CN103040845A - Fat emulsion injection for supplementing fat-soluble vitamins - Google Patents
Fat emulsion injection for supplementing fat-soluble vitamins Download PDFInfo
- Publication number
- CN103040845A CN103040845A CN2013100213821A CN201310021382A CN103040845A CN 103040845 A CN103040845 A CN 103040845A CN 2013100213821 A CN2013100213821 A CN 2013100213821A CN 201310021382 A CN201310021382 A CN 201310021382A CN 103040845 A CN103040845 A CN 103040845A
- Authority
- CN
- China
- Prior art keywords
- vitamin
- injection
- emulsion
- type injection
- years
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002347 injection Methods 0.000 title claims abstract description 190
- 239000007924 injection Substances 0.000 title claims abstract description 190
- 229940088594 vitamin Drugs 0.000 title abstract description 34
- 229930003231 vitamin Natural products 0.000 title abstract description 34
- 235000013343 vitamin Nutrition 0.000 title abstract description 34
- 239000011782 vitamin Substances 0.000 title abstract description 34
- 239000002960 lipid emulsion Substances 0.000 title abstract description 7
- 230000001502 supplementing effect Effects 0.000 title abstract 4
- 238000000034 method Methods 0.000 claims abstract description 61
- 239000003814 drug Substances 0.000 claims abstract description 59
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 126
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 86
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 78
- 239000011719 vitamin A Substances 0.000 claims description 45
- 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 44
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 44
- 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 44
- 235000019155 vitamin A Nutrition 0.000 claims description 44
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- 229930003427 Vitamin E Natural products 0.000 claims description 43
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 43
- 239000011709 vitamin E Substances 0.000 claims description 43
- 235000019165 vitamin E Nutrition 0.000 claims description 43
- 229940046009 vitamin E Drugs 0.000 claims description 43
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 claims description 42
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 claims description 41
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 claims description 40
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- 235000001892 vitamin D2 Nutrition 0.000 claims description 40
- 239000011653 vitamin D2 Substances 0.000 claims description 40
- 239000011772 phylloquinone Substances 0.000 claims description 38
- ABSPRNADVQNDOU-UHFFFAOYSA-N Menaquinone 1 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(C)C(=O)C2=C1 ABSPRNADVQNDOU-UHFFFAOYSA-N 0.000 claims description 37
- 235000019175 phylloquinone Nutrition 0.000 claims description 37
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 claims description 37
- 229960001898 phytomenadione Drugs 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 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 claims description 34
- 238000003860 storage Methods 0.000 claims description 30
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 24
- 235000010445 lecithin Nutrition 0.000 claims description 24
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- 229940067606 lecithin Drugs 0.000 claims description 24
- 235000012424 soybean oil Nutrition 0.000 claims description 23
- 239000003549 soybean oil Substances 0.000 claims description 23
- 239000008215 water for injection Substances 0.000 claims description 20
- VYGQUTWHTHXGQB-UHFFFAOYSA-N Retinol hexadecanoate Natural products CCCCCCCCCCCCCCCC(=O)OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-UHFFFAOYSA-N 0.000 claims description 17
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- 239000011769 retinyl palmitate Substances 0.000 claims description 17
- 238000012856 packing Methods 0.000 claims description 11
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 239000003708 ampul Substances 0.000 description 7
- 102000002322 Egg Proteins Human genes 0.000 description 6
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
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- 239000011712 vitamin K Substances 0.000 description 5
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- 229940046010 vitamin k Drugs 0.000 description 5
- 229910000831 Steel Inorganic materials 0.000 description 4
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
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- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
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- 239000005642 Oleic acid Substances 0.000 description 2
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
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- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
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- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to fat emulsion injection for supplementing fat-soluble vitamins. The injection is emulsion type injection, wherein the injection comprises four lipophilic vitamins. The invention further relates to a method for treating the emulsion type injection. According to the fat emulsion injection for supplementing fat-soluble vitamins, the method for supplementing fat-soluble vitamins is beneficial to clinical medication.
Description
Technical field
The present invention relates to a kind of fat emulsion injection for replenishing fatsoluble vitamin, be specifically related to a kind of fatsoluble vitamin injection, be specifically related to a kind of emulsion-type injection that comprises vitamin A, vitamin D2, vitamin E and four kinds of fatsoluble vitamiies of vitamin K1.The invention still further relates to the method for preserving this fatsoluble vitamin injection and the medicine box product that comprises this fatsoluble vitamin injection.
Background technology
Already be used for clinical in order to replenish every day the fatsoluble vitamin injection of the physiological need of fat-soluble A, vitamin D2, vitamin E, vitamin K1 mainly being comprised fatsoluble vitamin injection (I) and fatsoluble vitamin injection (II) in China.The fatsoluble vitamin injection (I) that mainly is applicable to child below 11 years old and baby (the accurate word H32023003 of traditional Chinese medicines) produced of Wuxi Huarui Pharmaceutical Co. Ltd. for example, and in order to satisfy the adult and the two is all sold in China with the trade name Vitalipid N Adult to the fatsoluble vitamin injection (II) (the accurate word H32023138 of traditional Chinese medicines) of the physiological need of fat-soluble A, vitamin D2, vitamin E, vitamin K1 child every day more than 11 years old.Two kinds of medicament main distinctions that are applicable to different age people are that the proportioning of four kinds of active component is different.For example per 10 milliliters of contained components are in the child form fatsoluble vitamin injection (I): vitamin A is that 0.69mg, vitamin D2 are that 10 μ g, vitamin E are that 6.4mg, vitamin K1 are that 0.20mg, injection soybean oil 1g, injection lecithin 0.12g, glycerol (anhydrous) 0.22g and water for injection add to 10ml in right amount.And per 10 milliliters of contained components are in the adult type fatsoluble vitamin injection (II): vitamin A is that 0.99mg (3300IU), vitamin D2 are that 5 μ g (200IU), vitamin E are that 9.1mg (10IU), vitamin K1 are that 0.15mg, injection soybean oil are that 1g, injection lecithin are that 0.12g, glycerol (anhydrous) add to 10ml in right amount for 0.22g and water for injection.Wherein two kinds of described in the preparation vitamin A of injection all feed intake with vitamin A palmitate and the conversion of vitamin A amount, for example the vitamin A of 3300IU is 0.99mg in per 10 milliliters of the above-mentioned adult type fatsoluble vitamin injection (II), is the vitamin A palmitate of 1.815mg producing to feed intake.
After these present medicament listings stricter holding conditions is arranged, for example all stipulate will be in " 2～10 ℃ " preservation and/or in " cold place " preservation for the fatsoluble vitamin injection (I) produced of above Wuxi Huarui Pharmaceutical Co. Ltd. and fatsoluble vitamin injection (II), and this stricter preservation condition can increase many costs virtually for this routine clinical medication.Therefore those skilled in the art still need a kind of emulsion-type injection that comprises vitamin A, vitamin D2, vitamin E and four kinds of fatsoluble vitamiies of vitamin K1, expect that particularly this emulsion-type injection has good performance to be beneficial to it and better is applied to clinical.
Summary of the invention
The object of the present invention is to provide a kind of emulsion-type injection that comprises vitamin A, vitamin D2, vitamin E and four kinds of fatsoluble vitamiies of vitamin K1, expect that this emulsion-type injection has good performance to be beneficial to it and better is applied to clinical.The inventor unexpectedly finds not only have good stability when such emulsion-type injection is preserved under 12 ~ 20 ℃ of conditions, and compare under 2 ~ 10 ℃ of conditions, having in some aspects better performance.The present invention is based on this discovery and be accomplished.
First aspect present invention provides a kind of emulsion-type injection, comprising vitamin A, vitamin D2, vitamin E and four kinds of fatsoluble vitamiies of vitamin K1.
