CN101491499A - Composite liposome for injection containing 12 vitamins and preparation method thereof - Google Patents
Composite liposome for injection containing 12 vitamins and preparation method thereof Download PDFInfo
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- CN101491499A CN101491499A CNA2009100142533A CN200910014253A CN101491499A CN 101491499 A CN101491499 A CN 101491499A CN A2009100142533 A CNA2009100142533 A CN A2009100142533A CN 200910014253 A CN200910014253 A CN 200910014253A CN 101491499 A CN101491499 A CN 101491499A
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- vitamin
- acid
- preparation
- liposome
- cholecalciferol
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- 229940088594 vitamin Drugs 0.000 title claims abstract description 51
- 229930003231 vitamin Natural products 0.000 title claims abstract description 51
- 235000013343 vitamin Nutrition 0.000 title claims abstract description 51
- 239000011782 vitamin Substances 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000002502 liposome Substances 0.000 title claims abstract description 22
- 238000002347 injection Methods 0.000 title description 2
- 239000007924 injection Substances 0.000 title description 2
- 239000002131 composite material Substances 0.000 title 1
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims abstract description 22
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 22
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 22
- 108010007979 Glycocholic Acid Proteins 0.000 claims abstract description 14
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 claims abstract description 14
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims abstract description 14
- 229940099347 glycocholic acid Drugs 0.000 claims abstract description 14
- 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 claims abstract description 12
- 239000011665 D-biotin Substances 0.000 claims abstract description 11
- 235000000638 D-biotin Nutrition 0.000 claims abstract description 11
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims abstract description 11
- 229940087168 alpha tocopherol Drugs 0.000 claims abstract description 11
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 11
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 11
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 11
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 claims abstract description 11
- 239000011724 folic acid Substances 0.000 claims abstract description 11
- 235000019152 folic acid Nutrition 0.000 claims abstract description 11
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011764 pyridoxine hydrochloride Substances 0.000 claims abstract description 11
- 229960004172 pyridoxine hydrochloride Drugs 0.000 claims abstract description 11
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 claims abstract description 11
- 229950001574 riboflavin phosphate Drugs 0.000 claims abstract description 11
- 229940083466 soybean lecithin Drugs 0.000 claims abstract description 11
- 229960000984 tocofersolan Drugs 0.000 claims abstract description 11
- 239000011647 vitamin D3 Substances 0.000 claims abstract description 11
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims abstract description 11
- 235000005282 vitamin D3 Nutrition 0.000 claims abstract description 11
- 229940021056 vitamin d3 Drugs 0.000 claims abstract description 11
- 239000002076 α-tocopherol Substances 0.000 claims abstract description 11
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 claims abstract description 10
- 239000011703 D-panthenol Substances 0.000 claims abstract description 10
- 235000004866 D-panthenol Nutrition 0.000 claims abstract description 10
- 229960003949 dexpanthenol Drugs 0.000 claims abstract description 10
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 20
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 20
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 18
- -1 compound vitamin Chemical class 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 10
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 10
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims description 10
- 229960000304 folic acid Drugs 0.000 claims description 10
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 10
- 230000036571 hydration Effects 0.000 claims description 10
- 238000006703 hydration reaction Methods 0.000 claims description 10
- 230000006340 racemization Effects 0.000 claims description 10
- 229960003471 retinol Drugs 0.000 claims description 10
- 235000020944 retinol Nutrition 0.000 claims description 10
- 239000011607 retinol Substances 0.000 claims description 10
- 235000020955 thiamine monophosphate Nutrition 0.000 claims description 10
- 239000011621 thiamine monophosphate Substances 0.000 claims description 10
- 235000004835 α-tocopherol Nutrition 0.000 claims description 10
- 239000004471 Glycine Substances 0.000 claims description 9
- 239000001508 potassium citrate Substances 0.000 claims description 9
- 229960002635 potassium citrate Drugs 0.000 claims description 9
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 9
