000007779 soft material Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- 238000012216 screening Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 9
- JFQQIWNDAXACSR-UHFFFAOYSA-L magnesium malate Chemical compound [Mg+2].[O-]C(=O)C(O)CC([O-])=O JFQQIWNDAXACSR-UHFFFAOYSA-L 0.000 claims description 9
- 229940096424 magnesium malate Drugs 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- OLOZVPHKXALCRI-UHFFFAOYSA-L calcium malate Chemical compound [Ca+2].[O-]C(=O)C(O)CC([O-])=O OLOZVPHKXALCRI-UHFFFAOYSA-L 0.000 claims description 7
- 239000001362 calcium malate Substances 0.000 claims description 7
- 229940016114 calcium malate Drugs 0.000 claims description 7
- 235000011038 calcium malates Nutrition 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229940116298 l- malic acid Drugs 0.000 claims description 6
- CLWNPUARORRDFD-UHFFFAOYSA-N 2-hydroxybutanedioic acid;zinc Chemical compound [Zn].OC(=O)C(O)CC(O)=O CLWNPUARORRDFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 235000013305 food Nutrition 0.000 claims description 4
- 229940049920 malate Drugs 0.000 claims description 4
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims description 3
- KRUJOKMDEHYPOP-UHFFFAOYSA-L 2-hydroxybutanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)C(O)CC([O-])=O KRUJOKMDEHYPOP-UHFFFAOYSA-L 0.000 claims description 3
- JLLRXSCNTCSLFX-UHFFFAOYSA-H 2-hydroxybutanedioate;iron(3+) Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C(O)CC([O-])=O.[O-]C(=O)C(O)CC([O-])=O.[O-]C(=O)C(O)CC([O-])=O JLLRXSCNTCSLFX-UHFFFAOYSA-H 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 claims description 3
- 235000016709 nutrition Nutrition 0.000 claims description 3
- 230000035764 nutrition Effects 0.000 claims description 3
- SVICABYXKQIXBM-UHFFFAOYSA-L potassium malate Chemical compound [K+].[K+].[O-]C(=O)C(O)CC([O-])=O SVICABYXKQIXBM-UHFFFAOYSA-L 0.000 claims description 3
- 235000011033 potassium malate Nutrition 0.000 claims description 3
- 239000001415 potassium malate Substances 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 235000019265 sodium DL-malate Nutrition 0.000 claims description 3
- 239000001394 sodium malate Substances 0.000 claims description 3
- 230000001502 supplementing effect Effects 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002417 nutraceutical Substances 0.000 claims 1
- 235000021436 nutraceutical agent Nutrition 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 6
- 230000002378 acidificating effect Effects 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 230000006866 deterioration Effects 0.000 abstract description 3
- 210000004211 gastric acid Anatomy 0.000 abstract description 3
- 235000019658 bitter taste Nutrition 0.000 abstract description 2
- 239000000843 powder Substances 0.000 description 27
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 14
- 239000005913 Maltodextrin Substances 0.000 description 11
- 229920002774 Maltodextrin Polymers 0.000 description 11
- 229910000019 calcium carbonate Inorganic materials 0.000 description 11
- WLJUMPWVUPNXMF-UHFFFAOYSA-L calcium;3-hydroxy-3-methylbutanoate Chemical compound [Ca+2].CC(C)(O)CC([O-])=O.CC(C)(O)CC([O-])=O WLJUMPWVUPNXMF-UHFFFAOYSA-L 0.000 description 11
- 229940035034 maltodextrin Drugs 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 6
- 235000019640 taste Nutrition 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003017 thermal stabilizer Substances 0.000 description 3
- QUKRTJQSGPLQKQ-UHFFFAOYSA-N 5-methylsulfonyl-3h-1,3-benzoxazol-2-one Chemical compound CS(=O)(=O)C1=CC=C2OC(=O)NC2=C1 QUKRTJQSGPLQKQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- WMYBXRITVYIFCO-UHFFFAOYSA-N copper;2-hydroxybutanedioic acid Chemical compound [Cu].OC(=O)C(O)CC(O)=O WMYBXRITVYIFCO-UHFFFAOYSA-N 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 235000019614 sour taste Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- OHZCFWMJMWFNFP-ZVGUSBNCSA-L (2r,3r)-2,3-dihydroxybutanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O OHZCFWMJMWFNFP-ZVGUSBNCSA-L 0.000 description 1