According to the emulsion-type injection of first aspect present invention, comprise among its every 10ml:
| Vitamin A | 0.62 ~ 1.19mg |
| Vitamin D2 | 4.5 ~ 12 μ g |
| Vitamin E | 5.8 ~ 12.0mg |
| Vitamin K1 | 0.135 ~ 0.24mg |
| The injection soybean oil | 0.8 ~ 1.2g |
| Injection lecithin | 0.1 ~ 0.14 |
| Glycerol | 0.2 ~ 0.24 |
| Sodium hydroxide | In right amount, adjust pH is 6.5 ~ 9.0, for example is about 8 |
| Water for injection | In right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, comprise among its every 10ml
| Vitamin A | 0.69~0.99mg |
| Vitamin D2 | 5~10μg |
| Vitamin E | 5.8~10.0mg |
| Vitamin K1 | 0.15~0.2mg |
| The injection soybean oil | 0.8~1.2g |
| Injection lecithin | 0.1~0.14 |
| Glycerol | 0.2 ~ 0.24 |
| Sodium hydroxide | In right amount, adjust pH is 6.5 ~ 9.0, for example is about 8 |
| Water for injection | In right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, comprise among its every 10ml:
| Vitamin A | 0.62 ~ 1.19mg |
| Vitamin D2 | 4.5 ~ 12 μ g |
| Vitamin E | 6.4 ~ 10mg |
| Vitamin K1 | 0.135 ~ 0.24mg |
| The injection soybean oil | 0.8 ~ 1.2g |
| Injection lecithin | 0.1 ~ 0.14 |
| Glycerol | 0.2 ~ 0.24 |
| Sodium hydroxide | In right amount, adjust pH is 6.5 ~ 9.0, for example is about 8 |
| Water for injection | In right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, comprise among its every 10ml
| Vitamin A | 0.69 ~ 0.99mg |
| Vitamin D2 | 5 ~ 10 μ g |
| Vitamin E | 6.4 ~ 9.1mg |
| Vitamin K1 | 0.15 ~ 0.2mg |
| The injection soybean oil | 0.8 ~ 1.2g |
| Injection lecithin | 0.1 ~ 0.14 |
| Glycerol | 0.2 ~ 0.24 |
| Sodium hydroxide | In right amount, adjust pH is 6.5 ~ 9.0, for example is about 8 |
| Water for injection | In right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, comprise among its every 10ml
| Vitamin A | 0.69mg |
| Vitamin D2 | 10μg |
| Vitamin E | 6.4mg |
| Vitamin K1 | 0.2mg |
| The injection soybean oil | 1g |
| Injection lecithin | 0.12g |
| Glycerol | 0.22g |
| Sodium hydroxide | In right amount, adjust pH is 6.5 ~ 9.0, for example is about 8 |
| Water for injection | In right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, comprise among its every 10ml
| Vitamin A | 0.99mg |
| Vitamin D2 | 5 μ g |
| Vitamin E | 9.1mg |
| Vitamin K1 | 0.15mg |
| The injection soybean oil | 1g |
| Injection lecithin | 0.12g |
| Glycerol | 0.22g |
| Sodium hydroxide | In right amount, adjust pH is 6.5 ~ 9.0, for example is about 8 |
| Water for injection | In right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, wherein said vitamin A is that the form with vitamin A palmitate joins in the described injection.
According to the emulsion-type injection of first aspect present invention, wherein said vitamin A is that the form with vitamin A palmitate joins in the described injection, and it is, and the amount that is converted to vitamin A is calculated.
Second aspect present invention provides the method for disposing each described emulsion-type injection of first aspect present invention, and the method is included in the described emulsion-type injection of storage under the condition that covers 12 ~ 20 ℃ of temperature ranges.
According to the method for second aspect present invention, the method is included in that the described emulsion-type injection of storage reaches at least 1.5 years under the condition that covers 12 ~ 20 ℃ of temperature ranges.
According to the method for second aspect present invention, the method is included in that the described emulsion-type injection of storage reaches 1.5 ~ 3 years (for example 1.5 ~ 2.5 years) under the condition that covers 12 ~ 20 ℃ of temperature ranges.
According to the method for second aspect present invention, the method is included in that the described emulsion-type injection of storage reaches 2 years under the condition that covers 12 ~ 20 ℃ of temperature ranges.
Third aspect present invention provides a kind of medicine box product, and this medicine box product comprises at least one vial, be sealed in each described emulsion-type injection of first aspect present invention in the described vial, the box of the described vial of packing and put down in writing the information detail file of the method for disposing described emulsion-type injection.
According to the medicine box product of third aspect present invention, the method for the described emulsion-type injection of disposal of putting down in writing in the wherein said information detail file provides with written form.
According to the medicine box product of third aspect present invention, put down in writing the information of the described emulsion-type injection of storage under the condition that covers 12 ~ 20 ℃ of temperature ranges in the wherein said information detail file.
According to the medicine box product of third aspect present invention, put down in writing in the wherein said information detail file covering that the described emulsion-type injection of storage reaches the information at least 1.5 years under the condition of 12 ~ 20 ℃ of temperature ranges.
According to the medicine box product of third aspect present invention, put down in writing in the wherein said information detail file and covered reach 1.5 ~ 3 years information of (for example 1.5 ~ 2.5 years) of the described emulsion-type injection of storage under the condition of 12 ~ 20 ℃ of temperature ranges.
According to the medicine box product of third aspect present invention, put down in writing in the wherein said information detail file covering that the described emulsion-type injection of storage reaches the information in 2 years under the condition of 12 ~ 20 ℃ of temperature ranges.
According to the medicine box product of third aspect present invention, wherein said information detail file is to be printed on described box inwall and/or outer wall (thereby itself and described box combine together).
Medicine box product according to third aspect present invention, wherein said information detail file is to be printed on the independent paper and to place in the described box (thereby can place with the form of inset described box, for example be the common form that is inserted into the package insert in the medicine inner packaging box).
Medicine box product according to third aspect present invention, wherein said information detail file is to be printed on the label paper, and described label paper is pasted on the described vial (thereby itself and described vial combine together) or is pasted on described box inwall and/or outer wall (thereby itself and described box combine together).
According to the medicine box product of third aspect present invention, wherein said vial in each packing have the amount of described emulsion-type injection can be 1 ~ 100ml, for example be 5 ~ 20ml, for example 10ml.
Fourth aspect present invention provides the method for storage each described emulsion-type injection of first aspect present invention or each described medicine box product of third aspect present invention, and the method is included in the process of preserving described emulsion-type injection or described medicine box product under the condition that covers 12 ~ 20 ℃ of temperature ranges.
According to the method for fourth aspect present invention, the method is included under the condition that covers 12 ~ 20 ℃ of temperature ranges the described emulsion-type injection of storage or described medicine box product reaches at least 1.5 years.
According to the method for fourth aspect present invention, the method is included under the condition that covers 12 ~ 20 ℃ of temperature ranges the described emulsion-type injection of storage or described medicine box product reaches 1.5 ~ 3 years (for example 1.5 ~ 2.5 years).
According to the method for fourth aspect present invention, the method is included under the condition that covers 12 ~ 20 ℃ of temperature ranges the described emulsion-type injection of storage or described medicine box product reaches 2 years.
In either side of the present invention, emulsion-type injection of the present invention is to preserve under the condition of shading or lucifuge.
Arbitrary embodiment of either side of the present invention can make up with other embodiment, as long as they contradiction can not occur.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they contradiction can not occur.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, as long as they can be not conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.The below is further described with characteristics to various aspects of the present invention.
All documents that the present invention quotes from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this these terms and phrase to be described in more detail and to explain, the term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
In the present invention, for writing conveniently, such as not in addition explanation, vitamin A can be abbreviated as VA, and vitamin A palmitate can be abbreviated as the VA ester, and vitamin D2 can be abbreviated as VD2, and vitamin E can be abbreviated as VE, and vitamin K1 can be abbreviated as VK1.
