CN103271879B - Stable fructose composition preparation and preparation method thereof - Google Patents
Stable fructose composition preparation and preparation method thereof Download PDFInfo
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- CN103271879B CN103271879B CN201210566723.9A CN201210566723A CN103271879B CN 103271879 B CN103271879 B CN 103271879B CN 201210566723 A CN201210566723 A CN 201210566723A CN 103271879 B CN103271879 B CN 103271879B
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- fructose
- glycerol
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- water
- injection
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- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 title claims abstract description 120
- 239000005715 Fructose Substances 0.000 title claims abstract description 89
- 229930091371 Fructose Natural products 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 239000000203 mixture Substances 0.000 title claims abstract description 23
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 119
- 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 abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000002347 injection Methods 0.000 claims abstract description 28
- 239000007924 injection Substances 0.000 claims abstract description 28
- 239000000843 powder Substances 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 16
- 238000004108 freeze drying Methods 0.000 claims abstract description 10
- 239000008215 water for injection Substances 0.000 claims description 16
- 239000002131 composite material Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 12
- 239000012982 microporous membrane Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 4
- LKDRXBCSQODPBY-ZXXMMSQZSA-N alpha-D-fructopyranose Chemical compound OC[C@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-ZXXMMSQZSA-N 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims 2
- 239000012467 final product Substances 0.000 claims 1
- 235000011187 glycerol Nutrition 0.000 abstract description 32
- 239000003814 drug Substances 0.000 abstract description 16
- 238000005516 engineering process Methods 0.000 abstract description 12
- -1 fructose glycerin compound Chemical class 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 229960002737 fructose Drugs 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 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 4
- 230000000694 effects Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FXLJDRXREUZRIC-BAOOBMCLSA-N (3s,4r,5r)-1,3,4,5,6-pentahydroxyhexan-2-one;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO FXLJDRXREUZRIC-BAOOBMCLSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- XOHUEYCVLUUEJJ-UHFFFAOYSA-N 2,3-Bisphosphoglyceric acid Chemical compound OP(=O)(O)OC(C(=O)O)COP(O)(O)=O XOHUEYCVLUUEJJ-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- LKDRXBCSQODPBY-VRPWFDPXSA-N D-fructopyranose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-VRPWFDPXSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000001105 Phosphofructokinases Human genes 0.000 description 1
- 108010069341 Phosphofructokinases Proteins 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 235000019846 buffering salt Nutrition 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000006567 cellular energy metabolism Effects 0.000 description 1
- 229940107161 cholesterol Drugs 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940021171 curative drug Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to belongs to the field of medicament synthesis and preparation thereof, and relates to the stable fructose composition preparation and preparation method thereof. Aseptic beta-fructose is suspended in water, and aseptic fructose is added for adjusting pH for dissolving the aseptic beta-fructose totally, and the aqueous solution of fructose/glycerin is obtained, and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) is added into the aqueous solution for clathration, and after package and freeze drying, the fructose powder injection for injection is obtained. The preparation method provided by the invention is simple, and the fructose glycerin compound is clathrated by hydroxypropyl-beta-cyclodextrin, thereby the water-solubility and stability of fructose medicament are increased, and the biological availability of the medicament is improved; the preparation technology is simple and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of energy and body fluid supplement medicine and preparation method thereof, particularly a kind of stable fructose composite and preparation method thereof, belongs to field of medicine preparations.
Background technology
Fructose, chemical name is: D-(-)-fructopyranose, molecular formula: C
6h
12o
6, molecular weight: 180.16.A kind of clinically as the intermediate product in glucose metabolism process, ectogenic fructose diphosphate can act on cell membrane, by the phosphofructokinase on active cell film, increase the concentration of the interior energy-rich phosphate bond of cell and adenosine triphosphate, thereby stream in promotion potassium ion, recover cell quiescent condition, increase the content of diphosphoglyceric acid in erythrocyte, suppress oxygen-derived free radicals and histamine releasing, be of value to shock, ischemia, anoxia, tissue injury, extracorporeal circulation, cellular energy metabolism under the states such as blood transfusion and the utilization to glucose, play and promote to repair, improve the effect of cell function.Numerous relevant its safely and effectively data all prove, clinical efficacy is high, toxic and side effects is low, anaphylaxis is few, can be widely used in the control of clinical various infectious disease.