- RWYRUDPAALLKPX-UHFFFAOYSA-N 2,2-difluoro-n-methylethanamine;hydrochloride Chemical compound Cl.CNCC(F)F RWYRUDPAALLKPX-UHFFFAOYSA-N 0.000 description 1
- 239000001749 Calcium fumarate Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 description 1
- 239000001747 Potassium fumarate Substances 0.000 description 1
- 239000001744 Sodium fumarate Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000019296 calcium fumarate Nutrition 0.000 description 1
- GUPPESBEIQALOS-UHFFFAOYSA-L calcium tartrate Chemical compound [Ca+2].[O-]C(=O)C(O)C(O)C([O-])=O GUPPESBEIQALOS-UHFFFAOYSA-L 0.000 description 1
- 239000001427 calcium tartrate Substances 0.000 description 1
- 235000011035 calcium tartrate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- FXGNPUJCPZJYKO-TYYBGVCCSA-L copper;(e)-but-2-enedioate Chemical compound [Cu+2].[O-]C(=O)\C=C\C([O-])=O FXGNPUJCPZJYKO-TYYBGVCCSA-L 0.000 description 1
- RSJOBNMOMQFPKQ-UHFFFAOYSA-L copper;2,3-dihydroxybutanedioate Chemical compound [Cu+2].[O-]C(=O)C(O)C(O)C([O-])=O RSJOBNMOMQFPKQ-UHFFFAOYSA-L 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- -1 cyclic ester Chemical class 0.000 description 1
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960000225 ferrous fumarate Drugs 0.000 description 1
- 239000011773 ferrous fumarate Substances 0.000 description 1
- 235000002332 ferrous fumarate Nutrition 0.000 description 1
- 229940057006 ferrous tartrate Drugs 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229940095060 magnesium tartrate Drugs 0.000 description 1
- MUZDLCBWNVUYIR-ZVGUSBNCSA-L magnesium;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Mg+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O MUZDLCBWNVUYIR-ZVGUSBNCSA-L 0.000 description 1
- QUIOHQITLKCGNW-TYYBGVCCSA-L magnesium;(e)-but-2-enedioate Chemical compound [Mg+2].[O-]C(=O)\C=C\C([O-])=O QUIOHQITLKCGNW-TYYBGVCCSA-L 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000037257 muscle growth Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 description 1
- SHPKCSFVQGSAJU-SEPHDYHBSA-L potassium fumarate Chemical compound [K+].[K+].[O-]C(=O)\C=C\C([O-])=O SHPKCSFVQGSAJU-SEPHDYHBSA-L 0.000 description 1
- 235000019295 potassium fumarate Nutrition 0.000 description 1
- 239000001472 potassium tartrate Substances 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 235000011005 potassium tartrates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- VRGNUPCISFMPEM-ZVGUSBNCSA-L zinc;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Zn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VRGNUPCISFMPEM-ZVGUSBNCSA-L 0.000 description 1
- HJSYJHHRQVHHMQ-TYYBGVCCSA-L zinc;(e)-but-2-enedioate Chemical compound [Zn+2].[O-]C(=O)\C=C\C([O-])=O HJSYJHHRQVHHMQ-TYYBGVCCSA-L 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a thermal protective agent for beta-hydroxy-beta-methylbutyrate (HMB) and application thereof, wherein the thermal protective agent comprises one or more of malic acid and salts thereof, tartaric acid and salts thereof and fumaric acid and salts thereof. Can prevent HMB from being deteriorated by heat, and fundamentally eliminate the bitter taste and sourness of the HMB caused by the deterioration by heat. The invention also provides a beta-hydroxy-beta-methylbutyrate derivative which is generated by the reaction of a thermal protective agent and beta-hydroxy-beta-methylbutyrate, is an HMB derivative which can react reversibly under an acidic condition, is decomposed into HMB and the thermal protective agent again when meeting an acidic environment such as hydrochloric acid (gastric acid), and can be applied as a novel HMB effective substance.
Description
Technical Field
The invention relates to the technical field of food health products, in particular to a thermal protective agent of HMB and application thereof, and an HMB derivative and application thereof.
