CN1706828A - Metal ion double salt with vitamin F as active component and its orally taken solid prepn and freeze dried injection - Google Patents
Metal ion double salt with vitamin F as active component and its orally taken solid prepn and freeze dried injection Download PDFInfo
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- CN1706828A CN1706828A CN 200410046495 CN200410046495A CN1706828A CN 1706828 A CN1706828 A CN 1706828A CN 200410046495 CN200410046495 CN 200410046495 CN 200410046495 A CN200410046495 A CN 200410046495A CN 1706828 A CN1706828 A CN 1706828A
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- vitamin
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- amino acid
- metal ion
- double salt
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- 239000011782 vitamin Substances 0.000 title claims abstract description 138
- 229940088594 vitamin Drugs 0.000 title claims abstract description 136
- 229930003231 vitamin Natural products 0.000 title claims abstract description 136
- 235000013343 vitamin Nutrition 0.000 title claims abstract description 136
- 150000003722 vitamin derivatives Chemical class 0.000 title claims abstract description 135
- 238000002347 injection Methods 0.000 title claims abstract description 35
- 239000007924 injection Substances 0.000 title claims abstract description 35
- 229910021645 metal ion Inorganic materials 0.000 title claims abstract description 29
- 150000003839 salts Chemical class 0.000 title claims abstract description 27
- 239000007787 solid Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 63
- 239000000843 powder Substances 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 150000001413 amino acids Chemical class 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 23
- 229920002472 Starch Polymers 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 239000008107 starch Substances 0.000 claims description 18
- 235000019698 starch Nutrition 0.000 claims description 18
- 239000008215 water for injection Substances 0.000 claims description 18
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 239000002775 capsule Substances 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 13
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 13
- 229960000583 acetic acid Drugs 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 12
- -1 compound salt Chemical class 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000007873 sieving Methods 0.000 claims description 9
- 229940037627 magnesium lauryl sulfate Drugs 0.000 claims description 7
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 229940119744 dextran 40 Drugs 0.000 claims description 5
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 5
- 229910021487 silica fume Inorganic materials 0.000 claims description 5
- 239000008227 sterile water for injection Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 238000003825 pressing Methods 0.000 claims description 4
- 239000007779 soft material Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
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- 239000012047 saturated solution Substances 0.000 claims description 3
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- 230000001954 sterilising effect Effects 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 2
- 238000009835 boiling Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 239000012266 salt solution Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 13
- 206010012735 Diarrhoea Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 208000004998 Abdominal Pain Diseases 0.000 abstract description 3
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
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- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 60
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 56
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 36
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 35
- 239000011575 calcium Substances 0.000 description 35
- 229910052791 calcium Inorganic materials 0.000 description 35
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 19
- 239000011701 zinc Substances 0.000 description 17
- 229910052725 zinc Inorganic materials 0.000 description 17
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 16
- 238000009472 formulation Methods 0.000 description 12
- 239000011777 magnesium Substances 0.000 description 12
- 229910052749 magnesium Inorganic materials 0.000 description 12
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 10
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 7
- 239000001639 calcium acetate Substances 0.000 description 7
- 229960005147 calcium acetate Drugs 0.000 description 7
- 235000011092 calcium acetate Nutrition 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
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- 206010067484 Adverse reaction Diseases 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- MCDLETWIOVSGJT-UHFFFAOYSA-N acetic acid;iron Chemical compound [Fe].CC(O)=O.CC(O)=O MCDLETWIOVSGJT-UHFFFAOYSA-N 0.000 description 4
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 4
- 230000006838 adverse reaction Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 4
- 239000011654 magnesium acetate Substances 0.000 description 4
- 229940069446 magnesium acetate Drugs 0.000 description 4
- 235000011285 magnesium acetate Nutrition 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-L tyrosinate(2-) Chemical compound [O-]C(=O)C(N)CC1=CC=C([O-])C=C1 OUYCCCASQSFEME-UHFFFAOYSA-L 0.000 description 4
- 239000004246 zinc acetate Substances 0.000 description 4
- 235000008524 evening primrose extract Nutrition 0.000 description 3
- 229940089020 evening primrose oil Drugs 0.000 description 3
- 239000010475 evening primrose oil Substances 0.000 description 3
- VZCCETWTMQHEPK-UHFFFAOYSA-N gamma-Linolensaeure Natural products CCCCCC=CCC=CCC=CCCCCC(O)=O VZCCETWTMQHEPK-UHFFFAOYSA-N 0.000 description 3
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 description 3
- 235000020664 gamma-linolenic acid Nutrition 0.000 description 3
- 229960002733 gamolenic acid Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
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- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
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- 159000000003 magnesium salts Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- ZUUFLXSNVWQOJW-MBIXAETLSA-N (2e,4e,6e)-octadeca-2,4,6-trienoic acid Chemical compound CCCCCCCCCCC\C=C\C=C\C=C\C(O)=O ZUUFLXSNVWQOJW-MBIXAETLSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
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- 206010012438 Dermatitis atopic Diseases 0.000 description 1
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- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
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- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses one kind of vitamin F-amino acid metal ion double salt, solid oral preparation and the freeze dried powder for injection with the double salt, and their preparation process. Unlike to available similar medicine, the present invention has no serious side reaction when being used in treating diarrhea and abdominal pain. The present invention has wider indication range and higher curative effect compared with vitamin F, and may be used widely in treating various cardiac vascular diseases, etc. clinically.