In the fructose dosage form of listing, be at present aseptic subpackaged, when clinical use, dissolve again, preparation adopts common production technology to make.But these fructose injections are all the time in aqueous solution state, be produce or storing process in vibration and illumination under be all easy to oxidation Decomposition, particularly more easily be oxidized and be hydrolyzed when high temperature sterilize, causing patient to occur the infusion reactions such as urticaria, being unfavorable for its extensive life-time service.In addition, because this product is unstable to temperature, illumination, humidity, when use, easily produce precipitation, in production and transport, use, very easily cause mass change, increased the insecurity of clinical application.
Chinese patent literature CN1608674A discloses compound fructose injection, comprises fructose and the curative drug without incompatibility.Patent documentation CN1650873A discloses the fructose injection of being prepared by aseptic powder.In patent documentation CN1602881A, introduce a kind of preparation method of fructose for injection, formed by fructose and mannitol, mix aseptic subpackaged making, the fructose injection in these patent documentations is equally all to adopt common formula and production technology, does not fundamentally solve its stability problem.
Someone attempts fructose to be prepared into Liposomal formulation, for example, CN200910230315 discloses a kind of levulose liposome preparation, and said preparation has fructose, soybean lecithin, cholesterol, PLURONICS F87, osmotic pressure regulator and the preparation of buffering salt to form, and CN2009101419647 discloses a kind of glycerol fructose liposome preparation, said preparation is by 2 parts of glycerol, 1 part, fructose, phosphatidase 15～20 part, 1.5～2 parts, cholesterol, 1～1.5 part of NaTDC, 0.1～0.5 part, sodium chloride is prepared from.Fructose is prepared into Liposomal formulation, not only prescription is complicated, wherein contain the adjuvant of multiple large usage quantity, increase impurity content in medicine, increase pharmacy cost, and to use the organic solvents such as chloroform in the preparation process of said preparation, and in subsequent treatment, be difficult to thoroughly remove, cause said preparation industrially to utilize.Country not yet ratifies the production permit of any levulose liposome preparation at present.
Urgent need development is a kind of can having good stability of industrialization utilization be suitable for the fructose pharmaceutical preparation of clinical use.
Summary of the invention
In order to overcome the deficiencies in the prior art, solve prior art and prepare fructose injection poor stability, being placed with for a long time related substance increases a lot, pH value alters a great deal, the problem of the prescription in the time can not satisfy the prescriptive period, the invention provides a kind of stable fructose composite preparation and preparation method thereof, solve above problem, for the use of fructose for injection provides technical support more reliably, improve the clinical drug safety of fructose injection, and extended storage time of injection, be conducive to industrialized mass.
The present invention seeks to by fructose and glycerol are prepared into fructose glycerol complex, thereby be then coated and prepared stable fructose injection by HP-β-CD, particularly, technical solution of the present invention is as follows:
An object of the present invention is to provide that a kind of prescription and preparation technology are simple, steady quality, medicinal fructose composition that can preservation steady in a long-term.Medicinal fructose composition of the present invention only contains β-fructose, glycerol and HP-β-CD (HP-β-CD).