Background
Beta-hydroxy-beta-methylbutyrate (HMB) is a five-carbon organic acid, a derivative of the essential amino acid leucine produced in vivo by its metabolite, alpha-ketoisocaproic acid (alpha-KIC). Leucine is not synthesized in the human body and must be taken in from the outside. The beta-hydroxy-beta-methylbutyric acid is usually used in the form of salts such as calcium beta-hydroxy-beta-methylbutyrate and the like, can be used for promoting muscle growth, enhancing immunity, reducing the level of cholesterol and low-density lipoprotein (LDL) in vivo to reduce the occurrence of coronary heart disease and cardiovascular disease, can also enhance the nitrogen fixation capacity of a human body, maintains the level of protein in vivo, and has wide application.
Beta-hydroxy-beta-methylbutyrate preparations such as calcium beta-hydroxy-beta-methylbutyrate and the like are easy to deteriorate and yellow in a high-temperature environment, and are irreversible after deterioration, so that the content of effective substances in the preparations is reduced. And the yellow β -hydroxy- β -methylbutyrate formulation also has a bitter, astringent, sour taste which is undesirable for oral administration.
Chinese patent CN101785566 discloses a sports drink containing HMB, which effectively masks the pungent chemical odor of HMB by adding sweeteners, artificial or perfume to the drink. However, the taste of beta-hydroxy-beta-methylbutyrate is only masked by a flavoring agent, and the taste of HMB deteriorated by heat is not treated, so that the problem that the HMB is deteriorated, yellowed and smelled is not solved.
Disclosure of Invention
In order to solve the technical problems, the invention provides a thermal protective agent for beta-hydroxy-beta-methylbutyrate, which can prevent the beta-hydroxy-beta-methylbutyrate from being deteriorated by heat and fundamentally eliminate the bitter taste and sour taste of the beta-hydroxy-beta-methylbutyrate caused by the deterioration of the beta-hydroxy-beta-methylbutyrate by heat.
The invention also discovers that the thermal protective agent can be used as a novel HMB effective substance by pre-forming a beta-hydroxy-beta-methylbutyrate derivative which can reversibly react with the beta-hydroxy-beta-methylbutyrate under an acidic condition, and decomposing the beta-hydroxy-beta-methylbutyrate derivative into beta-hydroxy-beta-methylbutyrate and the thermal protective agent when encountering an acidic environment such as hydrochloric acid (gastric acid).
In order to achieve the above object, a first aspect of the present invention provides a thermal protectant for beta-hydroxy-beta-methylbutyrate comprising one or more of malic acid and salts thereof, tartaric acid and salts thereof, and fumaric acid and salts thereof.
Preferably, the malic acid and its salt comprise one or more of DL-malic acid, D-malic acid, L-malic acid, sodium malate, potassium malate, calcium malate, magnesium malate, zinc malate, ferrous malate, ferric malate, and copper malate.
The second aspect of the invention provides the application of the thermal protective agent in the technical scheme in the preparation of beta-hydroxy-beta-methylbutyrate salt drugs.
Preferably, the thermal protective agent is added during the preparation of the beta-hydroxy-beta-methylbutyrate drug prior to heating the beta-hydroxy-beta-methylbutyrate to a temperature above 45 ℃.
In a third aspect, the present invention provides a composition comprising beta-hydroxy-beta-methylbutyrate and a thermal protectant according to the foregoing claim; the mass ratio of the beta-hydroxy-beta-methylbutyrate to the thermal protective agent is not less than 3.5: 1.
Preferably, the mass ratio of the beta-hydroxy-beta-methylbutyrate to the thermal protectant is 3.5-10: 1.
Preferably, the composition comprises the following raw materials in parts by weight:
preferably, when the dosage form of the composition is a tablet, the preparation method comprises the following steps:
(1) pulverizing the raw materials except magnesium stearate and water, and mixing the pulverized raw materials with water at 25-35 deg.C to obtain soft material;
(2) wet granulating, drying and screening the soft material to obtain dry granules;
(3) the dry granules were mixed with magnesium stearate and compressed to obtain tablets of the composition.
