CN103040845B - Fat emulsion injection for supplementing fat-soluble vitamins - Google Patents
Fat emulsion injection for supplementing fat-soluble vitamins Download PDFInfo
- Publication number
- CN103040845B CN103040845B CN201310021382.1A CN201310021382A CN103040845B CN 103040845 B CN103040845 B CN 103040845B CN 201310021382 A CN201310021382 A CN 201310021382A CN 103040845 B CN103040845 B CN 103040845B
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- China
- Prior art keywords
- vitamin
- injection
- appropriate
- emulsion
- type injection
- Prior art date
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- 239000002960 lipid emulsion Substances 0.000 title abstract description 7
- 230000001502 supplementing effect Effects 0.000 title abstract description 6
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 120
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- 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 54
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- 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 49
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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 for supplementing the fat emulsion injection of 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 mainly comprised fatsoluble vitamin injection (I) and fatsoluble vitamin injection (II) for the clinical fatsoluble vitamin injection in order to supplement the physiological need of every day to fat-soluble A, vitamin D2, vitamin E, vitamin K1 in China.The fatsoluble vitamin injection (I) (the accurate word H32023003 of traditional Chinese medicines) that is mainly applicable to child below 11 years old and baby of for example Wuxi Huarui Pharmaceutical Co. Ltd. production, and in order to meet the fatsoluble vitamin injection (II) (the accurate word H32023138 of traditional Chinese medicines) of adult and the more than 11 years old child every day physiological need to fat-soluble A, vitamin D2, vitamin E, vitamin K1, the two is all sold in China with trade name Vitalipid N Adult.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 in child form fatsoluble vitamin injection (I), every 10 milliliters of contained components are: 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 every 10 milliliters of contained components are in 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 to be 0.12g, glycerol (anhydrous) add to 10ml in right amount for 0.22g and water for injection for 1g, injection lecithin.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 in every 10 milliliters of above-mentioned adult type fatsoluble vitamin injection (II), the vitamin A of 3300IU is 0.99mg, on producing, feeds intake as the vitamin A palmitate of 1.815mg.
After these present medicament listings, there is stricter holding conditions, the fatsoluble vitamin injection (I) that for example above Wuxi Huarui Pharmaceutical Co. Ltd. produces and fatsoluble vitamin injection (II) all specifys will be in " 2～10 DEG C " preservation and/or in " cold place " preservation, thisly for this routine clinical medication, can virtually increase many costs compared with strict preservation condition.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, particularly expect that this emulsion-type injection has good performance to be beneficial to it and is better 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 is better applied to clinical.The inventor have been surprisingly found that such emulsion-type injection not only has good stability while storage under 12 ~ 20 DEG C of conditions, and compare in there is in some aspects better performance under 2 ~ 10 DEG C of conditions.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, its every 10ml comprises:
| 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 |
| 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, be about 8 |
| water for injection | in right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, its every 10ml comprises
| Vitamin A | 0.69~0.99mg |
| Vitamin D2 | 5~10μg |
| Vitamin E | 5.8~10.0mg |
| Vitamin K1 | 0.15~0.2mg |
| 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, be about 8 |
| water for injection | in right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, its every 10ml comprises:
| vitamin A | 0.62 ~ 1.19mg |
| vitamin D2 | 4.5 ~ 12 μ g |
| vitamin E | 6.4 ~ 10mg |
| vitamin K1 | 0.135 ~ 0.24mg |
| 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, be about 8 |
| water for injection | in right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, its every 10ml comprises
| vitamin A | 0.69 ~ 0.99mg |
| vitamin D2 | 5 ~ 10 μ g |
| vitamin E | 6.4 ~ 9.1mg |
| vitamin K1 | 0.15 ~ 0.2mg |
| 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, be about 8 |
| water for injection | in right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, its every 10ml comprises
| Vitamin A | 0.69mg |
| Vitamin D2 | 10μg |
| Vitamin E | 6.4mg |
| Vitamin K1 | 0.2mg |
| 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, be about 8 |
| water for injection | in right amount, add to 10ml. |
According to the emulsion-type injection of first aspect present invention, its every 10ml comprises
| vitamin A | 0.99mg |
| vitamin D2 | 5 μ g |
| vitamin E | 9.1mg |
| vitamin K1 | 0.15mg |
| 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, be 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 to join in described injection with the form of vitamin A palmitate.