Further preferably, the component that medicinal fructose composition of the present invention contains following weight proportion:
β-fructose 1～2
Glycerol 0.5～1
HP-β-CD (HP-β-CD) 1～4
Preferably, the component that medicinal fructose composition of the present invention contains following weight proportion:
β-fructose 1～1.5
Glycerol 0.5～0.8
HP-β-CD (HP-β-CD) 1～3
Further preferably, the component that medicinal fructose composition of the present invention contains following weight proportion:
β-fructose 1～1.2
Glycerol 0.5～0.7
HP-β-CD (HP-β-CD) 1～2
Most preferably, the component that medicinal fructose composition of the present invention contains following weight proportion:
β-fructose 1～1.2
Glycerol 0.5～0.6
HP-β-CD (HP-β-CD) 1～1.8
Still more preferably, the component that medicinal fructose composition of the present invention contains following weight proportion:
β-fructose 1
Glycerol 0.6
HP-β-CD (HP-β-CD) 1
Or:
β-fructose 1
Glycerol 0.75
HP-β-CD (HP-β-CD) 1.5
The hydroxyl that one end opening part in beta-schardinger dextrin-(β-CD) molecule hole has C2 on glucose molecule, C3 to link, other end opening is the hydroxyl that C6 links, so, the two ends of tubular structure are hydrophilic, and its hole have glucosyl group oxo bridge and-CH-group, therefore be hydrophobic in hole.Some sizeable drug molecules, often by Van der Waals force, form inclusion complex by its inclusion in hydrophobic region.HP-β-CD (HP-β-CD) is that beta-schardinger dextrin-(β-CD) obtains polytype CD in alkaline aqueous solution with ethylene chlorhydrin condensation.HP-β-CD tool safe dose is large, good with blood compatibility, do not change drug effect, increase the feature such as water solublity, stability of medicine, is considered to more promising drug carrier material.The coated active component fructose of HP-β-CD for pharmaceutical composition of the present invention, prepares the stable fructose pharmaceutical preparation that formulation and technology is simplified.
Medicinal fructose composition of the present invention is ejection preparation, and this ejection preparation comprises injection and lyophilized injectable powder.Therefore, fructose composite of the present invention must use water for injection in preparation process, and the consumption of water for injection is not particularly limited, and determines corresponding water for injection use amount according to product specification.If lyophilized injectable powder, the composition of above-mentioned composition refers to that said preparation is the composition content of lyophilized injectable powder, now, and by due to factors such as techniques, it is also understandable in final preparation, existing pharmacy to allow the water of content, for example, in preparation, may contain the water of weight percentage 0～6%.If said preparation is injection, the weight ratio of fructose and water for injection changes in 1: 5～100 scope, preferably 1: 10～80, more preferably 1: 10-50, further preferably 1: 15～50.If final preparation is lyophilized injectable powder, the water for injection using in preparation process also changes in above-mentioned scope.
Another object of the present invention is to provide a kind of preparation method of described medicinal fructose composition, the method is directly suspended in aseptic β-fructose in water for injection, add aseptic glycerol to regulate pH value, it is all dissolved, obtain the aqueous solution of fructose/glycerol, in this aqueous solution, add HP-β-CD (HP-β-CD) to carry out enclose, through subpackage, obtain fructose injection compositions of the present invention, if need, injection lyophilization obtained to fructose for injection lyophilized injectable powder compositions.
Preparation method of the present invention, adopts inclusion technique to prepare stable fructose/glycerin compositions, comprises the steps:
1) in room temperature downhill reaction still, add aseptic β-fructose to be suspended in water for injection; Add aseptic glycerol to regulate pH value, it is all dissolved, obtain the aqueous solution of fructose/glycerol; Add completely, regulate pH value 5～7, preferably 6～7; Wherein the weight of aseptic β-fructose is in C13H17N5O8S2.
2) react and in backward reactor, add HP-β-CD (HP-β-CD), stirring at room temperature enclose 0.5～2.0 hour; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally, by the filtering with microporous membrane of 0.22 μ m, subpackage, obtains fructose for injection freeze-dried powder through lyophilization.
Preferably, described step 2) stirring at room temperature enclose 0.5～2.0 hour, preferably 1.0～1.5 hours;
The present invention directly suspends in water aseptic β-fructose, adds aseptic glycerol to regulate pH value, and it is all dissolved, obtain the aqueous solution of fructose/glycerol, in this aqueous solution, add HP-β-CD (HP-β-CD) to carry out enclose, through subpackage, lyophilization obtains fructose for injection.The preparation method that this invention provides is simple, and fructose glycerol complex, after HP-β-CD enclose, increases water solublity and the stability of aseptic β-fructose medicine, has reduced its toxic and side effects, has improved drug utilization degree.
Detailed description of the invention
Below in conjunction with embodiment and test example, the present invention will be further described, but be not limited to this.