In a fourth aspect, the present invention provides a beta-hydroxy-beta-methylbutyrate derivative represented by formula (I):
wherein R1 is a group formed by condensing carboxyl of malic acid and salts thereof, tartaric acid and salts thereof, and fumaric acid and salts thereof with beta-hydroxy-beta-methylbutyrate beta-hydroxy
Preferably, the beta-hydroxy-beta-methylbutyrate derivative is beta-hydroxy-beta-methylbutyrate malate represented by the formula (II):
the fifth aspect of the invention provides application of the beta-hydroxy-beta-methylbutyrate derivative in the technical scheme in preparing foods, medicines or health-care products for preventing or treating and enhancing immunity, reducing blood fat and supplementing nutrition.
Compared with the prior art, the invention has the beneficial effects that:
under the action of higher temperature (generally over 45 ℃), two beta-hydroxy-beta-methylbutyrates are dehydrated to form six-membered cyclic ester, namely the compound of the formula (III). The compound of formula (iii) is yellow, has a special odor, and the reaction to produce the compound of formula (iii) is irreversible, losing the efficacy of HMB.
The research of the invention finds that the thermal protective agent such as malic acid and salt thereof can perform esterification reaction with the carboxyl of HMB under the heated state to form HMB derivative, namely the compound of formula (I). After the compound of the formula (I) is formed, the positions of alpha hydroxyl and carboxyl in the compound of the formula (I) do not react with carboxylic acid of HMB due to steric hindrance, so that the carboxylic acid of beta-hydroxy-beta-methylbutyrate is protected, the compound of the formula (III) is not generated any more, the special odor of the compound of the formula (III) can be eliminated, the loss of effective substances of the HMB in the preparation process can be prevented, and the content of the effective substances of the product can be increased.
In another aspect of the invention, the reaction of the thermoprotectant of the invention with HMB to produce the compound of formula (i) is reversible, and in an acidic environment, such as that of gastric acid, the compound of formula (i) will hydrolyze to HMB and the thermoprotectant, maintaining their original functions. The invention thus also provides HMB derivatives of formula (i) which are useful as potential active agents for administration.
In some preferred embodiments of the invention, the thermoprotectant is malic acid and salts thereof, and compositions comprising malic acid and salts thereof can, in addition to providing thermal protection and taste correction to the HMB formulation, impart a fruity taste to the malic acid, further correcting the taste of the HMB formulation, making it more acceptable.
Detailed Description
The technical solution of the present invention will be described with reference to the following examples. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments; and are not intended to represent the entirety of the present invention. It should be noted that all other embodiments obtained by those skilled in the art based on the embodiments of the present invention belong to the protection scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The invention provides in a first aspect a thermoprotectant for beta-hydroxy-beta-methylbutyrate comprising one or more of malic acid and salts thereof, tartaric acid and salts thereof, and fumaric acid and salts thereof. The carboxyl of the thermal protective agent can be subjected to esterification reaction with the carboxyl of HMB in preference to HMB under the heating condition, and the reaction is reversible, so that the HMB can be effectively protected from generating a compound shown in a formula (III) with special odor, and the thermal protection of the HMB is realized. In the present invention, the malic acid and salts thereof include, but are not limited to, one or more of DL-malic acid, D-malic acid, L-malic acid, sodium malate, potassium malate, calcium malate, magnesium malate, zinc malate, ferrous malate, ferric malate, and copper malate; preferably one or more selected from the group consisting of L-malic acid, calcium malate and magnesium malate. In the present invention, the tartaric acid and salts thereof include, but are not limited to, sodium tartrate, potassium tartrate, calcium tartrate, magnesium tartrate, zinc tartrate, ferrous tartrate, and copper tartrate. In the present invention, the fumaric acid and its salt include, but are not limited to, sodium fumarate, potassium fumarate, calcium fumarate, magnesium fumarate, zinc fumarate, ferrous fumarate, copper fumarate.
The second aspect of the invention provides the application of the thermal protective agent in the technical scheme in the preparation of beta-hydroxy-beta-methylbutyrate salt drugs. Preferably, in the process of preparing the beta-hydroxy-beta-methylbutyrate drugs, the thermal protective agent is added before the beta-hydroxy-beta-methylbutyrate is heated to a temperature of more than 45 ℃, namely the thermal protective agent is added before the HMB reacts at a high temperature to generate the compound of the formula (III) to realize the thermal protection effect.