Description
Technical Field
The invention relates to a medicament, in particular to a medicament with vitamin F as an active ingredient, which comprises an oral solid preparation and a freeze-dried injection.
Background
Vitamin F, also known as gamma-linolenic acid, is octadecatrienoic acid. Vitamin F is a structural material for forming biological membranes of various tissues of a human body, is also a precursor for synthesizing prostate, has very wide physiological activity, and is clinically applied to the treatment and prevention of the following diseases: vitamin F deficiency, diabetes and its vascular system complications, hyperlipidemia, hyperviscosity, hypertension, cerebral artery, pulmonary artery, coronary artery, renal artery, limb atherosclerosis, thrombotic cardiovascular and cerebrovascular diseases, cancer, gastric ulcer, obesity, schizophrenia, atopic eczema, rheumatoid arthritis, vasculitis, and pre-schizophyllan for preventing and treating AIDS, enhancing immunity against epidemic diseases, gamma ray resistance, thinking ability and physical ability of human body.
The vitamin F medicines used at present, such as the lipid-lowering medicine evening primrose oil soft capsules (the effective components are vitamin F and linoleic acid), have the main defect that the side effects of nausea, bellyache or diarrhea and the like appear after people take the vitamin F medicines, so the clinical application of the medicines is limited. At the same time, the clinical application range is not very wide.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a double salt with vitamin F as an active ingredient, an oral solid preparation, a freeze-dried injection and a corresponding preparation method thereof.
The invention achieves the purpose through the following technical scheme.
Using vitamin F as raw material, and mixing with tryptophan or tyrosine and divalent metal ion, such as Ca2+、Mg2+、Fe2+、Zn2+Etc. to form double salts. Then the compound salt is prepared into oral solid preparation and freeze-dried injection.
The present invention will be described in detail below.
Preparation of vitamin F amino acid metal ion double salt
The formula is as follows: vitamin F4.8-6.0mol
Calcium acetate 4.3-5.0mol
Tryptophan 2.1-2.5mol
6800 Anhydrous methanol 9000ml
10000-20000ml isopropanol
Injection water 6400-10000ml
Glacial acetic acid 50ml-150ml
Wherein calcium acetate can be replaced by magnesium acetate, ferrous acetate and zinc acetate, and tryptophan can be replaced by tyrosine.
The reaction principle is as follows:
A.
B.
or
Wherein R is1＝
R2＝
Or
M2+＝Ca2+、Mg2+、Fe2+、Zn2+
The preparation method comprises the following steps:
1. dissolving vitamin F in anhydrous methanol, and filtering with a dipolar titanium rod filter stick for later use;
2. weighing calcium acetate, adding appropriate amount of sterile water for injection, adding glacial acetic acid, stirring to dissolve completely, and filtering with a dipolar titanium filter stick. Injecting the filtrate into the solution obtained in the step 1, stirring, cooling to room temperature, adjusting pH to 5.0-7.5, stopping stirring when crystal is separated out, cooling to-15 + -5 deg.C, and crystallizing completely. Filtering with G3 sand core funnel, washing crystal with anhydrous methanol below-15 deg.C, and draining. Storing at-15 + -5 deg.C.
3. Weighing tryptophan, adding sterilized water for injection preheated to 50 ℃ for dissolving, adding vitamin F calcium prepared in the step 2 for dissolving, adding active carbon for injection, stirring, filtering with a titanium rod, adding the filtrate into isopropanol filtered by the titanium rod, slowly stirring, regulating pH value to 5.5-9.0 at room temperature, stirring until crystal is separated out, and stopping stirring. Cooling to-10 +/-5 deg.C for complete crystallization. Filtering with G3 sand core funnel, washing the crystal with isopropanol of-10 deg.C filtered with titanium rod, vacuum drying at-10 deg.C to-4 deg.C in freeze drier until the isopropanol is completely removed. The crystals were dried and stored at-10 ℃. The sterile pyrogen-qualified pharmaceutical grade vitamin F tryptophan calcium salt is prepared.