Embodiment 1:
Preparation technology:
In room temperature downhill reaction still, add aseptic β-fructose to be suspended in water for injection; Add aseptic glycerol to regulate pH value, it is all dissolved, obtain the aqueous solution of fructose/glycerol; .Add complete, regulate pH value 6.0 β-fructose is all dissolved; In reactor, add HP-β-CD (HP-β-CD), stir enclose 1.0 hours; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally, by the filtering with microporous membrane of 0.22 μ m, subpackage, obtains fructose for injection freeze-dried powder through lyophilization.
Embodiment 2:
Preparation technology:
In room temperature downhill reaction still, add aseptic β-fructose to be suspended in water for injection; Add aseptic glycerol to regulate pH value, it is all dissolved, obtain the aqueous solution of fructose/glycerol; .Add complete, regulate pH value 6.5 aseptic β-fructose is all dissolved; In reactor, add HP-β-CD (HP-β-CD), stir enclose 1.5 hours; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally, by the filtering with microporous membrane of 0.22 μ m, subpackage, obtains fructose injection.
Embodiment 3:
Preparation technology:
In room temperature downhill reaction still, add aseptic β-fructose to be suspended in water for injection; Add aseptic glycerol to regulate pH value, it is all dissolved, obtain the aqueous solution of fructose/glycerol; .Add complete, regulate pH value 7.0 aseptic β-fructose is all dissolved; In reactor, add HP-β-CD (HP-β-CD), stir enclose 2.0 hours; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally, by the filtering with microporous membrane of 0.22 μ m, subpackage, obtains fructose for injection freeze-dried powder through lyophilization.
Embodiment 4:
Preparation technology:
In room temperature downhill reaction still, add aseptic β-fructose to be suspended in water for injection; Add aseptic glycerol to regulate pH value, it is all dissolved, obtain the aqueous solution of fructose/glycerol; .Add complete, regulate pH value 5.0 aseptic β-fructose is all dissolved; In reactor, add HP-β-CD (HP-β-CD), stir enclose 1.5 hours; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally, by the microporous filter membrane fine straining of 0.22 μ m, subpackage, obtains fructose for injection freeze-dried powder through lyophilization.
Embodiment 5:
Preparation technology:
In room temperature downhill reaction still, add aseptic β-fructose to be suspended in water for injection; Add aseptic glycerol to regulate pH value, it is all dissolved, obtain the aqueous solution of fructose/glycerol; .Add complete, regulate pH value 5.5 aseptic β-fructose is all dissolved; In reactor, add HP-β-CD (HP-β-CD), stir enclose 2.0 hours; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally, by the microporous filter membrane fine straining of 0.22 μ m, subpackage, obtains fructose for injection freeze-dried powder through lyophilization.
Test example: (stability experiment)
1, comparative example 1:: commercially available sample fructose for injection (ChongQing LaiMei Pharmacy Co., Ltd produces, lot number 20101006)
2, comparative example 2: the method according to Chinese patent literature 2009101419647 embodiment 1 is prepared fructose preparation, as a comparison case.
3, influence factor: sample is placed in respectively to room temperature (25 DEG C), high temperature (60 DEG C), relative humidity 75%, under six kinds of conditions of relative humidity 92.5% and illumination 4500Lx.
4, investigate result: investigate indices in sampling in the 5th day, 10 days, and taking 0 day result as contrast, the results are shown in following table 1: factors influencing result
Table 1: factors influencing result
The product of above 1～5 embodiment is examined entirely according to the quality standard WS-1035 of fructose freeze-dried powder State Food and Drug Administration (X-775)-2002, be the results are shown in Table 1.
Table 2 fructose freeze-dried powder assay
The fructose freeze-dried powder quality that result: embodiment 1～5 produces all meets the requirements.
To above embodiment 1～4 product according to fructose injection state quality standard WS
1-(X-029)-2003Z examines entirely, the results are shown in Table 3.
Table 3 fructose liquid drugs injection assay
The fructose water acanthin amount that result: embodiment 1～4 produces all meets the requirements.