According to the emulsion-type injection of first aspect present invention, wherein said vitamin A is to join in described injection with the form of vitamin A palmitate, and it is, and the amount that is converted to vitamin A is calculated.
Second aspect present invention provides the method for disposing emulsion-type injection described in first aspect present invention any one, and the method is included under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserves described emulsion-type injection.
According to the method for second aspect present invention, the method is included in to cover and under the condition of 12 ~ 20 DEG C of temperature ranges, preserves described emulsion-type injection and reach at least 1.5 years.
According to the method for second aspect present invention, the method is included in to cover and under the condition of 12 ~ 20 DEG C of temperature ranges, preserves described emulsion-type injection and reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years).
According to the method for second aspect present invention, the method is included in to cover and under the condition of 12 ~ 20 DEG C of temperature ranges, preserves described emulsion-type injection and reach 2 years.
Third aspect present invention provides a kind of medicine box product, and this medicine box product comprises at least one vial, be sealed in emulsion-type injection described in the first aspect present invention any one in described vial, pack the box of described vial and recorded 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 recording in wherein said information detail file provides with written form.
According to the medicine box product of third aspect present invention, in wherein said information detail file, record the information of preserving described emulsion-type injection under the condition of 12 ~ 20 DEG C of temperature ranges covering.
According to the medicine box product of third aspect present invention, in wherein said information detail file, record under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserved the information that described emulsion-type injection reaches at least 1.5 years.
According to the medicine box product of third aspect present invention, in wherein said information detail file, record and under the condition of 12 ~ 20 DEG C of temperature ranges, preserved described emulsion-type injection reach 1.5 ~ 3 years information of (for example 1.5 ~ 2.5 years) covering.
According to the medicine box product of third aspect present invention, in wherein said information detail file, record under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserved the information that described emulsion-type injection reaches 2 years.
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).
According to the medicine box product of third aspect present invention, wherein said information detail file is be printed on independent paper and be placed in described box (thereby can be placed in described box with the form of inset, for example, be the common form that is inserted into the package insert in medicine inner packaging box).
According to the medicine box product of third aspect present invention, wherein said information detail file is to be printed on label paper, and described label paper is pasted on 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, it can be 1 ~ 100ml that the each middle subpackage of wherein said vial has the amount of described emulsion-type injection, for example, be 5 ~ 20ml, for example 10ml.
Fourth aspect present invention provides the method for medicine box product described in emulsion-type injection described in storage first aspect present invention any one or third aspect present invention any one, 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 DEG C of temperature ranges.
According to the method for fourth aspect present invention, the method is included in to cover preserves described emulsion-type injection under the condition of 12 ~ 20 DEG C of temperature ranges or described medicine box product reaches at least 1.5 years.
According to the method for fourth aspect present invention, the method is included in to cover preserves described emulsion-type injection under the condition of 12 ~ 20 DEG C of temperature ranges 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 in to cover preserves described emulsion-type injection under the condition of 12 ~ 20 DEG C of temperature ranges 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 combine with other embodiment, as long as they there will not be contradiction.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 there will not be contradiction.
Arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, 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.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are 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 be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
In the present invention, for writing conveniently, if not otherwise indicated, vitamin A can be abbreviated as VA, and vitamin A palmitate can be abbreviated as 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 (conventionally in anhydrous glycerol) 0.22g, the appropriate 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 (being equivalent to 3300IU), vitamin D2 are that 5 μ g (being equivalent to 200IU), vitamin E are that 9.1mg (being equivalent to 10IU), vitamin K1 are that 0.15mg, injection soybean oil 1g, injection lecithin 0.12g, glycerol (conventionally in anhydrous glycerol) 0.22g, the appropriate 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 is wherein one of requisite ingredient of intravenous nutrition, in order to meet the physiological need of every day to fat-soluble A, vitamin D2, vitamin E, vitamin K1 of being grown up.