In the preparation method, tyrosine is used for replacing tryptophan, or magnesium acetate, ferrous acetate and zinc acetate are used for replacing calcium acetate, and the corresponding magnesium salt, ferrous salt and zinc salt of the vitamin F amino acid are prepared according to the formula and the process parameters.
The vitamin F, the amino acid and the metal ion double salt can be analyzed by means of elemental analysis, ultraviolet spectroscopy, infrared chromatography, mass spectrometry, nuclear magnetic resonance, X diffraction, thermogravimetry, differential thermal analysis and the like, and simultaneously, the quantitative analysis of the vitamin F, the amino acid and the metal ion is carried out, so that the structural formula of the vitamin F, the amino acid and the metal ion double salt is determined as follows:
【R1COO-，R1COO-】·M2+
NH3+or [ R]1COO-】·M2+·【-OOCCH(NH2)R2】
R2CHCOO-
Preparation of oral solid preparation of (di) vitamin F amino acid metal ion double salt
| Formulation of | 0.2-0.3 g/tablet specification | 0.4-0.5 g/tablet specification |
| Vitamin F calcium tryptophan | 2-3Kg | 4-5Kg |
| Pulping dry starch (15% strength) | 100-150g | 200-250g |
| Sucrose powder | 14-21g | 28-35g |
| Polyvinylpyrrolidone (PVP) | 15-23g | 30-38g |
| Additional dry starch | 160-240g | 265-330g |
| Magnesium lauryl sulfate | 6-9g | 10-13g |
| Silica gel micropowder | 3-5g | 5-6.5g |
The preparation method comprises the following steps:
1. crushing vitamin F tryptophan calcium powder, sieving with a 100-mesh sieve, and sieving starch with a 100-mesh sieve. Starch is made into 15% paste, and sucrose powder is dissolved in the paste.
2. And (3) putting the vitamin F calcium tryptophan and the starch slurry prepared in the step (1) into a mixing stirrer to be stirred to prepare a soft material. Sieving with 12-14 mesh sieve, granulating, and drying at 50-60 deg.C in a fluidized bed dryer.
3. Mixing the dry granules prepared in the step 2 with magnesium lauryl sulfate, micro silica gel powder, polyvinylpyrrolidone and additional dry starch, granulating, and pressing into tablets by flat die; or making into capsule with enteric capsule.
Tryptophan in the vitamin F tryptophan calcium in the formula can be replaced by tyrosine, calcium can be replaced by zinc, magnesium and ferrous iron, the proportion and the preparation method of the components are the same, and the oral solid preparation of the corresponding vitamin F amino acid metal ion double salt is prepared.
Preparation of vitamin F, amino acid and metal ion double salt freeze-dried injection
The formula (parts by weight) is as follows:
| vitamin F calcium tryptophan | 20-100 |
| 2-hydroxypropyl- β -cyclodextrin | 20-120 |
| Dextran-40 | 40-60 |
| Water for injection is added to | 2500 |
The preparation method comprises the following steps:
1. dissolving vitamin F tryptophan calcium with a proper amount of water for injection to form a nearly saturated solution, preparing 2-hydroxypropyl- β -cyclodextrin into a 60-75% solution with the water for injection, and dropwise adding the vitamin F tryptophan calcium solution into the 2-hydroxypropyl- β -cyclodextrin solution under rapid stirring until the solution is completely dissolved and the inclusion is finished.
2. Preparing dextran-40 into 6% solution with appropriate amount of water for injection, mixing with the mixed solution obtained in the step 1, stirring uniformly, adding water for injection to reach a total volume of 2500ml, adding activated carbon for injection, sealing, performing moist heat sterilization for 20 minutes, cooling to 65 +/-5 ℃, filtering with a hot double-layer filter membrane, cooling the filtrate to room temperature, adjusting the volume with water for injection, adjusting the pH value to 5.5-7.0 with 8% sodium hydroxide solution, subpackaging, half plugging, freeze-drying at-35 ℃ to 30 ℃ and 50Pa-2Pa until the water content is less than or equal to 2%, plugging under vacuum, and capping.
Tryptophan in the vitamin F tryptophan calcium in the formula can be replaced by tyrosine, and calcium can be replaced by zinc, magnesium and ferrous iron. The components are mixed in the same ratio and prepared in the same preparation method, and the freeze-dried injection of the corresponding vitamin F amino acid metal ion double salt is prepared.