According to two annex XIX C medicine stability test guidelines of Chinese Pharmacopoeia version in 2005, the sample of producing by the embodiment of the present invention 1～5 is carried out to long-time stability investigation.
Get fructose freeze-dried powder, place in room temperature by commercially available back, respectively at 0,3,6,9,12,18,24,36 sampling at the end of month, the projects such as character, acidity, visible foreign matters, particulate matter, related substance and content are measured, result is as table 4.
Table 4 fructose freeze-dried powder long-term stable experiment measurement result
Result shows, embodiment 1～6 places 36 months under long-term storage requirement, except acidity declines to some extent, related substance increases to some extent, outside content declines to some extent, but in scope, meet the requirement of drug standard, but just there is place against regulation in comparative example product, cannot meet industrialization demand after preserving 9 months.
As seen from the above table, sample of the present invention and control sample contrast are known, under the condition of 25 DEG C of room temperatures, 60 DEG C of high temperature, relative humidity 75%, relative humidity 92.5% and illumination 4500Lx, place 5 days, 10 days, and sample indices of the present invention is without significant change; Control sample related substance slightly raises, and under 60 DEG C of conditions of high temperature, related substance raises very fast, therefore fructose glycerol complex is after HP-β-CD enclose, the stability that increases fructose medicine, has reduced its toxic and side effects, has improved drug utilization degree, and preparation technology is simple, be applicable to suitability for industrialized production.
Content disclosed according to the present invention, those skilled in the art can apply the present invention to greatest extent.Therefore, above-mentioned preferred embodiment only illustrates, but not limits the scope of the invention by any way.
Claims (9)
1. a fructose composite, it is characterized in that said composition HP-β-CD is coated fructose glycerol complex, and be to inject by the component of following weight proportion the fructose lyophilized injectable powder that water is prepared from according to described method: β-fructose: glycerol: HP-β-CD=1:0.5～1:1～4, described method comprises the steps:
1) under room temperature, in reactor, aseptic β-fructose is suspended in water for injection; Add aseptic glycerol, regulate pH value, add complete, regulate pH value 5～7; It is all dissolved, obtain the aqueous solution of fructose/glycerol;
2) react in backward reactor and add HP-β-CD, stirring at room temperature enclose 0.5～2.0 hour; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally by the microporous filter membrane fine straining of 0.22 μ m, by gained filtrate through lyophilization and get final product.
2. according to the fructose composite of claim 1, it is characterized in that said composition injects water by the component of following weight proportion and is prepared from:
β-fructose: glycerol: HP-β-CD=1:0.5～0.8:1～3.
3. according to the fructose composite of claim 2, it is characterized in that the weight proportion of each component is
β-fructose: glycerol: HP-β-CD=1:0.7:1.2.
4. according to the fructose composite of claim 2, it is characterized in that the weight proportion of each component is:
β-fructose: glycerol: HP-β-CD=1:0.6:1.
5. according to the fructose composite of any one in claim 1 to 4, wherein the weight proportion of fructose and water for injection is 1: 5～100.
6. fructose composite according to claim 5, wherein the weight proportion of fructose and water for injection is 1: 10～50.
7. the preparation method of the fructose composite of any one in claim 1-6, is characterized in that the method comprises the steps:
1) under room temperature, in reactor, aseptic β-fructose is suspended in water for injection; Add aseptic glycerol, regulate pH value, add complete, regulate pH value 5～7; It is all dissolved, obtain the aqueous solution of fructose/glycerol;
2) react in backward reactor and add HP-β-CD, stirring at room temperature enclose 0.5～2.0 hour; Inject and be diluted with water to required mass concentration, then use the filtering with microporous membrane of 0.45 μ m, finally, by the microporous filter membrane fine straining of 0.22 μ m, gained filtrate obtained to fructose for injection freeze-dried powder through lyophilization.
8. the preparation method of fructose composite according to claim 7, is characterized in that described step 1) adjusting pH value to 6～7.
9. the preparation method of fructose composite according to claim 7, is characterized in that described step 2) stirring at room temperature enclose 1.0～1.5 hours.
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