In a third aspect, the present invention provides a composition comprising beta-hydroxy-beta-methylbutyrate and a thermal protectant according to the foregoing claim; the mass ratio of the beta-hydroxy-beta-methylbutyrate to the thermal protective agent is not less than 3.5: 1. In a preferred embodiment of the present invention, the mass ratio of beta-hydroxy-beta-methylbutyrate to thermal protectant is 3.5-10:1, such as 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 10:1, etc. When the mass ratio of beta-hydroxy-beta-methylbutyrate to the thermal protectant is below the ratio defined in the present invention, insufficient thermal protectant usage may still result in a compound of formula (iii).
Beta-hydroxy-beta-methylbutyrate is currently most often prepared in tablet form, and HMB is easily denatured by heating steps such as drying during wet granulation. In some embodiments of the present invention, the composition is a tablet, and comprises the following raw materials in parts by weight: the feed comprises the following raw materials in parts by weight: beta-hydroxy-beta-methylbutyrate 3800-4200 parts, calcium carbonate 3800-4000 parts, thermal protective agent 950-1050 parts, maltodextrin 900-1000 parts, magnesium stearate 40-60 parts and water 500-700 parts; preferably, the raw materials comprise 3950-. The preparation method of the composition comprises the following steps:
(4) pulverizing the raw materials except magnesium stearate and water, and mixing the pulverized raw materials with water at 25-35 deg.C to obtain soft material;
(5) wet granulating, drying and screening the soft material to obtain dry granules;
(6) the dry granules were mixed with magnesium stearate and compressed to obtain tablets of the composition.
In the invention, the raw materials HMB, calcium carbonate, the thermal protective agent and the maltodextrin in the step (1) preferably have the crushed particle size D97 being less than or equal to 380 mu m. Preferably, the mixing time in the step (1) is 5-10 min; further preferably, the mixing is carried out in a condenser jacketed tellurion mixer. Preferably, in the wet granulation in the step (2), the granulation is performed by screen granulation; the mesh number of the screen is preferably 10 meshes. Preferably, the drying channel in the step (2) is 50-60 ℃; further preferably, the drying is carried out in a boiling dryer. Preferably, the mesh number of the screen used for sieving in the step (2) is 20-200 meshes; further preferably, the screening is performed in a screening machine.
In the present invention, the composition may be prepared into other dosage forms known in the art, including but not limited to capsules, paste, syrup, powder, granules, oral liquid, in addition to tablets. Adding various adjuvants when preparing into different dosage forms.
In a fourth aspect, the present invention provides a beta-hydroxy-beta-methylbutyrate derivative represented by formula (I):
wherein R1 is a group formed by condensing carboxyl of malic acid and salts thereof, tartaric acid and salts thereof, and fumaric acid and salts thereof with beta-hydroxy-beta-methylbutyrate beta-hydroxy.
In some embodiments of the invention, when the thermal protectant is malic acid or a salt thereof, the beta-hydroxy-beta-methylbutyrate derivative is beta-hydroxy-beta-methylbutyrate malate, as represented by formula (ii):
the fifth aspect of the invention provides application of the beta-hydroxy-beta-methylbutyrate derivative in the technical scheme in preparing foods, medicines or health-care products for preventing or treating and enhancing immunity, reducing blood fat and supplementing nutrition.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 1 composition containing HMB and thermal stabilizer tablet 1
The composition comprises the following raw materials: 4000g of calcium beta-hydroxy-beta-methylbutyrate, 4000g of calcium carbonate, 1000g of magnesium malate, 950g of maltodextrin, 50g of magnesium stearate and 600g of water.
(1) Sieving with 40 mesh sieve to obtain fine powder of beta-hydroxy-beta-methylbutyrate calcium with D90 no more than 380 μm, calcium carbonate, magnesium malate, maltodextrin and magnesium stearate;
(2) adding 4000g of the beta-hydroxy-beta-methylbutyrate calcium fine powder, 4000g of calcium carbonate fine powder, 1000g of magnesium malate fine powder, 950g of maltodextrin fine powder, 50g of magnesium stearate fine powder and 600g of water into a high-speed mixer, mixing for 10 minutes at the mixing temperature of 35 ℃ to prepare a soft material;
(3) granulating the soft material by a wet granulator, and screening wet granules of 10 meshes;
(4) drying the wet granules in a fluidized bed at 60 ℃, and screening the granules with a sieve of 20-200 meshes to obtain dry granules;
(5) mixing the dry granules with 40g of magnesium stearate;
(6) the mixture was compressed to give 9500 tablets of composition tablet 1.