II type formula is 10ml for adult and the every consumption per day of ten one-year-old above children, 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 be prepared according to following technique:
(1) take vitamin A palmitate (being converted to the amount of vitamin A when 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 of preparation total amount approximately 80% is added to stainless cylinder of steel, add while stirring the glycerol (injection) of recipe quantity.
(3) preparation of oil phase: the soybean oil of recipe quantity (injection) 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 Ovum Gallus domesticus Flavus lecithin and dissolve.
(4) preparation of colostrum: pass into nitrogen current, oil phase is slowly added in the water of high-speed stirred, continue high-speed stirred after at least 5 minutes, use 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 after 5MPa low pressure homogenizing 4 times, and under 30MPa pressure, high pressure homogenize 1 time, cooling, then uses the membrane filtration of 10 μ m.
(6) filtrate fill is in 10ml glass ampule, sealing by fusing after inflated with nitrogen, 118 DEG C of moist heat sterilization 25min.
(7) sterilising prods labeling after lamp inspection, packaging, 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 for 9.1mg, the vitamin K1 injection that is 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 for example comprising in every 10ml can be within the scope of 0.89 ~ 1.19mg; The amount of vitamin E can be in 90 ~ 110% scopes of its labelled amount, and the amount of the vitamin E for example comprising in every 10ml can be within the scope of 8.2 ~ 10.0mg.
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 with the following method and measure: precision measures emulsion-type injection 2.5ml of the present invention, put in conical flask, 100ml adds water, add 5 of bromocresol purple indicator solutions, shake up, if aobvious acid, drip 0.1mol/L sodium hydroxide solution, make solution be bluish violet; If aobvious alkalescence, should first drip 0.5mol/L sulfuric acid solution is adjusted to solution and is just yellow, drip again 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 the water-bath of 37～40 DEG C and be incubated 15 minutes, and jolting constantly, add 1,2-PD 3ml, place 5 minutes, be titrated to solution with 0.1mol/L sodium hydroxide volumetric solution and be just bluish violet, to obtain 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 (can represent with abbreviation TG 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 with the following method and measure:
Measure according to high performance liquid chromatography (two annex VD of Chinese Pharmacopoeia version in 2010);
Chromatographic condition and system suitability: the preparation of system suitability solution, get the each 10mg of triglyceride and oleic acid, to 25ml measuring bottle, dissolve and be diluted to scale by mobile phase, shake up, to obtain final product;
With silica gel be filler, normal hexane-isopropyl alcohol-formic acid (90:9:1) is mobile phase, evaporative light scattering detector (atomization gas: N2, atomization gas pressure: 240Pa, evaporator temperature: 60 DEG C) detect; 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 50ml measuring bottle, dissolve and be diluted to scale with the appearance such as normal hexane and isopropyl alcohol mixed solution, be stock solution; Precision measures stock solution 3ml and 4ml, puts respectively in 25ml measuring bottle, is diluted to scale by mobile phase, shakes up, and is reference substance solution 1 and reference substance solution 2;
The preparation of need testing solution: precision measures this product 4ml, puts in 50ml measuring bottle, dissolves and is diluted to scale with the appearance such as normal hexane and isopropyl alcohol mixed solution, shakes up; Precision measures 3ml, puts in 25ml measuring bottle, is diluted to scale by mobile phase, shakes up, and to obtain final product;