In one embodiment of the invention, the every 10ml of described emulsion-type injection comprises: vitamin A is that 0.69mg, vitamin D2 are that 10 μ g, vitamin E are that 6.4mg, vitamin K1 are that 0.2mg, injection soybean oil 1g, injection lecithin 0.12g, glycerol (namely usually in anhydrous glycerol) 0.22g, an amount of adjust pH of sodium hydroxide are about 8, water for injection adds to 10ml.
In one embodiment of the invention, the every 10ml of described emulsion-type injection comprises: vitamin A is that 0.99mg (namely being equivalent to 3300IU), vitamin D2 are that 5 μ g (namely being equivalent to 200IU), vitamin E are that 9.1mg (namely being equivalent to 10IU), vitamin K1 are that 0.15mg, injection soybean oil 1g, injection lecithin 0.12g, glycerol (namely usually in anhydrous glycerol) 0.22g, an amount of adjust pH of sodium hydroxide are about 8, water for injection adds to 10ml.
Generally speaking emulsion-type injection of the present invention is white emulsion liquid, active component wherein is one of requisite ingredient of intravenous nutrition, in order to satisfy the physiological need of every day to fat-soluble A, vitamin D2, vitamin E, vitamin K1 of being grown up.
II type prescription is used for the adult and the every consumption per day of ten one-year-old above children is 10ml, and it can be diluted in fat emulsion injection or 5% glucose injection before use to carry out intravenous drip.
In one embodiment of the invention, described emulsion-type injection can prepare according to following technique:
(1) takes by weighing vitamin A palmitate (being converted to the amount of vitamin A during recipe calculation), vitamin D2, vitamin E, vitamin K by recipe quantity
1, soybean oil (injection), Ovum Gallus domesticus Flavus lecithin, glycerol (injection), for subsequent use.
(2) preparation of water: the water for injection that will prepare total amount about 80% adds stainless cylinder of steel, adds while stirring the glycerol (injection) of recipe quantity.
(3) preparation of oil phase: the soybean oil (injection) of recipe quantity is added in another stainless cylinder of steel, pass into nitrogen current, add vitamin A palmitate, vitamin D2, vitamin E, the vitamin K of recipe quantity
1And Ovum Gallus domesticus Flavus lecithin, be stirred to the Ovum Gallus domesticus Flavus lecithin dissolving.
(4) preparation of colostrum: pass into nitrogen current, oil phase is slowly added the aqueous phase of high-speed stirred, continues high-speed stirred after at least 5 minutes, with 1M sodium hydroxide solution regulator solution pH value in 7.0～10.0 scopes, again colostrum is settled to theoretical amount, stirs.
(5) pass into nitrogen current, colostrum is behind 5MPa low pressure homogenizing 4 times, and high pressure homogenize is 1 time under 30MPa pressure, cools off, and then uses the membrane filtration of 10 μ m.
(6) the filtrate fill is in the 10ml glass ampule, sealing by fusing behind the inflated with nitrogen, 118 ℃ of moist heat sterilization 25min.
(7) sterilising prods labeling behind lamp inspection, packing is after the full review of sampling is qualified and get final product.
In emulsion-type injection of the present invention, the amount of each active component can admit of suitable fluctuation, for example comprise for every 10ml: vitamin A is that 0.99mg, vitamin D2 are that 5 μ g, vitamin E are that 9.1mg, vitamin K1 are for the injection of 0.15mg, wherein vitamin A, vitamin D2, vitamin K1 three's amount respectively can be in 90 ~ 120% scopes of its labelled amount, and the amount of the vitamin A that for example comprises among every 10ml can be in 0.89 ~ 1.19mg scope; The amount of vitamin E can be in 90 ~ 110% scopes of its labelled amount, and the amount of the vitamin E that for example comprises among every 10ml can be in 8.2 ~ 10.0mg scope.
In emulsion-type injection of the present invention, wherein the content of glycerol is generally 19.5～24.5mg/ml.The content of glycerol can be measured according to the method for well known to a person skilled in the art, for example can adopt following method to measure: precision is measured emulsion-type injection 2.5ml of the present invention, put in the conical flask, add water 100ml, add 5 of bromocresol purple indicator solutions, shake up, if aobvious acid, drip the 0.1mol/L sodium hydroxide solution, make solution be bluish violet; If aobvious alkalescence, should drip first the 0.5mol/L sulfuric acid solution is adjusted to solution and just is yellow, drip again the 0.1mol/L sodium hydroxide solution and make solution be bluish violet, add 0.7% Potassium metaperiodate. solution (facing with newly joining) 100ml, put in 37～40 ℃ the water-bath insulation 15 minutes, and constantly jolting, add 1,2-PD 3ml, placed 5 minutes, be titrated to solution with 0.1mol/L sodium hydroxide volumetric solution and just be bluish violet, and get final product.The 0.1mol/L sodium hydroxide volumetric solution of every 1ml is equivalent to the C3H8O3 of 9.210mg.
In emulsion-type injection of the present invention, wherein the content of triglyceride (available abbreviation TG represents in this article) is generally 90.0～110.0mg/ml.The content of triglyceride can be measured according to the method for well known to a person skilled in the art, for example can adopt following method to measure:
Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2010);
Chromatographic condition and system suitability: the preparation of system suitability solution, get each 10mg of triglyceride and oleic acid, to the 25ml measuring bottle, with mobile phase dissolving and be diluted to scale, shake up, and get final product;
Be filler with silica gel, normal hexane-isopropyl alcohol-formic acid (90:9:1) is mobile phase, and evaporative light scattering detector (atomization gas: N2, atomization gas pressure: 240Pa, evaporator temperature: 60 ℃) detects; The separating degree of triolein and oleic acid should be greater than 2, and the relative standard deviation of the peak area of triglyceride should be not more than 3.0%;
The preparation of reference substance solution: get the about 0.35g of soybean oil reference substance, accurately weighed, put in the 50ml measuring bottle, with the appearance mixed solutions such as normal hexane and isopropyl alcohol dissolvings and be diluted to scale, be stock solution; Precision is measured stock solution 3ml and 4ml, puts respectively in the 25ml measuring bottle, is diluted to scale with mobile phase, shakes up, and is reference substance solution 1 and reference substance solution 2;
The preparation of need testing solution: precision is measured this product 4ml, puts in the 50ml measuring bottle, with the appearance mixed solutions such as normal hexane and isopropyl alcohol dissolvings and be diluted to scale, shakes up; Precision is measured 3ml, puts in the 25ml measuring bottle, is diluted to scale with mobile phase, shakes up, and get final product;
Algoscopy respectively precision is measured reference substance solution 1, reference substance solution 2, and each 10 μ l of need testing solution alternately in the injection liquid chromatography, get calculated by peak area through chromatographic isolation, and get final product.
In emulsion-type injection of the present invention, wherein the content of VitAVitE, vitamin K1 can be measured according to the method for well known to a person skilled in the art, for example can adopt following method to measure simultaneously three's content:
Measure according to high performance liquid chromatography (2010 editions two appendix V D of Chinese Pharmacopoeia);
Chromatographic condition and system suitability test: be filler with octadecylsilane chemically bonded silica; Take acetonitrile-methanol-dichloromethane (80:10:10) as mobile phase; The detection wavelength is 270nm.Theoretical cam curve is calculated with vitamin peak E should be not less than 3000, and the peak-to-peak separating degree of each vitamin should meet the requirements;
The preparation of need testing solution: precision is measured this product 5ml and is put in the 50ml measuring bottle, with the isopropyl alcohol dissolving and be diluted to scale, shakes up, and get final product;
The preparation of vitamin A palmitate stock solution: get the about 45mg of vitamin A palmitate reference substance, accurately weighed, put in the 50ml measuring bottle, add the isopropyl alcohol dissolving and be diluted to scale, shake up, and get final product;
The preparation of vitamin E stock solution: get the about 45mg of vitamin E reference substance, accurately weighed, put in the 50ml measuring bottle, add the isopropyl alcohol dissolving and be diluted to scale, shake up, and get final product;
The preparation of vitamin K1 stock solution: get the about 30mg of vitamin K1 reference substance, accurately weighed, put in the 200ml measuring bottle, add the isopropyl alcohol dissolving and be diluted to scale, shake up, and get final product;
The preparation of reference substance solution: precision is measured vitamin A palmitate stock solution 2ml, vitamin E stock solution 10ml, vitamin K1 stock solution 1ml, puts in the 100ml measuring bottle, adds the isopropyl alcohol dissolving and is diluted to scale, shakes up, and get final product;
Algoscopy: get respectively each 20ul of need testing solution and reference substance solution, the injection liquid chromatography, the record chromatogram is by the content of external standard method with vitamin A palmitate, vitamin E, vitamin K1 in each vitamin calculated by peak area test sample.