The beneficial effects of the invention are as follows:
1. overcomes the adverse reactions of medicines such as evening primrose oil medicine, monomer vitaminF (gamma-linolenic acid) medicine, simple metal ion double salt of vitamin F, simple amino acid salt of vitamin F and the like to diarrhea and abdominal pain of a human body.
2 compared with the monomer vitamin F (gamma-linolenic acid) medicine, the product of the invention is more applicable to disease species and has better curative effect.
The invention is further illustrated by the following specific examples.
[ example 1]preparation of vitamin F Tryptophan calcium salt
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.4 | 6.0 |
| Calcium acetate mol | 4.3 | 4.5 | 5.0 |
| Tryptophan mol | 2.1 | 2.4 | 2.5 |
| Anhydrous methanol ml | 6800 | 7500 | 9000 |
| Isopropanol ml | 10000 | 15000 | 20000 |
| Water ml for injection | 6400 | 8200 | 10000 |
| Glacial acetic acid ml | 50 | 100 | 150 |
The preparation method comprises the following steps:
1. dissolving vitamin F in anhydrous methanol, and filtering with 0.8 μm and 0.22 μm dipolar titanium rod filter sticks respectively;
2. weighing calcium acetate, adding 2400-. Injecting the filtrate into the solution obtained in the step 1, stirring, cooling to room temperature, adjusting pH to 5.0-7.5, stopping stirring when crystal is separated out, cooling to-15 + -5 deg.C, and crystallizing completely. Filtering with G3 sand core funnel, washing crystal with anhydrous methanol below-15 deg.C, and draining. Storing at-15 + -5 deg.C.
3. Weighing tryptophan, adding 4000-6000ml of sterilized injection water preheated to 50 ℃ for dissolving, adding 20-40g of active carbon for injection after the vitamin F calcium prepared in the step 2 is dissolved, stirring, filtering by a 0.8 mu m titanium rod and a 0.22 mu m titanium rod in a dipolar manner, adding the filtrate into isopropanol filtered by the 0.22 mu m titanium rod, slowly stirring, regulating the pH value to 5.5-9.0 at room temperature, stirring until crystallization is separated out, and stopping stirring. Cooling to-10 +/-5 deg.C for complete crystallization. Filtering with G3 sand core funnel, washing the crystal with-10 deg.C isopropanol filtered with 0.22 μm titanium rod, vacuum drying at-10 deg.C to-4 deg.C in freeze dryer until the isopropanol is completely removed. The crystals were dried and stored at-10 ℃. The sterile pyrogen-qualified medicinal vitamin F tryptophan calcium salt is prepared.
[ example 2]preparation of magnesium salt of vitamin F tryptophan
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.5 | 6.0 |
| Magnesium acetate mol | 4.3 | 4.4 | 5.0 |
| Tryptophan mol | 2.1 | 2.3 | 2.5 |
| Anhydrous methanol ml | 6800 | 7800 | 9000 |
| Isopropanol ml | 10000 | 15000 | 20000 |
| Water ml for injection | 640 | 7200 | 10000 |
| Glacial acetic acid ml | 50 | 120 | 150 |
Example 3 preparation of ferrous salts of vitamin F tryptophan
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.4 | 6.0 |
| Ferrous acetate mol | 4.3 | 4.5 | 5.0 |
| Tryptophan mol | 2.1 | 2.3 | 2.5 |
| Anhydrous methanol ml | 6800 | 7500 | 9000 |
| Isopropanol ml | 10000 | 18000 | 20000 |
| Water ml for injection | 6400 | 8200 | 10000 |
| Glacial acetic acid ml | 50 | 110 | 150 |
Example 4 preparation of vitamin F tryptophan zinc salt
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.5 | 6.0 |
| Mol of zinc acetate | 4.3 | 4.5 | 5.0 |
| Tryptophan mol | 2.1 | 2.2 | 2.5 |
| Anhydrous methanol ml | 6800 | 7500 | 9000 |
| Isopropanol ml | 10000 | 19000 | 20000 |
| Water ml for injection | 6400 | 8200 | 10000 |
| Glacial acetic acid ml | 50 | 140 | 150 |
[ example 5]preparation of vitamin F tyrosine calcium salt
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.4 | 6.0 |
| Calcium acetate mol | 4.3 | 4.5 | 5.0 |