Algoscopy respectively precision measures reference substance solution 1, reference substance solution 2, and the each 10 μ l of need testing solution alternately, in injection liquid chromatography, obtain calculated by peak area through chromatographic isolation, to obtain 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 the content of simultaneously measuring with the following method three:
Measure according to high performance liquid chromatography (2010 editions two annex V D of Chinese Pharmacopoeia);
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica be filler; Taking acetonitrile-methanol-dichloromethane (80:10:10) as mobile phase; Detection wavelength is 270nm.Theoretical cam curve is calculated and should be not less than 3000 with vitamin peak E, and the peak-to-peak separating degree of each vitamin should meet the requirements;
The preparation of need testing solution: precision measures this product 5ml and puts in 50ml measuring bottle, dissolves and is diluted to scale with isopropyl alcohol, shakes up, and to obtain final product;
The preparation of vitamin A palmitate stock solution: get the about 45mg of vitamin A palmitate reference substance, accurately weighed, put in 50ml measuring bottle, add isopropyl alcohol and dissolve and be diluted to scale, shake up, to obtain final product;
The preparation of vitamin E stock solution: get the about 45mg of vitamin E reference substance, accurately weighed, put in 50ml measuring bottle, add isopropyl alcohol and dissolve and be diluted to scale, shake up, to obtain final product;
The preparation of vitamin K1 stock solution: get the about 30mg of vitamin K1 reference substance, accurately weighed, put in 200ml measuring bottle, add isopropyl alcohol and dissolve and be diluted to scale, shake up, to obtain final product;
The preparation of reference substance solution: precision measures vitamin A palmitate stock solution 2ml, vitamin E stock solution 10ml, vitamin K1 stock solution 1ml, puts in 100ml measuring bottle, adds isopropyl alcohol and dissolves and be diluted to scale, shakes up, and to obtain final product;
Algoscopy: get respectively the each 20ul of need testing solution and reference substance solution, injection liquid chromatography, records chromatogram, the content by 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 and measure with the following method content:
Measure according to high performance liquid chromatography (2010 editions two annex V D of Chinese Pharmacopoeia);
Chromatographic condition and system suitability test: with silica gel be filler; Cyclohexane extraction-isopropyl alcohol (95:5) is mobile phase; Detection wavelength is 265nm; Theoretical cam curve is calculated and should be not less than 3000 with vitamin D2 peak;
The preparation of reference substance solution: get the about 20mg of vitamin D2 reference substance, accurately weighed, to put in 100ml measuring bottle, methylate tertbutyl ether dissolves and is diluted to scale, shake up, precision measures 1ml, puts in 200ml measuring bottle, methylate tertbutyl ether is diluted to scale, shakes up, and to obtain final product;
Algoscopy: measure 10% fat emulsion injection (C14-C24) 10ml by inner capacities pipet precision and put in 20ml tool plug rub oral examination tube, precision adds reference substance solution 5ml, obturation, shake well 3 minutes, adds appropriate anhydrous sodium sulfate, inaccessible, jolting, stratification, gets supernatant 20ul, injection liquid chromatography, records chromatogram; Separately measure this product 10ml by inner capacities pipet precision and put in 20ml tool plug rub oral examination tube, precision adds methyl tertiary butyl ether(MTBE) 5ml, from " shake well 3 minutes ", with method time-and-motion study.Content by external standard method with vitamin D2 in calculated by peak area test sample.
Typically, the pH value of emulsion-type injection of the present invention should be 6.5～9.0.