- 235000011082 potassium citrates Nutrition 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000012982 microporous membrane Substances 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 229960004756 ethanol Drugs 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 239000011265 semifinished product Substances 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- 238000004659 sterilization and disinfection Methods 0.000 claims description 3
- 239000008215 water for injection Substances 0.000 claims description 3
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 abstract 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 abstract 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 abstract 1
- KLOLNRGPRQYTIW-UHFFFAOYSA-N [2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethoxy-hydroxyphosphoryl] hydrogen phosphate;tetrahydrate Chemical compound O.O.O.O.CC1=C(CCOP(O)(=O)OP(O)([O-])=O)SC=[N+]1CC1=CN=C(C)N=C1N KLOLNRGPRQYTIW-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 239000011666 cyanocobalamin Substances 0.000 abstract 1
- 229960002104 cyanocobalamin Drugs 0.000 abstract 1
- 235000000639 cyanocobalamin Nutrition 0.000 abstract 1
- 229940064302 folacin Drugs 0.000 abstract 1
- 229960003966 nicotinamide Drugs 0.000 abstract 1
- 239000011570 nicotinamide Substances 0.000 abstract 1
- 235000005152 nicotinamide Nutrition 0.000 abstract 1
- 229940108325 retinyl palmitate Drugs 0.000 abstract 1
- 235000019172 retinyl palmitate Nutrition 0.000 abstract 1
- 239000011769 retinyl palmitate Substances 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 150000003904 phospholipids Chemical group 0.000 description 3
- GUGWNSHJDUEHNJ-UHFFFAOYSA-N thiamine(1+) monophosphate chloride Chemical compound [Cl-].CC1=C(CCOP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N GUGWNSHJDUEHNJ-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a liposome lyophilized preparation prepared from twelve compound vitamins. The lyophilized preparation is characterized in that the lyophilized preparation is prepared from a liposome which consists of soybean lecithin and glycocholic acid and is encapsulated with twelve vitamins of retinyl palmitate, cocarboxylase tetrahydrate, riboflavin sodium phosphate, pyridoxine hydrochloride, cyanocobalamin, cholecalciferol, ascorbic acid, racemization-alpha tocopherol, D-biotin, niacinamide, folacin and dexpanthenol.
Description
Technical field
The present invention relates to 12 kinds of compound vitamin lipidosome freeze-dried preparations and preparation method thereof.
Background technology
Vitamin has another name called vitamin, is to keep the essential type organic matter of human life activity, also is the important active substances that keeps health.Vitamin content in vivo seldom but plays an important role in people's bulk-growth, metabolism, growth course, can cause dysbolismus during shortage, and cause multiple disease.
The vitamin preparation of domestic production at present is mostly with the separate constituent administration, Cernevit-12 is less, and dosage form mostly is tablet and capsular oral formulations, has limited the absorption of human body to different vitamin greatly, cause the medication trouble, also may influence drug safety.The Cernevit-12 that comprises water soluble vitamins and fatsoluble vitamin can make human body absorb required vitamin comprehensively, has overcome the effect limitation of single vitamin, is easilier accepted by the patient.
Yet most of vitamin are all unstable, very easily oxidation, and it is rotten to see that light easily decomposes, and loses efficacy after the long term storage, when the preparation that prior art discloses contains the dosage form of water soluble vitamins and fatsoluble vitamin, also causes vitamin to decompose easily, influences its curative effect.Therefore, adopt a kind of new method to prepare Cernevit-12 and become current pressing for.
Prior art CN200610054218.0 discloses the method that a kind of system contains multivitamin lyophilized formulations, and aqueous solution vitamin and fatsoluble vitamin are to mix with adjuvant earlier, do not form liposome, are unfavorable for the stability of final products.Preparation method of the present invention is different with it, by wrapping up vitamin with liposome, and adopts specific buffer system, verified its stability of further raising.
Summary of the invention
At vitamin stability is poor mostly at present, there is the defective of unicity and quality problems, the invention provides a kind of compound vitamin lipidosome freeze-dried preparation and preparation method thereof, by wrapping up, solved stability problem and improved its curative effect with liposome.
The present invention adopts following technical scheme: a kind of compound vitamin lipidosome freeze-dried preparation is the complex vitamin freeze-dried preparation of being made by soybean lecithin and the formed liposomal encapsulated 12 kinds of vitamin of glycocholic acid.
12 kinds of vitamin are to be selected from retinol cetylate, four hydration thiamine monophosphates, riboflavin sodium phosphate, Pyridoxine Hydrochloride, cobalamin, cholecalciferol, ascorbic acid, racemization alpha-tocopherol, D-biotin, nicotiamide, folic acid, Dexpanthenol.