In emulsion-type injection of the present invention, wherein the content of vitamin D2 can be measured according to the method for well known to a person skilled in the art, for example can adopt following method to measure content:
Measure according to high performance liquid chromatography (2010 editions two appendix V D of Chinese Pharmacopoeia);
Chromatographic condition and system suitability test: be filler with silica gel; Cyclohexane extraction-isopropyl alcohol (95:5) is mobile phase; The detection wavelength is 265nm; Theoretical cam curve is calculated with the vitamin D2 peak should be not less than 3000;
The preparation of reference substance solution: get the about 20mg of vitamin D2 reference substance, accurately weighed, to put in the 100ml measuring bottle, the dissolving of methylate tertbutyl ether also is diluted to scale, shake up, precision is measured 1ml, puts in the 200ml measuring bottle, the methylate tertbutyl ether is diluted to scale, shakes up, and get final product;
Algoscopy: measure 10% fat emulsion injection (C14-C24) 10ml with inner capacities pipet precision and put in the 20ml tool plug rub oral examination tube, the accurate reference substance solution 5ml that adds, obturation, shake well 3 minutes adds an amount of anhydrous sodium sulfate, inaccessible, jolting, standing demix is got supernatant 20ul, the injection liquid chromatography, the record chromatogram; Measure this product 10ml with inner capacities pipet precision in addition and put in the 20ml tool plug rub oral examination tube, the accurate methyl tertiary butyl ether(MTBE) 5ml that adds is from " shake well 3 minutes ", with the method time-and-motion study.By the content of external standard method with vitamin D2 in the calculated by peak area test sample.
Usually, the pH value of emulsion-type injection of the present invention should be 6.5～9.0.
Usually, the breast grain of emulsion-type injection of the present invention should meet the requirement of used for intravenous injection Emulsion, usually can measure with enumerator at microscopically, perhaps can use light scattering determining.Usually breast grain greater than 1 μ m must not be crossed 10% (for example must not cross 8%, for example must not cross 6%, for example must not cross 5%, for example must not cross 4%, for example must not cross 3%) in the injection of the present invention, and must not detect the breast grain greater than 5 μ m.
The method of the content of vitamin A in some every physical and chemical parameter example emulsion type injection of measuring emulsion-type injection of the present invention has been described in the context of the invention.Except as otherwise noted, these methods are used for the hereinafter test job in the concrete test of embodiment of the present invention.
In the present invention, injection of the present invention can be preserved under the condition that covers 12 ~ 20 ℃ of temperature ranges.In one embodiment, the phrase conditions of 12 ~ 20 ℃ of temperature ranges " cover " is such as but not limited to the known condition that comprises this temperature range of pharmaceutical field technical staff, for example " cool place " condition of " room temperature " condition of Chinese Pharmacopoeia regulation, for example Chinese Pharmacopoeia regulation, the condition of 12 ~ 20 ℃ of temperature ranges for example.In an embodiment of either side of the present invention, injection of the present invention is preserved under the condition of 12 ~ 20 ℃ of temperature ranges.In an embodiment of either side of the present invention, injection of the present invention is preserved under the condition of 12 ~ 20 ℃ of temperature ranges and is reached at least 1.5 years.In an embodiment of either side of the present invention, injection of the present invention is preserved under the condition of 12 ~ 20 ℃ of temperature ranges and is reached 1.5 ~ 3 years (for example 1.5 ~ 2.5 years).In an embodiment of either side of the present invention, injection of the present invention is preserved under the condition of 12 ~ 20 ℃ of temperature ranges and is reached 2 years.
Injection of the present invention can provide the fatsoluble vitamin of physiological need every day, comprises vitamin A, vitamin D
2, vitamin E, vitamin K
1Vitamin A can promote the synthetic and regeneration of rhodopsin in the eyeball, keeps twenty-twenty vision, and the control nyctalopia is kept epithelial growth and differentiation, improves immunity and resistance.Vitamin D increase calcium and phosphorus are in enteral absorption, and is essential by the homergy of regulating calcium and phosphorus, promotes the normal growth of tooth and skeleton.Vitamin E has anti-oxidation function, keeps erythrocytic integrity, participates in the biosynthesis of DNA (deoxyribonucleic acid), improves immunity of organisms, and is relevant with reproductive performance and spermatogenesis.Vitamin K participates in the synthetic of thrombinogen, participates in the oxidation-reduction process in the histiocyte, increases the elasticity of muscular tissue.
In the present invention, provide a kind of emulsion-type injection, term " emulsion-type injection " is usually understandable Emulsions for injection of those skilled in the art.
In the present invention, a kind of emulsion-type injection is provided, its described emulsion-type injection of storage under the condition that covers 12 ~ 20 ℃ of temperature ranges reaches at least 1.5 years and (for example reaches 1.5 ~ 3 years (for example 1.5 ~ 2.5 years), for example reach 2 years), and every quality index of medicine still meets the standard code of this medicine after storage during this.Perhaps can be understood as, emulsion-type injection of the present invention, it reaches at least 1.5 years effect duration of (for example reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years), for example reach 2 years) covering storage under the condition of 12 ~ 20 ℃ of temperature ranges.The implication of this effect duration be applicable to first aspect present invention the emulsion-type injection, be equally applicable to the method for second aspect present invention, also be applicable to the medicine box product of third aspect present invention.Therefore, the emulsion-type injection of first aspect present invention reaches at least 1.5 years (for example reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years), for example reach 2 years) covering the effect duration of preserving under the condition of 12 ~ 20 ℃ of temperature ranges; Perhaps use the method for second aspect present invention to dispose each described emulsion-type injection of first aspect present invention, namely reach at least 1.5 years (for example reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years), for example reach 2 years) covering under the condition of 12 ~ 20 ℃ of temperature ranges the described emulsion-type injection of storage effect duration; Perhaps in the medicine box product of third aspect present invention this medicine box product of mark the emulsion-type injection reaching at least 1.5 years (for example reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years), for example reach 2 years) covering under the condition of 12 ~ 20 ℃ of temperature ranges storage effect duration.
In addition, medicine box product according to third aspect present invention, it can be understood as for clinical medicine, this medicine comprises the emulsion-type injection medicinal liquid that is sealed in the vial, wrap up the box (carton for example of this vial, plastic casing etc., carton box normally), and set forth this emulsion-type injection and preserve, the operation instructions of the information such as use, particularly comprise the information of setting forth this emulsion-type injection storage, namely this emulsion-type injection is covering storage under the condition of 12 ~ 20 ℃ of temperature ranges effect duration reach at least 1.5 years storage information of (for example reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years), for example reach 2 years).This storage information can directly be printed on the described box, perhaps can be printed on the independent paper also this paper to be inserted in this box with the form of package insert, perhaps can be printed on the label that is pasted on the vial surface.
According to the medicine box product of third aspect present invention, can comprise a vial in the one box, can also comprise a plurality of vials, 1 ~ 20 vial of for example can packing into simultaneously in box.
For the vial that the present invention mentions, it can be the vial that meets injection medicine packing glass container relevant regulations.This vial can be colourless or brown, and is preferably brown, is conducive to like this avoid illumination to the harmful effect of drug quality.In addition, the shape of this vial is not particularly limited, and for example it can be the ampoule form, in packing seal by the mode of flame sealing by fusing behind the medicinal liquid; Also can be the form of cillin bottle or phial, behind the packing medicinal liquid by stopper for example the mode of rubber stopper with bottle sealing.