Typically, the breast grain of emulsion-type injection of the present invention should meet the requirement of Emulsion used for intravenous injection, typically can measure with enumerator under the microscope, or can use light scattering determining.The breast grain that is typically greater than 1 μ m in injection of the present invention 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%), and must not detect the breast grain that is 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 for the below 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 DEG C of temperature ranges.In one embodiment, phrase " covers the condition of 12 ~ 20 DEG C of temperature ranges " such as but not limited to the known condition that comprises this temperature range of pharmaceutical field technical staff, for example " cool place " condition, for example condition of 12 ~ 20 DEG C of temperature ranges of " room temperature " condition of Chinese Pharmacopoeia regulation, for example Chinese Pharmacopoeia regulation.In an embodiment of either side of the present invention, injection of the present invention is preserved under the condition of 12 ~ 20 DEG C of temperature ranges.In an embodiment of either side of the present invention, injection of the present invention is preserved and is reached at least 1.5 years under the condition of 12 ~ 20 DEG C of temperature ranges.In an embodiment of either side of the present invention, injection of the present invention is preserved and is reached 1.5 ~ 3 years (for example 1.5 ~ 2.5 years) under the condition of 12 ~ 20 DEG C of temperature ranges.In an embodiment of either side of the present invention, injection of the present invention is preserved and is reached 2 years under the condition of 12 ~ 20 DEG C of temperature ranges.
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
1.Vitamin A can promote the synthetic and regeneration of rhodopsin in eyeball, maintains twenty-twenty vision, and control nyctalopia, maintains epithelial growth and differentiation, improves immunity and resistance.Vitamin D increase calcium and phosphorus, in enteral absorption, by regulating the homergy of calcium and phosphorus essential, promote 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, relevant with reproductive performance and spermatogenesis.Vitamin K participates in the synthetic of thrombinogen, participates in the oxidation-reduction process in histiocyte, increases the elasticity of muscular tissue.
In the present invention, provide a kind of emulsion-type injection, term " emulsion-type injection " is those skilled in the art's understandable Emulsions for injecting conventionally.
In the present invention, a kind of emulsion-type injection is provided, it is preserved described emulsion-type injection and reaches at least 1.5 years and (for example reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years) covering under condition of 12 ~ 20 DEG C of temperature ranges, for example reach 2 years), and after storage during this, every quality index of medicine still meets the standard regulation of this medicine.Or 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 DEG C of temperature ranges.The implication of this effect duration be applicable to first aspect present invention emulsion-type injection, be equally applicable to the method for second aspect present invention, be also applicable to the medicine box product of third aspect present invention.Therefore the effect duration that, the emulsion-type injection of first aspect present invention is preserved under the condition of 12 ~ 20 DEG C of temperature ranges of covering 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); Or emulsion-type injection described in the method disposal first aspect present invention any one of use second aspect present invention, under the condition of 12 ~ 20 DEG C of temperature ranges, preserve described emulsion-type injection effect duration and 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; Or in the medicine box product of third aspect present invention, mark this medicine box product emulsion-type injection under the condition of 12 ~ 20 DEG C of temperature ranges, preserve effect duration and 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.
In addition, according to the medicine box product of third aspect present invention, it can be understood as for clinical medicine, this medicine comprises the emulsion-type injection medicinal liquid being sealed in vial, wrap up box (for example carton of this vial, plastic casing etc., normally carton box), 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, this emulsion-type injection is preserved effect duration and is reached at least 1.5 years and (for example reach 1.5 ~ 3 years (for example 1.5 ~ 2.5 years) covering under the condition of 12 ~ 20 DEG C of temperature ranges, for example reach 2 years) storage information.This storage information can directly be printed on described box, or can be printed on independent paper and by this paper and insert in this box with the form of package insert, or can be printed on the label that is pasted on vial surface.
According to the medicine box product of third aspect present invention, in an one box, can comprise a vial, can also comprise multiple vials, for example in a box, can pack 1 ~ 20 vial into simultaneously.
The vial of mentioning for the present invention, it can be the vial that meets injection medicine packaging glass container relevant regulations.This vial can be colourless or brown, preferably brown, is conducive to like this avoid the harmful effect of illumination to drug quality.In addition, the shape of this vial is not particularly limited, and for example it can be ampoule form, at subpackage after medicinal liquid, seal by the mode of flame sealing by fusing; Also can be the form of cillin bottle or phial, after subpackage medicinal liquid, pass through the mode of for example rubber stopper of stopper by bottle sealing.