The weight proportion for preparing required above each component of 1000 bottles of unit dosage forms is:
The retinol cetylate 280～4,200,000 nicotiamide 41.4～50.6g of unit
Four hydration thiamine monophosphates, 5.22～6.38g folic acid, 332～496mg
Riboflavin sodium phosphate 5.10～6.24g Dexpanthenol 14.54～17.77mg
Pyridoxine hydrochloride 4.95～6.05g soybean lecithin 100～150g
Cobalamin 4.8～7.2mg glycocholic acid 110～170g
The cholecalciferol 17.6 ten thousand citric acid 5～60g of unit
Ascorbic acid 112.5～137.5g potassium citrate 5～60g
Racemization alpha-tocopherol 9.18～11.22g glycine 200～300g
D-biotin 55.2～82.5mg
The solution of citric acid and potassium citrate constitutes preferred buffer system.
Glycine is as preferred frozen-dried supporting agent.
The present invention also provides a kind of method for preparing above-mentioned 12 kinds of compound vitamin lipidosome freeze-dried preparations, it is characterized in that comprising the steps:
(1) take by weighing soybean lecithin, glycocholic acid, make its dissolving with an amount of chloroform, mix homogeneously is removed chloroform with the solution decompression that forms then, the preparation lipid film;
(2) secure ph is 6.0～8.0 the citric acid and the buffer of potassium citrate, this buffer is joined in the lipid film of system in the step (1), treat its complete aquation after, be equipped with liposome with homogenate mechanism, standby;
(3) take by weighing 12 kinds of vitamin, nicotiamide, four hydration thiamine monophosphates, folic acid, riboflavin sodium phosphate, Dexpanthenol, pyridoxine hydrochloride, cobalamin, ascorbic acid, D-biotin are dissolved in water for injection, retinol cetylate, cholecalciferol, racemization alpha-tocopherol are dissolved in dehydrated alcohol, with aqueous solution and ethanol solution respectively after the filtering with microporous membrane degerming, mix homogeneously is at 50～60 ℃ of water bath heat preservations;
(4) liposome that makes in the step (2) is joined in the vitamin solution of the preheating that step (3) makes, add glycine again, be incubated 20～30 minutes in 50～60 ℃ of water-baths, jolting frequently is then through the filtering with microporous membrane degerming;
(5), get finished product with semi-finished product lyophilizing after the filtration sterilization.
In the above-mentioned described preparation method, select the filtering with microporous membrane degerming of 0.22 μ m for use.
Liposome belongs to the novel form of microencapsulation.The main component of liposome is phospholipid and glycocholic acid, and the two all has hydrophilic and hydrophobic two kinds of groups, and its molecule space aligns that to form hydrophobic group inside, the lipoids bilayer that hydrophilic group is outside.In liposome interior is water, and water soluble drug can be encapsulated in the inside of liposome.A hydrophobic microenvironment is arranged in phospholipid bilayer, and lyophobic dust or facultative molecule can combine with the double-layer of lipoid hydrophobic group and embed in the film of liposome or insert in the liposome membrane.The solvent phospholipid of liposome is inherent composition in the organism, and nontoxic, non-immunogenicity can degradation in vivo, so liposome is one of optimum selection as pharmaceutical carrier.
Prior art CN200610054218.0 discloses the method that a kind of system contains multivitamin lyophilized formulations, earlier with soybean phospholipid and water soluble vitamins dissolve with ethanol, again the aqueous solution that makes glycocholic acid separately, two solution are mixed the aqueous solution that adds water soluble vitamins afterwards again, at last filtration, lyophilizing.In this method, Semen sojae atricolor phosphoric acid glycocholic acid uses as solubilizing agent, produces parcel vitamin micelle, does not seal vitamin fully, is easy to generate decomposition.
The present invention makes liposome earlier, again the hot mixt of water soluble vitamins and fatsoluble vitamin is sealed simultaneously, can realize sealing fully of vitamin, be more conducive to it and avoid decomposing and promoting dissolving, realize intravenously administrable, not only solved the defective of water solublity and fatsoluble vitamin administration simultaneously, also solved the simultaneous quality stability problem of multivitamin, drug action significantly improves, and toxic and side effects also reduces relatively.
The particle diameter of liposome of the present invention is between 150nm～200nm, and the medicine encapsulation ratio can reach 99.9%, and crucial equal grain step can be finished by high-pressure homogenate device efficiently in the production process, and is simple to operation, promotes the suitability for industrialized production of said preparation.