Emulsion-type injection provided by the invention is carried out cold place (setting 3 ~ 9 ℃) to this product to the inventor and shady and cool place (setting 12 ~ 20 ℃) has carried out 30 months stable comparative study, the result shows under two kinds of holding conditions for the conventional sense project of this product emulsion-type injection, the stability of sample all meets common quality standard requirement without significant difference under two kinds of holding conditions.
Yet the inventor finds that unexpectedly under 12 ~ 20 ℃ temperature conditions, the amount that is dissolved in the active component in the breast grain shows more stable trend.Thus, emulsion-type injection of the present invention can use the more loose temperature conditions of holding conditions instead and quality without impact.
The specific embodiment
Further specify the present invention below by concrete Preparation Example and biological test example, still, should be understood to, these embodiment and test example are only used for the more detailed usefulness that specifically describes, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in the test.Although for realizing that the employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and operational approach are well known in the art.Prepare hereinafter in the test of injection, each batch feeds intake by the scale that 20000 * 10ml/ props up ampoule bottle.
One, emulsion-type injection preparation example part of the present invention
Preparation example 1: prepare emulsion-type injection of the present invention (I type)
Prepare burden among every bottle of 10ml
| Vitamin A | 0.69mg |
| Vitamin D2 | 10 μ g |
| Vitamin E | 6.4mg |
| Vitamin K1 | 0.2mg |
| The injection soybean oil | 1g |
| Injection lecithin | 0.12g |
| Glycerol | 0.22g |
| Sodium hydroxide | In right amount, adjust pH is 8.0 ± 0.2 |
| Water for injection | In right amount, add to 10ml. |
Wherein vitamin A is that form with vitamin A palmitate feeds intake, and calculating every inventory by vitamin A in the formula table is 0.69mg, and the context of the invention has therewith identical meanings.
Preparation technology:
(1) takes by weighing vitamin A palmitate, vitamin D2, vitamin E, vitamin K by recipe quantity
1, soybean oil (injection), Ovum Gallus domesticus Flavus lecithin, glycerol (injection), for subsequent use;
(2) preparation of water: the water for injection that will prepare total amount about 80% adds stainless cylinder of steel, adds while stirring the glycerol (injection) of recipe quantity;
(3) preparation of oil phase: the soybean oil (injection) of recipe quantity is added in another stainless cylinder of steel, pass into nitrogen current, add vitamin A palmitate, vitamin D2, vitamin E, the vitamin K of recipe quantity
1And Ovum Gallus domesticus Flavus lecithin, be stirred to the Ovum Gallus domesticus Flavus lecithin dissolving;
(4) preparation of colostrum: pass into nitrogen current, oil phase is slowly added the aqueous phase of high-speed stirred, continues high-speed stirred after at least 5 minutes, with 1M sodium hydroxide solution regulator solution pH value in 8.0 ± 0.2 scopes, again colostrum is settled to theoretical amount, stirs;
(5) pass into nitrogen current, colostrum is behind 5MPa low pressure homogenizing 4 times, and high pressure homogenize is 1 time under 30MPa pressure, cools off, and then uses the membrane filtration of 10 μ m;
(6) the filtrate fill is in 10ml clear glass ampoule bottle, sealing by fusing behind the inflated with nitrogen, 118 ℃ of moist heat sterilization 25min;
(7) sterilising prods labeling behind lamp inspection, packing is after the full review of sampling is qualified and get final product.
Above composition and engineering is produced three batches altogether, and lot number is respectively: I-101, I-102 and I-103.
Preparation example 2: prepare emulsion-type injection of the present invention (II type)
Prepare burden among every bottle of 10ml
| Vitamin A | 0.99mg |
| Vitamin D2 | 5 μ g |
| Vitamin E | 9.1mg |
| Vitamin K1 | 0.15mg |
| The injection soybean oil | 1g |
| Injection lecithin | 0.12g |
| Glycerol | 0.22g |
| Sodium hydroxide | In right amount, adjust pH is 8.0 ± 0.2 |
| Water for injection | In right amount, add to 10ml. |
Wherein vitamin A is that form with vitamin A palmitate feeds intake, and calculating its every inventory by vitamin A palmitate is 1.815mg (being equivalent to vitamin A is 0.99mg), and the context of the invention has therewith identical meanings.
Method for making is with embodiment 1.Above composition and engineering is produced three batches altogether, and lot number is respectively: II-101, II-102 and II-103.
Preparation example 3: prepare emulsion-type injection of the present invention
Prepare burden among every bottle of 10ml
| Vitamin A | 0.62mg |
| Vitamin D2 | 12μg |
| Vitamin E | 5.8mg |
| Vitamin K1 | 0.24mg |
| The injection soybean oil | 0.8g |
| Injection lecithin | 0.14g |
| Glycerol | 0.2g |
| Sodium hydroxide | In right amount, adjust pH is 8.0 ± 0.2 |
| Water for injection | In right amount, add to 10ml. |
Method for making is with embodiment 1.On inspection/measure, the content of active component is all in 95 ~ 105% scopes of labelled amount in this emulsion-type injection, and such as breast grain granularity, outward appearance, pH value etc. of every physical property all meets general Emulsion particularly fatsoluble vitamin injection (I) or standard code (II), for example product characteristics are milky emulsion, pH value is 7.5～8.5, use light scattering determining, be no more than 4% greater than the breast grain of 1 μ m, and do not detect the breast grain greater than 5 μ m.
Preparation example 4: prepare emulsion-type injection of the present invention
Prepare burden among every bottle of 10ml
| Vitamin A | 1.19mg |
| Vitamin D2 | 4.5 μ g |
| Vitamin E | 10.0mg |
| Vitamin K1 | 0.135mg |
| The injection soybean oil | 1.2g |
| Injection lecithin | 0.1g |
| Glycerol | 0.24g |
| Sodium hydroxide | In right amount, adjust pH is 8.0 ± 0.2 |
| Water for injection | In right amount, add to 10ml. |
Method for making is with embodiment 1.On inspection/measure, the content of active component is all in 95 ~ 105% scopes of labelled amount in this emulsion-type injection, and such as breast grain granularity, outward appearance, pH value etc. of every physical property all meets general Emulsion particularly fatsoluble vitamin injection (I) or standard code (II), for example product characteristics are milky emulsion, pH value is 7.5～8.5, use light scattering determining, be no more than 4% greater than the breast grain of 1 μ m, and do not detect the breast grain greater than 5 μ m.
Each Lot sample of above preparation example 1-4 preparation, the amount of propping up with 10ml/ is sub-packed in the flint glass ampoule bottle, and then this pastille ampoule bottle put in the carton, in carton, place simultaneously package insert, put down in writing the drug storage condition in this description, the temperature range of this holding conditions that indicates in the package insert has covered 12 ~ 20 ℃ temperature range (being specially " (be no more than 20 ℃) in the cool and preserve, must not be freezing ").In addition, the carton that this is equipped with medicine placed under the condition that covers 12 ~ 20 ℃ of temperature ranges storage 1.5 years, 2 years, 2.5 years, 3 years.
In the test that replenishes in addition, prescription is identical with preparation example 2 with method for making, and different is with medicinal liquid is 6.7 ± 0.2 or 8.8 ± 0.2 with the sodium hydroxide adjust pH.On inspection/measure, the content of active component is all in 95 ~ 105% scopes of labelled amount in two batches of emulsion-type injection of gained, and such as breast grain granularity, outward appearance, pH value etc. of every physical property all meets general Emulsion particularly fatsoluble vitamin injection (I) or standard code (II), for example product characteristics are milky emulsion, pH value is 7.5～8.5, use light scattering determining, be no more than 4% greater than the breast grain of 1 μ m, and do not detect the breast grain greater than 5 μ m.