Emulsion-type injection provided by the invention is carried out to cold place (setting 3 ~ 9 DEG C) to this product to the inventor and shady and cool place (setting 12 ~ 20 DEG C) has carried out the stability comparative study of 30 months, result shows under two kinds of holding conditions for the conventional sense project of this product emulsion-type injection, under two kinds of holding conditions, the stability of sample, without significant difference, all meets common quality standard requirement.
But inventor have been surprisingly found that, under the temperature conditions of 12 ~ 20 DEG C, is dissolved in the more stable trend of amount demonstration of the active component in breast grain.Thus, emulsion-type injection of the present invention can use the more loose temperature conditions of holding conditions instead and quality without impact.
Detailed description of the invention
Further illustrate 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 use specifically describing more in detail, 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 test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention uses, 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 not specified, material therefor of the present invention and operational approach are well known in the art.Below preparing in the test of injection, the scale that each batch props up ampoule bottle by 20000 × 10ml/ feeds intake.
one, emulsion-type injection preparation example part of the present invention
preparation example 1: prepare emulsion-type injection of the present invention (I type)
In every bottle of 10ml, prepare burden
| vitamin A | 0.69mg |
| vitamin D2 | 10 μ g |
| vitamin E | 6.4mg |
| vitamin K1 | 0.2mg |
| 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 to feed intake with the form of vitamin A palmitate, and in formula table, calculating every inventory by vitamin A is 0.69mg, and the context of the invention has identical meanings therewith.
Preparation technology:
(1) take 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 of preparation total amount approximately 80% is added to stainless cylinder of steel, add while stirring the glycerol (injection) of recipe quantity;
(3) preparation of oil phase: the soybean oil of recipe quantity (injection) 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 Ovum Gallus domesticus Flavus lecithin and dissolve;
(4) preparation of colostrum: pass into nitrogen current, oil phase is slowly added in the water of high-speed stirred, continue high-speed stirred after at least 5 minutes, use 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 after 5MPa low pressure homogenizing 4 times, and under 30MPa pressure, high pressure homogenize 1 time, cooling, then uses the membrane filtration of 10 μ m;
(6) filtrate fill is in 10ml clear glass ampoule bottle, sealing by fusing after inflated with nitrogen, 118 DEG C of moist heat sterilization 25min;
(7) sterilising prods labeling after lamp inspection, packaging, after the full review of sampling is qualified and get final product.
Above composition and engineering, produces 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)
In every bottle of 10ml, prepare burden
| vitamin A | 0.99mg |
| vitamin D2 | 5 μ g |
| vitamin E | 9.1mg |
| vitamin K1 | 0.15mg |
| 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 to feed intake with the form of vitamin A palmitate, 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 identical meanings therewith.
Method for making is with embodiment 1.Above composition and engineering, produces 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
In every bottle of 10ml, prepare burden
| Vitamin A | 0.62mg |
| Vitamin D2 | 12μg |
| Vitamin E | 5.8mg |
| Vitamin K1 | 0.24mg |
| 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, in this emulsion-type injection, the content of active component is all in 95 ~ 105% scopes of labelled amount, and every physical property for example breast grain granularity, outward appearance, pH value etc. all meet particularly fatsoluble vitamin injection (I) or the regulation of standard (II) of general Emulsion, for example product characteristics are milky emulsion, pH value is 7.5～8.5, with light scattering determining, the breast grain that is greater than 1 μ m is no more than 4%, and does not detect the breast grain that is greater than 5 μ m.
preparation example 4: prepare emulsion-type injection of the present invention
In every bottle of 10ml, prepare burden
| vitamin A | 1.19mg |
| vitamin D2 | 4.5 μ g |
| vitamin E | 10.0mg |
| vitamin K1 | 0.135mg |
| 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, in this emulsion-type injection, the content of active component is all in 95 ~ 105% scopes of labelled amount, and every physical property for example breast grain granularity, outward appearance, pH value etc. all meet particularly fatsoluble vitamin injection (I) or the regulation of standard (II) of general Emulsion, for example product characteristics are milky emulsion, pH value is 7.5～8.5, with light scattering determining, the breast grain that is greater than 1 μ m is no more than 4%, and does not detect the breast grain that is greater than 5 μ m.