| Tyrosine mol | 2.1 | 2.4 | 2.5 |
| Anhydrous methanol ml | 6800 | 7500 | 9000 |
| Isopropanol ml | 10000 | 15000 | 20000 |
| Water ml for injection | 6400 | 8200 | 10000 |
| Glacial acetic acid ml | 50 | 100 | 150 |
[ example 6]preparation of magnesium vitamin F tyrosine
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.5 | 6.0 |
| Magnesium acetate mol | 4.3 | 4.4 | 5.0 |
| Tyrosine mol | 2.1 | 2.3 | 2.5 |
| Anhydrous methanol ml | 6800 | 7800 | 9000 |
| Isopropanol ml | 10000 | 15000 | 20000 |
| Water ml for injection | 6400 | 7200 | 10000 |
| Glacial acetic acid ml | 50 | 120 | 150 |
Example 7 preparation of ferrous salts of vitamin F tyrosine
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.0 | 6.0 |
| Ferrous acetate mol | 4.3 | 4.4 | 5.0 |
| Tyrosine mol | 2.1 | 2.3 | 2.5 |
| Anhydrous methanol ml | 6800 | 7800 | 9000 |
| Isopropanol ml | 10000 | 15000 | 20000 |
| Water ml for injection | 6400 | 7900 | 10000 |
| Glacial acetic acid ml | 50 | 120 | 150 |
Example 8 preparation of vitamin F tyrosine Zinc salt
| Formulation of | 1 | 2 | 3 |
| Vitamin F mol | 4.8 | 5.5 | 6.0 |
| Mol of zinc acetate | 4.3 | 4.4 | 5.0 |
| Tyrosinemol | 2.1 | 2.3 | 2.5 |
| Anhydrous methanol ml | 6800 | 7800 | 9000 |
| Isopropanol ml | 10000 | 15000 | 20000 |
| Water ml for injection | 6400 | 7200 | 10000 |
| Glacial acetic acid ml | 50 | 120 | 150 |
Examples 2-8 were prepared as in example 1.
[ example 9]preparation of vitamin F calcium tryptophan oral solid preparation
| Formulation of | 0.2-0.3 g/tablet specification | 0.4-0.5 g/tablet specification | ||||
| 1 | 2 | 3 | 1 | 2 | 3 | |
| Vitamin F calcium tryptophan | 2 | 2.5 | 3 | 4 | 4.5 | 5 |
| Pulping dry starch g (15% concentration) | 100 | 120 | 150 | 200 | 220 | 250 |
| Sucrose powder g | 14 | 18 | 21 | 28 | 30 | 35 |
| Polyvinylpyrrolidone g | 15 | 20 | 23 | 30 | 35 | 38 |
| Plus dry starch g | 160 | 200 | 240 | 265 | 300 | 330 |
| Magnesium lauryl sulfate g | 6 | 8 | 9 | 10 | 12 | 13 |
| Silica gel micropowder g | 3 | 4 | 5 | 5 | 6 | 6.5 |
The preparation method comprises the following steps:
1. crushing vitamin F tryptophan calcium powder, sieving with a 100-mesh sieve, and sieving starch with a 100-mesh sieve. Starch was made into l 5% paste, and sucrose powder was dissolved in the paste.
2. And (3) putting the vitamin F calcium tryptophan and the starch slurry prepared in the step (1) into a mixing stirrer to be stirred to prepare a soft material. Sieving with 12-14 mesh sieve, granulating, and drying at 50-60 deg.C in a fluidized bed dryer.
3. Mixing the dry particles prepared in the step 2 with magnesium lauryl sulfate, micro silica gel powder, polyvinylpyrrolidone and externally added dry starch, grading by 12-14 meshes, and pressing into 1000 tablets or 0.2 g/tablet or 0.3 g/tablet by a flat die; or filling the mixture into 1000 capsules of 0.2g by using enteric capsules.
[ example 10]preparation of vitamin F magnesium tryptophan oral solid preparation
The vitamin F tryptophan calcium in the example 9 is replaced by the vitamin F tryptophan magnesium, the mixture ratio and the preparation method are the same, and the vitamin F tryptophan magnesium oral solid preparation is prepared.
[ example 11]preparation of vitamin F Tryptophan ferrous oral solid preparation
The vitamin F tryptophan calcium in the example 9 is replaced by the vitamin F tryptophan ferrous, the mixture ratio and the preparation method are the same, and the vitamin F tryptophan ferrous oral solid preparation is prepared.
[ example 12]preparation of vitamin F Zinc Tryptophan oral solid preparation
The vitamin F tryptophan calcium in the example 9 is replaced by the vitamin F tryptophan zinc, the mixture ratio and the preparation method are the same, and the vitamin F tryptophan zinc oral solid preparation is prepared.