Example 2 composition containing HMB and thermal stabilizer tablet 2
The composition comprises the following raw materials: 3950g of calcium beta-hydroxy-beta-methylbutyrate, 3950g of calcium carbonate, 950g of calcium malate, 900g of maltodextrin, 40g of magnesium stearate and 500g of water.
(1) Sieving beta-hydroxy-beta-methylbutyrate calcium fine powder with D90 not more than 380 microns, calcium carbonate fine powder, calcium malate fine powder, maltodextrin fine powder and magnesium stearate fine powder by using a 40-mesh sieve for later use;
(2) adding 3950g of the beta-hydroxy-beta-methylbutyrate calcium fine powder, 3950g of calcium carbonate fine powder, 950g of L-malic acid fine powder, 900g of maltodextrin fine powder, 40g of magnesium stearate fine powder and 500g of water into a high-speed mixer, mixing for 5 minutes at the mixing temperature of 25 ℃ to obtain a soft material;
(3) granulating the soft material by a wet granulator, and screening wet granules of 10 meshes;
(4) drying the wet granules in a fluidized bed at 60 ℃, and screening the granules with a sieve of 20-200 meshes to obtain dry granules;
(5) mixing the dry granules with 40g of magnesium stearate;
(6) the above mixture was compressed to obtain 9000 tablets of composition tablet 2.
Example 3 composition containing HMB and thermal stabilizer tablet 3
The composition comprises the following raw materials: 4050g of beta-hydroxy-beta-methylbutyrate calcium, 4050g of calcium carbonate, 1050g of zinc malate, 1000g of maltodextrin, 60g of magnesium stearate and 700g of water.
(1) Sieving beta-hydroxy-beta-methylbutyrate calcium fine powder with D90 not more than 380 microns, calcium carbonate fine powder, calcium malate fine powder, maltodextrin fine powder and magnesium stearate fine powder by using a 40-mesh sieve for later use;
(2) adding 3950g of the beta-hydroxy-beta-methylbutyrate calcium fine powder, 3950g of calcium carbonate fine powder, 950g of L-malic acid fine powder, 900g of maltodextrin fine powder, 40g of magnesium stearate fine powder and 500g of water into a high-speed mixer, mixing for 5 minutes at the mixing temperature of 25 ℃ to obtain a soft material;
(3) granulating the soft material by a wet granulator, and screening wet granules of 10 meshes;
(4) drying the wet granules in a fluidized bed at 60 ℃, and screening the granules with a sieve of 20-200 meshes to obtain dry granules;
(5) mixing the dry granules with 40g of magnesium stearate;
(6) the above mixture was compressed to obtain 9000 tablets of composition tablet 3.
Comparative example 1
Comparative composition tablet 1 was obtained by following the same procedure as in example 1 except that magnesium malate was not contained in the raw materials.
Comparative example 2
Comparative composition tablet 2 was obtained in the same manner as in example 1 except that the mixing temperature in step (2) was 20 ℃.
Comparative example 3
Comparative composition tablet 3 was obtained in the same manner as in example 1 except that the mixing temperature in step (2) was 40 ℃.
Example 4
The composition tablets 1 to 3 obtained in examples 1 to 3 and comparative composition tablets 1 to 3 were subjected to sensory evaluation, and the smoothness, color and flavor of the tablet surface were evaluated by 10 sensory evaluation persons, and the results are shown in Table 1.
TABLE 1
As shown in Table 1, the tablets of the compositions obtained in examples 1-3 were granulated at a higher temperature, but the tablets were generally yellow and bitter sour as in comparative example 1, where the thermal protectant magnesium malate was not added, indicating that the thermal protectant provided by the present invention can prevent the thermal formation of the compound of formula (III) from HMB.
As shown in Table 1, comparative example 2 employs a lower temperature (20 ℃) at the time of raw material mixing, and the soft material cannot be granulated at the high-speed mixing stage. Comparative example 3 a higher temperature (40 c) was used for the raw material mixing, and the raw material was not able to be made soft because part of HMB was dissolved due to the high temperature during the high speed mixing stage. It can be seen that a tablet of the composition that is acceptable beyond the mixing temperature defined in the present invention (25-35 ℃) cannot be made.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be construed as the protection scope of the present invention.