Each Lot sample prepared by above preparation example 1-4, the amount of propping up with 10ml/ is sub-packed in flint glass ampoule bottle, and then this pastille ampoule bottle is put in carton, in carton, place package insert simultaneously, in this description, record drug storage condition, the temperature range of this holding conditions indicating in package insert has covered the temperature range (being specially " (be no more than 20 DEG C) in the cool and preserve, must not be freezing ") of 12 ~ 20 DEG C.In addition, the carton that this is equipped with to medicine is placed under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserves 1.5 years, 2 years, 2.5 years, 3 years.
In supplementary in addition test, formula and method for making are identical with preparation example 2, and different is is 6.7 ± 0.2 or 8.8 ± 0.2 by medicinal liquid sodium hydroxide adjust pH.On inspection/measure, in two batches of emulsion-type injection of gained, the content of active component is all in 95 ~ 105% scopes of labelled amount, and every physical property for example breast grain granularity, outward appearance, pH value etc. all meet particularly fatsoluble vitamin injection (I) or the regulation of standard (II) of general Emulsion, for example product characteristics are milky emulsion, pH value is 7.5～8.5, with light scattering determining, the breast grain that is greater than 1 μ m is no more than 4%, and does not detect the breast grain that is greater than 5 μ m.
two, test example part
test example 1, emulsion-type injection steady dissolution of the present invention are investigated
1, the stability test method that keeps sample: each Lot sample that above preparation example part obtains, every Lot sample divides two parts sample (all to seal subpackage with ampoule bottle, shading), be placed in respectively design temperature at two temperature-controlled boxs that fluctuate between 3 ~ 9 DEG C and design temperature fluctuates between 12 ~ 20 DEG C, place 30 months, sampling during respectively at 0 month, 18 months, 24 months and 30 months, measures steady dissolution.
2, steady dissolution assay method and result: the sample of each point in time sampling (in 0 month sample, two temperature being merged into same sample) is placed in respectively to 10ml centrifuge tube and carries out centrifugal (different batches sample, 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, draw the latter half liquid appropriate, measure 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 the concentration of medicine in water (can be with C
waterrepresent), 0 month time, the concentration of medicine in water can be used C
water, 0 monthrepresent, 24 months time, the concentration of medicine in water can be used C
water, 24 monthsrepresent.
For every Lot sample, calculate its C in different time points
watervalue, then calculates each time point C
waterc while being worth with respect to 0 month
waterthe concentration change percent of value.Sample for example, during for 24 months, this concentration change percent calculating formula is as follows:
This concentration change percent can reflect the intensity of variation through certain hour after of medicine in continuous phase and the decentralized photo of Emulsion.
The result of part sample vitamin A concentration percent change of the present invention is as following table 1.
Table 1:
The result of part sample vitamin K1 concentration change percent of the present invention is as following table 2.
Table 2:
In addition, for vitamin D2 and vitamin E, find no above-mentioned 3 ~ 9 DEG C of variation tendencies at temperature that are similar to, the concentration change percent in the time of 18,24,30 months of vitamin D2 and vitamin E is all in the scope-2% ~ 3%.
This test example is to measure the method for vitamin content in Emulsion continuous phase (water), investigate the overwhelming majority be dissolved in medicine in Emulsion oil phase (decentralized photo) through different temperatures is long-time place after, permeate and be dissolved in the situation of change in water, if the fat-soluble medicine concentration change in water (particularly increasing) obviously, may there is hidden danger in medicine, for example, active component in being soluble in the aqueous phase may occur supersaturation 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 long term test, but from table 1 above, 2 result, for emulsion-type injection of the present invention, they place after 30 months at 3 ~ 9 DEG C of temperature, vitamin A and vitamin K1 there will be the variation that concentration increases in 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 place and have no this variation at 12 ~ 20 DEG C.