Compound vitamin Liposomal formulation provided by the invention carries out stability test and investigates, and places 10 days under 60 ℃ of high temperature, illumination 4500Lx condition, and every detection index has no significant change; Accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change; Long term test is 18 months under 25 ℃ of high temperature, relative humidity 60% ± 10% condition, and every detection index does not have significant change.Compound vitamin Liposomal formulation provided by the invention carries out acute toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof, and concrete experimental result vide infra.
The specific embodiment
1 12 kinds of compound vitamin lipidosome freeze-dried preparations of example
Prescription: the amount of 1000 bottles of required components of unit dosage forms:
The retinol cetylate 4,200,000 nicotiamide 50.6g of unit
Four hydration thiamine monophosphate 6.38g folic acid 496mg
Riboflavin sodium phosphate 6.24g Dexpanthenol 17.77mg
Pyridoxine hydrochloride 6.05g soybean lecithin 150g
Cobalamin 7.2mg glycocholic acid 170g
The cholecalciferol 26.4 ten thousand citric acid 35g of unit
Ascorbic acid 137.5g potassium citrate 60g
Racemization alpha-tocopherol 11.22g glycine 300g
D-biotin 82.5mg
Preparation technology:
(1) take by weighing soybean lecithin, glycocholic acid, make its dissolving with an amount of chloroform, mix homogeneously is removed chloroform with the solution decompression that forms then, the preparation lipid film;
(2) secure ph is 6.0～8.0 the citric acid and the buffer of potassium citrate, this buffer is joined in the lipid film of system in the step (1), treat its complete aquation after, be equipped with liposome with homogenate mechanism, standby;
(3) take by weighing 12 kinds of vitamin, nicotiamide, four hydration thiamine monophosphates, folic acid, riboflavin sodium phosphate, Dexpanthenol, pyridoxine hydrochloride, cobalamin, ascorbic acid, D-biotin are dissolved in water for injection, retinol cetylate, cholecalciferol, racemization alpha-tocopherol are dissolved in dehydrated alcohol, with aqueous solution and ethanol solution respectively after the filtering with microporous membrane degerming, mix homogeneously is at 50～60 ℃ of water bath heat preservations;
(4) liposome that makes in the step (2) is joined in the vitamin solution of the preheating that step (3) makes, add glycine again, be incubated 20～30 minutes in 50～60 ℃ of water-baths, jolting frequently is then through the filtering with microporous membrane degerming of 0.22 μ m;
(5), get finished product with semi-finished product lyophilizing after the filtration sterilization.
2 12 kinds of compound vitamin lipidosome freeze-dried preparations of example
Prescription: the amount of 1000 bottles of required components of unit dosage forms:
The retinol cetylate 2,800,000 nicotiamide 41.4g of unit
Four hydration thiamine monophosphate 5.22g folic acid 332mg
Riboflavin sodium phosphate 5.10g Dexpanthenol 14.54mg
Pyridoxine hydrochloride 4.95g soybean lecithin 100g
Cobalamin 4.8mg glycocholic acid 110g
The cholecalciferol 17.6 ten thousand citric acid 7.5g of unit
Ascorbic acid 112.5g potassium citrate 14g
Racemization alpha-tocopherol 9.18g glycine 200g
D-biotin 55.2mg
Preparation technology:
Adopt the product that makes embodiment 2 as the production method of embodiment 1.
3 12 kinds of compound vitamin lipidosome freeze-dried preparations of example
Prescription: the amount of 1000 bottles of required components of unit dosage forms:
The retinol cetylate 3,500,000 nicotiamide 46.0g of unit
Four hydration thiamine monophosphate 5.80g folic acid 414mg
Riboflavin sodium phosphate 5.67g Dexpanthenol 16.15mg
Pyridoxine hydrochloride 5.50g soybean lecithin 112.5g
Cobalamin 6.0mg glycocholic acid 140g
The cholecalciferol 22.0 ten thousand citric acid 30.8g of unit
Ascorbic acid 125.0g potassium citrate 41.6g
Racemization alpha-tocopherol 10.20g glycine 250g
D-biotin 69.0mg
Preparation technology
Adopt the product that makes embodiment 3 as the production method of embodiment 1.
Example 4 quality researches
With the product of above embodiment 1-3 and adopt the open method of CN200610054218.0 to make sample (sample A) and under 60 ℃ of high temperature, illumination 4500Lx condition, place and carried out the influence factor in 10 days and test investigation, the results are shown in Table 1 respectively; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 2; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 18 months, carry out long term test and investigate, detect the variation of every quality index, data result sees Table 3.