Two, test example part
Test example 1, emulsion-type injection steady dissolution of the present invention investigation
1, the stability test method that keeps sample: each Lot sample of partly obtaining of preparation example above, every Lot sample divides two parts sample (all to seal packing with ampoule bottle, shading), two temperature-controlled boxs that place respectively design temperature to fluctuate between 12 ~ 20 ℃ at fluctuation and design temperature between 3 ~ 9 ℃, placed 30 months, steady dissolution is measured in sampling during respectively at 0 month, 18 months, 24 months and 30 months.
2, steady dissolution assay method and result: place respectively the 10ml centrifuge tube to carry out centrifugal (different batches sample on the sample (in 0 month sample two temperature being merged into same sample) of each point in time sampling, at different minute points, the parameters such as centrifuge tube specification, centrifuge, Centrifugal Environment (room temperature), centrifugation time are all fixing, centrifugal radius 10cm), 15000rpm * 20min, it is an amount of to draw the latter half liquid, measures the wherein concentration (with μ g/ml represent) of Four Vitamins in liquid.This concentration can reflect the concentration of medicine in Emulsion continuous phase, and namely medicine (can be with C in the concentration of aqueous phase
WaterExpression), medicine can be used C in the concentration of aqueous phase in the time of 0 month
Water, 0 monthExpression, medicine can be used C in the concentration of aqueous phase in the time of 24 months
Water, 24 monthsExpression.
For every Lot sample, calculate it at the C of different time points
WaterThen value calculates each time point C
WaterValue C during with respect to 0 month
WaterThe concentration change percent of value.Sample during for example for 24 months, this concentration change percent calculating formula is as follows:
This concentration change percent can reflect that medicine is at the continuous phase of Emulsion and the intensity of variation behind certain hour in the decentralized photo.
Result such as the following table 1 of part sample vitamin A concentration percent change of the present invention.
Table 1:
Result such as the following table 2 of part sample vitamin K1 concentration change percent of the present invention.
Table 2:
In addition, for vitamin D2 and vitamin E, find no above-mentioned 3 ~ 9 ℃ of variation tendencies under the temperature that are similar to, namely in the scope of concentration change percentage number average-2% ~ 3% in the time of 18,24,30 months of vitamin D2 and vitamin E.
This test example is to measure the method for vitamin content in the Emulsion continuous phase (water), investigate the overwhelming majority be dissolved in the Emulsion oil phase (decentralized photo) medicine through different temperatures is long-time place after, permeate and be dissolved in the situation of change of aqueous phase, if the fat-soluble medicine concentration change (particularly increasing) at aqueous phase is obvious, may there be hidden danger in medicine, and the active component in for example being soluble in the aqueous phase may supersaturation occur and separate out.Although from hereinafter finding that two kinds of temperature holding conditions service property (quality) standard test methods have no the difference of two kinds of temperature storages the long term test, yet from table 1 above, 2 result as seen, for emulsion-type injection of the present invention, they are after placing 30 months under 3 ~ 9 ℃ of temperature, vitamin A and vitamin K1 can appear at the variation that concentration increases in the continuous phase, this variation is disadvantageous for medicine stability, and for example this can cause the possibility that medicine is separated out from water; And have no this variation 12 ~ 20 ℃ of lower placements.
Test example 2, medicine stability are investigated
1, investigation project and assay method
(1) appearance luster: the character of range estimation sample, the milkiness that is creamy white is aqueous for qualified.
(2) layering or break: this product is oil in water emulsion, should investigate the phenomenon of phase separation that may occur in the storage (layering or break).Emulsion creaming: claim again breast to analyse, refer to Emulsion the dispersed phase particles come-up occurs or sinks in put procedure phenomenon, the Emulsion outward appearance after the layering is more coarse, and jolting can revert to the Emulsion original state gently, is a reversible process.Emulsion breaks: refer to that emulsifying film destroys, dispersed phase drop is merged into large drop, further makes Emulsion be divided into oil, water is biphase, can not revert to original Emulsion state through jolting, is an irreversible process.
(3) pH value: according to two appendix VI of Chinese Pharmacopoeia version in 2010 H pH value algoscopy, each sample pH value is all in 7.5 ~ 8.5 scopes during preparation.
(4) breast grain: measure according to 2010 editions two appendix I X of Chinese Pharmacopoeia E light scattering method, meet two appendix I of Chinese Pharmacopoeia version in 2010 B to the granularity requirements of vein with emulsion droplet in the emulsion type injection, the granularity 90% of emulsion droplet should below 1 μ m, must not have the emulsion droplet greater than 5 μ m.
(5) free fatty (available abbreviation FFA represents in this article)
The preparation of contrast solution: get Palmic acid 0.64g, accurately weighed, put in the 500ml measuring bottle, add the normal heptane dissolving and be diluted to scale, shake up;
Algoscopy: precision is measured this product and each 1ml of contrast solution, puts respectively in the 20ml tool plug test tube, adds the mixed solution 5.0ml of isopropyl alcohol-normal heptane-0.5mol/L sulfuric acid solution (40: 10: 1), and jolting 1 minute was placed 10 minutes.Need testing solution pipe precision adds normal heptane and each 3ml of water, and reference substance solution pipe precision adds normal heptane 2ml and water 4ml, close plug, spin upside down 10 times, left standstill at least 15 minutes, and made layering, precision is measured upper strata liquid 3ml respectively, put in the 10ml centrifuge tube, add the Nile blue indicator solution (get Nile blue 0.04g, add water 200ml, make dissolving after, add normal heptane 100ml jolting, discard the upper strata normal heptane; Repeatable operation 4 times; Take off a layer aqueous solution 20ml, add dehydrated alcohol 180ml, mixing.This liquid is put in the brown bottle, can deposit one month under the room temperature) 1ml, under logical nitrogen condition, be titrated to the aobvious lavender of solution with sodium hydroxide volumetric solution (0.01mol/L); The milliliter number that need testing solution consumes sodium hydroxide volumetric solution (0.01mol/L) is A, and the milliliter number that reference substance solution consumes sodium hydroxide volumetric solution (0.01mol/L) is B, calculates according to following formula, contains free fatty and must not cross 5.0mmol/L;
Wherein 5.0 for the concentration of Palmic acid reference substance solution be 5.0mmol/L.
(6) peroxide value
Precision is measured this product 10ml, puts in the 250ml round-bottomed flask, removes moisture in 60 ℃ of water-bath rotary evaporation in vacuo.Add acetic acid-chloroform (3:2) mixed liquor 30ml, after the jolting dissolving, add saturated solution of potassium iodide 0.5ml, accurately shaking out is 1 minute, then add entry 30ml, violent jolting limit, limit is used sodium thiosulfate volumetric solution (0.01mol/L) to be titrated to the solution yellow almost to disappear immediately.Add starch indicator solution 1ml, shake up, continue to be titrated to the blueness disappearance of upper strata water.Do simultaneously blank assay, the consumption of sodium thiosulfate volumetric solution (0.01mol/L) must not be crossed 0.1ml in the blank assay.Calculate according to following formula, peroxide value must not be crossed 0.1mmol/kg.
In the formula, V is the volume that test sample consumes sodium thiosulfate volumetric solution (0.01mol/L), ml; V
0Be the volume of blank assay consumption sodium thiosulfate volumetric solution (0.01mol/L), ml; M is the weight of test sample, g; F is the correction factor of sodium thiosulfate volumetric solution concentration.
(7) LYSO-PHOSPHATIDYLCHOLINE LYSOPC (available abbreviation LPC represents in this article)
Chromatographic condition and system try out the property test: closing silica gel with dihydroxypropyl silane chain is filler (LiChrospher100DIOL); Take normal heptane-isopropyl alcohol (43:57) as mobile phase A, take normal heptane-isopropanol-water (29.5:59:11.5) as Mobile phase B, carry out gradient elution, flow velocity is per minute 1.5ml.Evaporative light scattering detector (atomization gas: N
2, atomization gas pressure: 240KPa, evaporator temperature: 70 ℃) detect.Number of theoretical plate calculates with the lysophosphatide peak and is not less than 2000.