[ example 13]preparation of vitamin F calcium tyrosine oral solid preparation
The vitamin F tryptophan calcium in the embodiment 9 is replaced by the vitamin F calcium tyrosine, the preparation method is the same according to the mixture ratio, and the oral solid preparation of the vitamin F calcium tyrosine is prepared.
[ example 14]preparation of vitamin F-magnesium tyrosinate oral solid preparation
The vitaminF tryptophan magnesium in the embodiment 10 is replaced by the vitamin F tyrosine magnesium, the mixture ratio and the preparation method are the same, and the vitamin F tyrosine magnesium oral solid preparation is prepared.
[ example 15]preparation of vitamin F tyrosine ferrous oral solid preparation
The ferrous tryptophan as vitamin F in the example 11 is replaced by ferrous tyrosine as vitamin F, the mixture ratio and the preparation method are the same, and the oral solid preparation of ferrous tyrosine as vitamin F is prepared.
[ example 16]preparation of vitamin F-zinc tyrosinate oral solid preparation
The vitamin F tryptophan zinc in the embodiment 12 is replaced by the vitamin F tyrosine zinc, the mixture ratio and the preparation method are the same, and the vitamin F tyrosine zinc oral solid preparation is prepared.
[ example 17]preparation of vitamin F calcium tryptophan lyophilized injection
| Formulation of | 1 | 2 | 3 |
| Vitamin F calcium tryptophan (g) | 20 | 50 | 100 |
| 2-hydroxypropyl- β -Cyclodextrin (g) | 20 | 58 | 120 |
| Dextran-40 (g) | 40 | 51 | 60 |
| Adding water for injection to (ml) | 2500 | 2500 | 2500 |
The preparation method comprises the following steps:
1. dissolving vitamin F tryptophan calcium with a proper amount of water for injection to form a nearly saturated solution, preparing 2-hydroxypropyl- β -cyclodextrin into a 60-75% solution with the water for injection, and dropwise adding the vitamin F tryptophan calcium solutioninto the 2-hydroxypropyl- β -cyclodextrin solution under rapid stirring until the solution is completely dissolved and the inclusion is finished.
2. Preparing dextran-40 into 6% solution with appropriate amount of water for injection, mixing with the mixed solution obtained in step 1, stirring, adding water for injection to reach a total volume of about 2500ml, adding 25-50 g of activated carbon for injection, sealing with a stainless steel barrel, sterilizing at 121 deg.C for 20 min, cooling to 65 + -5 deg.C, filtering while hot, and filtering with a sterilized 0.8 μm and 0.22 μm double-layer filter membrane. The filtrate is cooled to room temperature, the total volume is adjusted to 2500ml by sterilized water for injection at 20 ℃, and the pH value is adjusted to 5.5-7.0 by 8% sodium hydroxide solution. Subpackaging into 1000 pieces, half adding stopper, freeze drying in freeze dryer at-35 deg.C to 30 deg.C and 50Pa-2Pa until water content is less than or equal to 2%, pressing stopper under vacuum, and capping in sterile room.
All the production operations are in accordance with the drug production quality management standard.
The vitamin F calcium tryptophan in this embodiment is replaced with vitamin F magnesium tryptophan, vitamin F ferrous tryptophan, and vitamin F zinc tryptophan, or vitamin F calcium tyrosine, vitamin F magnesium tyrosine, vitamin F ferrous tyrosine, and vitamin F zinc tyrosine, and the freeze-dried injection of the corresponding vitamin F amino acid metal ion double salt can be prepared according to the formula and preparation method of this embodiment.
The product of the invention passes oral and injection tests of mice, and no abnormal reaction is found to prove that no acute or chronic toxicity exists.
The beneficial effects of the product of the invention are verified by animal experiments.
The test animal is a mouse, and the control drug is evening primrose oil capsule (500mg, vitamin F7-10%). Three representative disease species of hyperlipidemia, atherosclerosis and hyperglycemia are selected as test disease species.