Claims (10)
1. A thermal protectant for beta-hydroxy-beta-methylbutyrate comprising one or more of malic acid and salts thereof, tartaric acid and salts thereof, and fumaric acid and salts thereof.
2. The thermal protective agent of claim 1 wherein malic acid and salts thereof comprise one or more of DL-malic acid, D-malic acid, L-malic acid, sodium malate, potassium malate, calcium malate, magnesium malate, zinc malate, ferrous malate, ferric malate, and cupric malate.
3. Use of a thermoprotectant according to claim 1 or 2 for the preparation of a medicament of the β -hydroxy- β -methylbutyrate type.
4. Use according to claim 3, wherein the thermoprotectant is added during the manufacture of the medicament of the beta-hydroxy-beta-methylbutyrate before the beta-hydroxy-beta-methylbutyrate is heated to a temperature above 45 ℃.
5. A composition comprising beta-hydroxy-beta-methylbutyrate and the thermal protectant of claim 1 or claim 2; preferably, the mass ratio of beta-hydroxy-beta-methylbutyrate to thermal protectant is not less than 3.5: 1. More preferably, the mass ratio of beta-hydroxy-beta-methylbutyrate to thermoprotectant is from 3.5 to 10: 1.
6. The composition according to claim 5, wherein the composition comprises the following raw materials in parts by weight:
7. the composition of claim 6, wherein when the dosage form of the composition is a tablet, the preparation method comprises the following steps:
(1) pulverizing the raw materials except magnesium stearate and water, and mixing the pulverized raw materials with water at 25-35 deg.C to obtain soft material;
(2) wet granulating, drying and screening the soft material to obtain dry granules;
(3) the dry granules were mixed with magnesium stearate and compressed to obtain tablets of the composition.
8. A beta-hydroxy-beta-methylbutyrate derivative represented by formula (I):
wherein R1 is a group formed by condensing carboxyl of malic acid and salts thereof, tartaric acid and salts thereof, and fumaric acid and salts thereof with beta-hydroxy-beta-methylbutyrate beta-hydroxy.
9. The beta-hydroxy-beta-methylbutyrate derivative according to claim 8, wherein the beta-hydroxy-beta-methylbutyrate derivative is beta-hydroxy-beta-methylbutyrate malate according to formula (ii):
10. use of the beta-hydroxy-beta-methylbutyrate derivative according to claim 8 or 9 for the preparation of a food, pharmaceutical or nutraceutical product for preventing or treating immune enhancement, lowering blood lipids, supplementing nutrition.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116786020A (en) * | 2023-07-27 | 2023-09-22 | 连云港瑞邦药业有限公司 | Hot dissolving device for calcium methylbutyrate processing and preparation and application method thereof |
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| JP2020184922A (en) * | 2019-05-14 | 2020-11-19 | オルガノフードテック株式会社 | Hmb-containing composition, hmb-containing composition manufacturing method, hmb-containing preparation, hmb-containing preparation manufacturing method, hmb-containing food, and hmb-containing food manufacturing method |
| JP2020184911A (en) * | 2019-05-13 | 2020-11-19 | 日清オイリオグループ株式会社 | Inhibitor of allotriogeusia derived from hmb, food and drink containing inhibitor of allotriogeusia derived from hmb, and method of inhibiting allotriogeusia derived from hmb |
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| CN102711522A (en) * | 2010-01-29 | 2012-10-03 | 雅培制药有限公司 | Aseptically packaged nutritional liquids comprising HMB |
| JP2015107063A (en) * | 2013-12-03 | 2015-06-11 | 小林香料株式会社 | Acidic beverage including hmb |
| JP2019064929A (en) * | 2017-09-28 | 2019-04-25 | ライオン株式会社 | Liquid composition, agent for improving white turbidness thereof, agent for improving odor thereof, and production method therefor |
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| CN116786020A (en) * | 2023-07-27 | 2023-09-22 | 连云港瑞邦药业有限公司 | Hot dissolving device for calcium methylbutyrate processing and preparation and application method thereof |
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