Elution program is as follows:
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0.0 | 100 | 0 |
| 0.1 | 55 | 45 |
| 5.0 | 55 | 45 |
| 5.1 | 100 | 0 |
| 12.0 | 100 | 0 |
The preparation of standard curve: it is an amount of that precision takes by weighing lysophosphatide, adds isopropyl alcohol-n-heptane solution (2:1) dissolving and dilution, makes concentration and be respectively that every 1ml contains 0.02,0.04,0.1, the reference substance solution of 0.2mg.Precision is measured in each 50ml injection liquid chromatography of reference substance solution and is recorded chromatogram, according to the content of lysophosphatide in the test sample, selects the reference substance solution of three adjacent concentration, with concentration and corresponding calculated by peak area regression equation.
The preparation of need testing solution: precision is measured this product 1ml, puts in the 10ml measuring bottle, adds isopropyl alcohol-n-heptane solution (2:1) and is diluted to scale, shakes up, and get final product.
Algoscopy: precision is measured need testing solution 50ml, the injection liquid chromatography, and the record chromatogram is by lysophosphatide content in the regression equation calculation test sample.Contain lysophosphatide among every 1ml and must not cross 1.2mg.
(8) content: each vitamin, glycerol and triglyceride content are all undertaken by assay method mentioned above.
(9) bacterial endotoxin, aseptic: all the method by two regulations of Chinese Pharmacopoeia version in 2010 checks with investigation before stability keeps sample latter stage.
2, investigate sample
Three crowdes of the II-101 that above prepares in the preparation example, II-102, II-103,10ml/ bottle, sealing by fusing be (this comprises identical with commercially available product) in the 10ml Clear glass bottles and jars.
3, study on the stability method
(1) accelerated test: by the requirement of two appendix XI of Chinese Pharmacopoeia version in 2010 X C " crude drug and pharmaceutical preparation stability test guideline ", Emulsion directly adopts the condition of 30 ℃ ± 2 ℃ of temperature to test.
(2) 6 ± 2 ℃ of long term tests (keeping sample referred to as 6 ℃): sample places under 6 ± 2 ℃ the temperature conditions, places 30 months, in 0 month, June, December, sampling and measuring 18 months, 24 months, 30 months the time.
(3) 16 ± 4 ℃ of long term tests (keeping sample referred to as 16 ℃): sample places under 16 ± 4 ℃ the temperature conditions, places 30 months, in 0 month, June, December, sampling and measuring 18 months, 24 months, 30 months the time.
4, study on the stability result of the test
II-101, II-102, three batches of indexs of measuring each sample under accelerated test, 6 ± 2 ℃ of long term tests, three kinds of experimental conditions of 16 ± 4 ℃ of long term tests in different time points of II-103, the result sees respectively following table 3 ~ table 11.
Table 3: accelerated test result's (sample lot number: II-101)
| The investigation time (moon) | 0 | 3 | 6 |
| Appearance luster | Qualified | Qualified | Qualified |
| Layering/break | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.2 | 23.2 | 23.3 |
| TG(mg/ml) | 95.3 | 94.2 | 94.1 |
| Bacterial endotoxin | Up to specification | -- | Up to specification |
| Aseptic | Up to specification | -- | Up to specification |
In the upper table, for Four Vitamins content, the concentration that represents them with " qualified " all in 95% ~ 105% scope of this theoretical labelled amount of filling a prescription, also has similar meaning when hereinafter similar statement being arranged in the result of the test.
Table 4: accelerated test result's (sample lot number: II-102)
| The investigation time (moon) | 0 | 3 | 6 |
| Appearance luster | Qualified | Qualified | Qualified |
| Layering/break | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.0 | 23.1 | 23.0 |
| TG(mg/ml) | 96.1 | 94.8 | 94.3 |
| Bacterial endotoxin | Up to specification | -- | Up to specification |
| Aseptic | Up to specification | -- | Up to specification |
Table 5: accelerated test result's (sample lot number: II-103)
| The investigation time (moon) | 0 | 3 | 6 |
| Appearance luster | Qualified | Qualified | Qualified |
| Layering/break | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.6 | 23.6 | 23.6 |
| TG(mg/ml) | 100.0 | 99.1 | 98.5 |
| Bacterial endotoxin | Up to specification | -- | Up to specification |
| Aseptic | Up to specification | -- | Up to specification |
Table 6: long term test (6 ℃ keep sample) result's (sample lot number: II-101)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/break | Be showed no | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.2 | 23.1 | 23.1 | 23.2 |
| TG(mg/ml) | 95.3 | 94.4 | 93.1 | 91.8 |
| Bacterial endotoxin | Up to specification | -- | -- | Up to specification |
| Aseptic | Up to specification | -- | -- | Up to specification |
Table 7: long term test (6 ℃ keep sample) result's (sample lot number: II-102)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/break | Be showed no | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.0 | 22.9 | 23.0 | 23.0 |
| TG(mg/ml) | 96.1 | 95.2 | 93.8 | 93.1 |
| Bacterial endotoxin | Up to specification | -- | -- | Up to specification |
| Aseptic | Up to specification | -- | -- | Up to specification |
Table 8: long term test (6 ℃ keep sample) result's (sample lot number: II-103)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/break | Be showed no | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.6 | 23.5 | 23.6 | 23.6 |
| TG(mg/ml) | 100.0 | 98.6 | 97.4 | 96.9 |
| Bacterial endotoxin | Up to specification | -- | -- | Up to specification |
| Aseptic | Up to specification | -- | -- | Up to specification |
Table 9: long term test (16 ℃ keep sample) result's (sample lot number: II-101)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/break | Be showed no | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.2 | 23.3 | 23.3 | 23.1 |
| TG(mg/ml) | 95.3 | 94.1 | 92.2 | 91.7 |
| Bacterial endotoxin | Up to specification | -- | -- | Up to specification |
| Aseptic | Up to specification | -- | -- | Up to specification |
Table 10: long term test (16 ℃ keep sample) result's (sample lot number: II-102)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Milky emulsion | Milky emulsion | Milky emulsion | Milky emulsion |
| Layering/break | Be showed no | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.0 | 22.9 | 22.9 | 23.0 |
| TG(mg/ml) | 96.1 | 94.9 | 93.8 | 93.4 |
| Bacterial endotoxin | Up to specification | -- | -- | Up to specification |
| Aseptic | Up to specification | -- | -- | Up to specification |
Table 11: long term test (16 ℃ keep sample) result's (sample lot number: II-103)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Milky emulsion | Milky emulsion | Milky emulsion | Milky emulsion |
| Layering/break | Be showed no | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| The breast grain | Qualified | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Up to specification | Up to specification | Up to specification | Up to specification |
| LPC(mg/ml) | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 | 0.15~0.35 |
| VA ester (μ g/ml) | Qualified | Qualified | Qualified | Qualified |
| VD2(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| VE(mg/ml) | Qualified | Qualified | Qualified | Qualified |
| VK1(μg/ml) | Qualified | Qualified | Qualified | Qualified |
| Glycerol (mg/ml) | 23.6 | 23.5 | 23.6 | 23.6 |
| TG(mg/ml) | 100.0 | 98.2 | 96.6 | 96.2 |
| Bacterial endotoxin | Up to specification | -- | -- | Up to specification |
| Aseptic | Up to specification | -- | -- | Up to specification |
The test that is replenishing, also according to said method investigated I-101, I-102 sample and preparation example 3 and 4 that preparation example of the present invention 1 obtains obtain samples 6 ℃ keep sample and 16 ℃ of two kinds of conditions that keep sample under stability result, the result shows basically that with above for the coming to the same thing of the table 6 of sample II-101, II-102, II-103 three samples ~ table 11, namely these samples still meet general drug standard regulation after placing 30 months under two kinds of conditions that keep sample.