The comparative data are as follows:
[ COMPARATIVE TEST 1]FOR REDUCING BLOOD-LIPID
| Number of mice | Number of effect | Effective number | Total effective rate | Number of diarrhea | Rate of adverse reactions | |
| Control | 50 | 21 | 17 | 76％ | 24 | 48％ |
| 1 | 50 | 28 | 14 | 84％ | 12 | 24％ |
| 2 | 50 | 30 | 15 | 90％ | 14 | 28％ |
| 3 | 50 | 32 | 14 | 92％ | 8 | 16％ |
| 4 | 50 | 35 | 12 | 94％ | 9 | 18％ |
| 5 | 50 | 38 | 9 | 94％ | 3 | 6％ |
| 6 | 50 | 39 | 10 | 98％ | 4 | 8％ |
1. 0.2g of vitamin F calcium tryptophan tablet, the content of which is more than 90 percent of the marked amount;
2. 0.5g of vitamin F calcium tryptophan tablet, the content of which is more than 90 percent of the marked amount;
3. 0.2g of vitamin F tryptophan calcium oral enteric-coated capsule, the content of which is more than 90 percent of the marked amount;
4. 0.5g of vitamin F tryptophan calcium oral enteric-coated capsule, the content of which is more than 90 percent of the marked amount;
5. vitamin F tryptophan calcium freeze-dried injection, 20mg, the content is more than 90% of the marked amount;
6. the vitamin F tryptophan calcium freeze-dried injection has the content of 100mg and the labeled amount of more than 90 percent.
[ COMPARATIVE TEST 2]FOR TREATING ASTHROMOSIS
| Number of mice | Number of effect | Effective number | Total effective rate | Number of diarrhea | Rate of adverse reactions | |
| Control | 50 | 18 | 20 | 76％ | 25 | 50％ |
| 1 | 50 | 16 | 24 | 80％ | 11 | 22％ |
| 2 | 50 | 17 | 25 | 84％ | 12 | 24％ |
| 3 | 50 | 18 | 25 | 86％ | 10 | 20％ |
| 4 | 50 | 19 | 25 | 88％ | 12 | 24％ |
| 5 | 50 | 19 | 26 | 90％ | 4 | 8％ |
| 6 | 50 | 20 | 27 | 94％ | 5 | 10％ |
1. 0.2g of vitamin F tyrosine ferrous tablets, the content of which is more than 90 percent of the marked amount;
2. 0.5g of vitamin F tyrosine ferrous tablets, the content of which is more than 90 percent of the marked amount;
3. 0.2g of vitamin F tyrosine ferrous oral enteric capsule, the content of which is more than 90 percent of the marked amount;
4. 0.5g of vitamin F tyrosine ferrous oral enteric capsule, the content of which is more than 90 percent of the marked amount;
5. vitamin F tyrosine ferrous lyophilized injection, 20mg, the content is more than 90% of the marked amount;
6. the vitamin F tyrosine ferrous freeze-dried injection has the content of 100mg and the marked amount of more than 90 percent.
[ COMPARATIVE TEST 3]FOR REDUCING BLOOD GLYCOSE
| Number of mice | Number of effect | Effective number | Total effective rate | Number of diarrhea | Rate of adverse reactions | |
| Control | 50 | 16 | 18 | 71％ | 26 | 52％ |
| 1 | 50 | 17 | 20 | 74％ | 10 | 20％ |
| 2 | 50 | 16 | 22 | 76％ | 13 | 26％ |
| 3 | 50 | 18 | 22 | 80％ | 9 | 18％ |
| 4 | 50 | 19 | 23 | 84％ | 11 | 12％ |
| 5 | 50 | 20 | 24 | 88％ | 3 | 6％ |
| 6 | 50 | 22 | 26 | 96％ | 4 | 8％ |
1. 0.2g of vitamin F zinc tyrosine tablet, the content is more than 90 percent of the marked amount;
2. 0.5g of vitamin F zinc tyrosine tablet, the content is more than 90 percent of the marked amount;
3. 0.2g of vitamin F and zinc tyrosine oral enteric-coated capsules, the content of which is more than 90 percent of the marked amount;
4. 0.5g of vitamin F and zinc tyrosine oral enteric-coated capsules, the content of which is more than 90 percent of the marked amount;
5. vitamin F and zinc tyrosinate freeze-dried injection, 20mg, the content is more than 90% of the marked amount;
6. vitamin F and zinc tyrosinate freeze-dried injection, 100mg, the content is more than 90% of the marked amount.
Claims (8)
1. Vitamin F metallothioneinA sub-salt with the structural formula of [ R]1COO-】2·M2+，
Wherein,
M2+＝Ca2+、Mg2+、Fe2+、Zn2+。
2. a vitamin F amino acid metal ion double salt represented by formula (I) or formula (II):
wherein,
or
M2+＝Ca2+、Mg2+、Fe2+、Zn2+。
3. The vitamin F amino acid metal ion double salt according to claim 1, which is prepared from the following raw materials: 4.8 to 6.0mol of vitamin F, 4.3 to 5.0mol of acetate, 2.1 to 2.5mol of amino acid, 6800 ml of anhydrous methanol, 10000ml of isopropanol, 10000ml of water for injection and 50ml to 150ml of glacial acetic acid.