Table 1 influence factor result
Table 2 accelerated test result
Table 3 long-term test results
Conclusion:
Through influence factor 10 days, quicken June and long-term 18 months after, the product quality conformance with standard requirement that the present invention makes, and every quality index do not have significant change, all meets quality standard, illustrated that constant product quality of the present invention is fine; The sample A acidity that the open method of patent CN200610054218.0 makes changes greatly, and it is muddy that clarity becomes slightly, and each component content changes greatly, exceeds critical field.Illustrate that the stability of product of the present invention is higher than the product of prior art far away.
Claims (4)
1,12 kinds of compound vitamin lipidosome freeze-dried preparations are characterised in that it is by 12 kinds of lyophilized formulations that vitamin is made such as soybean lecithin and the formed liposomal encapsulated retinol cetylate of glycocholic acid, four hydration thiamine monophosphates, riboflavin sodium phosphate, Pyridoxine Hydrochloride, cobalamin, cholecalciferol, ascorbic acid, racemization alpha-tocopherol, D-biotin, nicotiamide, folic acid, Dexpanthenoies.
2, the described preparation of claim 1, the weight proportion that it is characterized in that making each required component of 1000 bottles of unit dosage forms is:
The retinol cetylate 280～4,200,000 nicotiamide 41.4～50.6g of unit
Four hydration thiamine monophosphates, 5.22～6.38g folic acid, 332～496mg
Riboflavin sodium phosphate 5.10～6.24g Dexpanthenol 14.54～17.77mg
Pyridoxine hydrochloride 4.95～6.05g soybean lecithin 100～150g
Cobalamin 4.8～7.2mg glycocholic acid 110～170g
The cholecalciferol 17.6 ten thousand citric acid 5～60g of unit
Ascorbic acid 112.5～137.5g potassium citrate 5～60g
Racemization alpha-tocopherol 9.18～11.22g glycine 200～300g
D-biotin 55.2～82.5mg
3, a kind of method for preparing the described compound vitamin lipidosome freeze-dried preparation of claim 1-2 is characterized in that comprising the steps:
(1) take by weighing soybean lecithin, glycocholic acid, make its dissolving with an amount of chloroform, mix homogeneously is removed chloroform with the solution decompression that forms then, the preparation lipid film;
(2) secure ph is 6.0～8.0 the citric acid and the buffer of potassium citrate, this buffer is joined in the lipid film of system in the step (1), treat its complete aquation after, make liposome with the homogenate machine, standby;
(3) take by weighing 12 kinds of vitamin, nicotiamide, four hydration thiamine monophosphates, folic acid, riboflavin sodium phosphate, Dexpanthenol, pyridoxine hydrochloride, cobalamin, ascorbic acid, D-biotin are dissolved in water for injection, retinol cetylate, cholecalciferol, racemization alpha-tocopherol are dissolved in dehydrated alcohol, with aqueous solution and ethanol solution respectively after the filtering with microporous membrane degerming, mix homogeneously is at 50～60 ℃ of water bath heat preservations;
(4) liposome that makes in the step (2) is joined in the vitamin solution of the preheating that step (3) makes, add glycine again, be incubated 20～30 minutes in 50～60 ℃ of water-baths, jolting frequently is then through the filtering with microporous membrane degerming;
(5), get finished product with semi-finished product lyophilizing after the filtration sterilization.
4, the preparation method of the described compound vitamin lipidosome freeze-dried preparation of claim 4, the filtering with microporous membrane degerming of wherein selecting 0.22 μ m for use.
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| CN101816632A (en) * | 2010-04-23 | 2010-09-01 | 广东药学院 | Composite functional liposome and preparation method and application thereof |
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| CN102397250A (en) * | 2011-08-11 | 2012-04-04 | 傅苗青 | Aqueous vitamin liposome for injection and preparation method thereof |
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| CN110151590A (en) * | 2019-06-19 | 2019-08-23 | 湖州浦瑞生物医药技术有限公司 | Retinol retinoic acid ester nanometer formulation and its preparation method and application |
| CN111329839A (en) * | 2020-04-02 | 2020-06-26 | 北京鑫兰医药科技有限公司 | Composite vitamin freeze-dried preparation and preparation method thereof |
| PL442854A1 (en) * | 2022-11-16 | 2024-05-20 | Formeds Spółka Z Ograniczoną Odpowiedzialnością | Preparation containing vitamin D3, hard enteric gel capsule containing the vitamin D3 preparation and method of its preparation |
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