The below is to II-101, II-102, II-103 three samples each main quality index amplitude of variation of long term test (30 months poor with 0 month numerical value under two kinds of holding conditions, take absolute value) as a comparison, the result sees Table respectively 12 ~ 14, being presented at two kinds of stability keeps sample under the experimental condition for a long time, the amplitude of variation of each index under two kinds of experimental conditions is basic identical, shows to detect routinely to indicate to investigate the difference that two kinds of holding conditions can't be determined two kinds of methods basically.
Table 12: each main quality index amplitude of variation contrast of long term test under two kinds of holding conditions, lot number: II-101
| Investigate change indicator | 6 ℃ of 30 monthly variation amplitudes that keep sample | 16 ℃ of 30 monthly variation amplitudes that keep sample |
| PH value | 0.4 | 0.3 |
| FFA(mmol/L) | 0.5 | 0.6 |
| LPC(mg/ml) | 0.04 | 0.05 |
| VA ester (μ g/ml) | 7 | 6 |
| VD2(μg/ml) | 0.01 | 0.02 |
| VE(mg/ml) | 0.03 | 0.03 |
| VK1(μg/ml) | 0.4 | 0.5 |
| Glycerol (mg/ml) | 0 | 0.1 |
| TG(mg/ml) | 3.5 | 3.6 |
Table 13: each main quality index amplitude of variation contrast of long term test under two kinds of holding conditions, lot number: II-102
| Investigate change indicator | 6 ℃ of 30 monthly variation amplitudes that keep sample | 16 ℃ of 30 monthly variation amplitudes that keep sample |
| PH value | 0.4 | 0.5 |
| FFA(mmol/L) | 0.7 | 0.4 |
| LPC(mg/ml) | 0.05 | 0.06 |
| VA ester (μ g/ml) | 5 | 5 |
| VD2(μg/ml) | 0.02 | 0.02 |
| VE(mg/ml) | 0.02 | 0.02 |
| VK1(μg/ml) | 0.3 | 0.4 |
| Glycerol (mg/ml) | 0 | 0 |
| TG(mg/ml) | 3.0 | 2.7 |
Table 14: each main quality index amplitude of variation contrast of long term test under two kinds of holding conditions, lot number: II-103
| Investigate change indicator | 6 ℃ of 30 monthly variation amplitudes that keep sample | 16 ℃ of 30 monthly variation amplitudes that keep sample |
| PH value | 0.5 | 0.4 |
| FFA(mmol/L) | 0.7 | 0.8 |
| LPC(mg/ml) | 0.05 | 0.08 |
| VA ester (μ g/ml) | 5 | 6 |
| VD2(μg/ml) | 0.02 | 0.02 |
| VE(mg/ml) | 0.02 | 0.03 |
| VK1(μg/ml) | 0.3 | 0.3 |
| Glycerol (mg/ml) | 0 | 0 |
| TG(mg/ml) | 3.1 | 3.9 |
The present invention relates to a kind of fatsoluble vitamin injection, be specifically related to a kind of emulsion-type injection that comprises vitamin A, vitamin D2, vitamin E and four kinds of fatsoluble vitamiies of vitamin K1.The invention still further relates to the method for preserving this fatsoluble vitamin injection and the medicine box product that comprises this fatsoluble vitamin injection.This emulsion-type injection has good performance to be beneficial to it better to be applied to clinical.
Claims (16)
1. emulsion-type injection is comprising vitamin A, vitamin D2, vitamin E and four kinds of fatsoluble vitamiies of vitamin K1.
2. according to claim 1 emulsion-type injection comprises among its every 10ml:
3. according to claim 1 emulsion-type injection comprises among its every 10ml
4. according to claim 1 emulsion-type injection comprises among its every 10ml
5. according to claim 1 emulsion-type injection comprises among its every 10ml
6. according to claim 1 emulsion-type injection, wherein said vitamin A are that the form with vitamin A palmitate joins in the described injection.
7. dispose the method for each described emulsion-type injection of claim 1 to 6, the method is included in the described emulsion-type injection of storage under the condition that covers 12 ~ 20 ℃ of temperature ranges.
8. according to claim 7 method, the method are included in that the described emulsion-type injection of storage reaches at least 1.5 years under the condition that covers 12 ~ 20 ℃ of temperature ranges, for example reach 1.5 ~ 3 years, for example reach 1.5 ~ 2.5 years, for example reach 2 years.
9. medicine box product, this medicine box product comprise at least one vial, be sealed in each described emulsion-type injection of claim 1 to 6 in the described vial, the box of the described vial of packing and put down in writing the information detail file of the method for disposing described emulsion-type injection.
10. according to claim 9 medicine box product, the method for the described emulsion-type injection of disposal of putting down in writing in the wherein said information detail file provides with written form.
11. medicine box product has according to claim 9 been put down in writing the information of preserving described emulsion-type injection under the condition that covers 12 ~ 20 ℃ of temperature ranges in the wherein said information detail file.
12. medicine box product according to claim 9, put down in writing in the wherein said information detail file covering that the described emulsion-type injection of storage reaches the information at least 1.5 years under the condition of 12 ~ 20 ℃ of temperature ranges, for example reach 1.5 ~ 3 years, for example reach 1.5 ~ 2.5 years, for example reach 2 years.
13. medicine box product according to claim 9, wherein said information detail file are to be printed on described box inwall and/or outer wall; Perhaps, described information detail file is to be printed on the independent paper and to place in the described box; Perhaps, described information detail file is to be printed on the label paper, and described label paper is pasted on the described vial or is pasted on described box inwall and/or outer wall.
14. medicine box product according to claim 9, wherein said vial in each packing the amount of described emulsion-type injection is arranged is 5 ~ 20ml.
15. the method for storage each described emulsion-type injection of claim 1 to 6 or each described medicine box product of claim 9 to 14, the method are included in the process of preserving described emulsion-type injection or described medicine box product under the condition that covers 12 ~ 20 ℃ of temperature ranges.
16. method according to claim 15, the method are included under the condition that covers 12 ~ 20 ℃ of temperature ranges the described emulsion-type injection of storage or described medicine box product reaches at least 1.5 years, for example reach 1.5 ~ 3 years, for example reach 1.5 ~ 2.5 years, for example reach 2 years.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191134A (en) * | 2013-04-26 | 2013-07-10 | 四川省惠达药业有限公司 | Pharmaceutical composition of lipid-soluble vitamin and preparation method thereof |
| EP4169386A1 (en) * | 2021-10-19 | 2023-04-26 | Lipoid GmbH | Liquid composition containing a combination of vitamins a, d, e and k in a liquid matrix |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102429864A (en) * | 2011-11-29 | 2012-05-02 | 海南灵康制药有限公司 | Medicinal compound of fat-soluble vitamin injection (II) and water-soluble vitamin for injection and preparation method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102429864A (en) * | 2011-11-29 | 2012-05-02 | 海南灵康制药有限公司 | Medicinal compound of fat-soluble vitamin injection (II) and water-soluble vitamin for injection and preparation method thereof |
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| 《消化系统疾病合理用药》 20100430 崔屹 脂溶性维生素注射液 山东科学技术出版社 323 1-16 , 第1版 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191134A (en) * | 2013-04-26 | 2013-07-10 | 四川省惠达药业有限公司 | Pharmaceutical composition of lipid-soluble vitamin and preparation method thereof |
| CN103191134B (en) * | 2013-04-26 | 2014-02-12 | 四川省惠达药业有限公司 | Pharmaceutical composition of lipid-soluble vitamin and preparation method thereof |
| EP4169386A1 (en) * | 2021-10-19 | 2023-04-26 | Lipoid GmbH | Liquid composition containing a combination of vitamins a, d, e and k in a liquid matrix |
| WO2023066815A1 (en) | 2021-10-19 | 2023-04-27 | Lipoid Gmbh | Liquid composition containing a combination of vitamins a, d, e and k in a liquid matrix |
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