4. The vitamin F amino acid metal ion double salt according to claim 2, which is prepared by the steps of:
(1) dissolving vitamin F in anhydrous methanol, and filtering with a dipolar titanium rod filter stick;
(2) weighing acetate, adding appropriate amount of sterile water for injection, adding glacial acetic acid, stirring, dissolving completely, filtering with dipolar titanium filter stick, injecting the filtrate into the solution obtained in step 1, stirring and cooling to room temperature, adjusting pH to 5.0-7.5, stopping stirring when crystal is separated out, cooling to-15 + -5 deg.C, crystallizing completely, vacuum filtering with G3 sand core funnel, washing crystal with anhydrous methanol below-15 deg.C, draining, and storing at-15 + -5 deg.C;
(3) weighing amino acid, adding sterilized water for injection preheated to 50 ℃ for dissolving, adding the vitamin F metal ion complex salt prepared in the step 2 for dissolving, adding active carbon for injection, stirring, filtering with a titanium rod in a two-stage manner, adding the filtrate into isopropanol filtered by the titanium rod, slowly stirring, regulating the pH value to 5.5-9.0 at room temperature, stirring until crystal is separated out, stopping stirring, cooling to-10 +/-5 ℃ for complete crystallization, filtering with a G3 sand core funnel, washing the crystal with isopropanol filtered by the titanium rod at-10 ℃, draining, and vacuum drying at-10 to-4 ℃ until the isopropanol is completely drained.
5. An oral solid preparation of vitamin F amino acid metal ion double salt is characterized by being prepared from the following formula:
the formula is 0.2-0.3 g/tablet and 0.4-0.5 g/tablet
2-3Kg of vitamin F, amino acid and metal ion double salt and 4-5Kg of vitamin F
Pulping dry starch (15% concentration) 100-
Sucrose powder 14-21g 28-35g
15-23g and 30-38g of polyvinylpyrrolidone
Additionally added with 160-265-330 g of dry starch
6-9g of magnesium lauryl sulfate and 10-13g of magnesium laurylsulfate
3-5g of micro silica gel powder and 5-6.5g of micro silica gel powder.
6. The oral solid preparation of a vitamin F amino acid metal ion double salt according to claim 4, which is prepared by the steps of:
(1) crushing the vitamin F amino acid metal ion double salt, sieving the crushed vitamin F amino acid metal ion double salt with a 100-mesh sieve, sieving the starch with the 100-mesh sieve, making the starch into 15% paste, and dissolving sucrose powder in the paste;
(2) placing vitamin F amino acid metal ion double salt and the starch slurry prepared in the step 1 into a mixing stirrer to be stirred to prepare a soft material, sieving the soft material by a swing granulator through a sieve of 12-14 meshes to granulate, and drying wet granules in a boiling dryer at 50-60 ℃;
(3) mixing the dry granules prepared in the step 2 with magnesium lauryl sulfate, micro silica gel powder, polyvinylpyrrolidone and additional dry starch, granulating, and pressing into tablets by flat die; or making into capsule with enteric capsule.
7. A freeze-dried injection of the compound salt of amino acid and metal ions of vitamine F is prepared from the compound salt of amino acid and metal ions of vitamine F (20-100 wt.%), 2-hydroxypropyl- β -cyclodextrin (20-120), dextran-4040-60 and water for injection (2500).
8. The freeze-dried injection of vitamin F amino acid metal ion double salt according to claim 6, characterized in that it is prepared by the following steps:
(1) dissolving vitamin F amino acid metal ion double salt with a proper amount of water for injection to form a nearly saturated solution, preparing 2-hydroxypropyl- β -cyclodextrin into a 60-75% solution with the water for injection, and dropwise adding the vitamin F amino acid metal ion double salt solution into the 2-hydroxypropyl- β -cyclodextrin solution under rapid stirring until complete dissolution and complete inclusion;
(2) preparing dextran-40 into 6% solution with appropriate amount of water for injection, mixing with the mixed solution obtained in the step 1, stirring uniformly, adding water for injection to reach a total volume of 2500ml, adding activated carbon for injection, sealing, performing moist heat sterilization for 20 minutes, cooling to 65 +/-5 ℃, filtering with a hot double-layer filter membrane, cooling the filtrate to room temperature, adjusting the volume with water for injection, adjusting the pH value to 5.5-7.0 with 8% sodium hydroxide solution, subpackaging, half plugging, freeze-drying at-35 ℃ to-30 ℃ and 50Pa-2Pa until the water content is less than or equal to 2%, plugging under vacuum, and capping.
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