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 storage (layering or break).Emulsion creaming: claim again breast to analyse, refer to that dispersed phase particles floating or the phenomenon of sinking appear in Emulsion in put procedure, the Emulsion outward appearance after layering is more coarse, and jolting can revert to 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 annex VI H pH value algoscopys of Chinese Pharmacopoeia version in 2010, when preparation, each sample pH value is all in 7.5 ~ 8.5 scopes.
(4) breast grain: measure according to 2010 editions two annex I X E light scattering methods of Chinese Pharmacopoeia, meet the granularity requirements of two annex I B of Chinese Pharmacopoeia version in 2010 to emulsion droplet in vein emulsion type injection, the granularity 90% of emulsion droplet should, below 1 μ m, must not have the emulsion droplet that is greater than 5 μ m.
(5) free fatty (can represent with abbreviation FFA in this article)
The preparation of contrast solution: get Palmic acid 0.64g, accurately weighed, put in 500ml measuring bottle, add normal heptane and dissolve and be diluted to scale, shake up;
Algoscopy: precision measures this product and the each 1ml of contrast solution, puts respectively in 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 is placed 10 minutes.Need testing solution pipe precision adds normal heptane and the each 3ml of water, and reference substance solution pipe precision adds normal heptane 2ml and water 4ml, close plug, spin upside down 10 times, leave standstill at least 15 minutes, make layering, precision measures upper strata liquid 3ml respectively, put in 10ml centrifuge tube, (get Nile blue 0.04g, the 200ml that adds water, after making to dissolve to add Nile blue indicator solution, add normal heptane 100ml jolting, discard upper strata normal heptane; Repeatable operation 4 times; Get lower aqueous solution 20ml, add dehydrated alcohol 180ml, mix.This liquid is put in brown bottle, under room temperature, can deposit one month) 1ml, under logical nitrogen condition, be titrated to solution with sodium hydroxide volumetric solution (0.01mol/L) and show lavender; The milliliter number that need testing solution consumes sodium hydroxide volumetric solution (0.01mol/L) is A, the milliliter number that reference substance solution consumes sodium hydroxide volumetric solution (0.01mol/L) is B, calculate according to following formula, must not cross 5.0mmol/L containing free fatty;
Wherein 5.0 for the concentration of Palmic acid reference substance solution be 5.0mmol/L.
(6) peroxide value
Precision measures this product 10ml, puts in 250ml round-bottomed flask, removes moisture in 60 DEG C of water-bath rotary evaporation in vacuo.Add acetic acid-chloroform (3:2) mixed liquor 30ml, after jolting is dissolved, add saturated solution of potassium iodide 0.5ml, accurately shaking out 1 minute, then add water 30ml, violent jolting limit, limit is used sodium thiosulfate volumetric solution (0.01mol/L) to be titrated to 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 blank assay, in blank assay, the consumption of sodium thiosulfate volumetric solution (0.01mol/L) must not be crossed 0.1ml simultaneously.Calculate according to following formula, peroxide value must not be crossed 0.1mmol/kg.
In formula, V is the volume that test sample consumes sodium thiosulfate volumetric solution (0.01mol/L), ml; V
0for 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 (can represent with abbreviation LPC in this article)
Chromatographic condition and system property test on probation: closing silica gel with dihydroxypropyl silane chain is filler (LiChrospher100DIOL); Taking normal heptane-isopropyl alcohol (43:57) as mobile phase A, taking normal heptane-isopropanol-water (29.5:59:11.5) as Mobile phase B, carry out gradient elution, flow velocity is 1.5ml per minute.Evaporative light scattering detector (atomization gas: N
2, atomization gas pressure: 240KPa, evaporator temperature: 70 DEG C) detect.Number of theoretical plate calculates and is not less than 2000 with lysophosphatide peak.
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 appropriate that precision takes lysophosphatide, adds isopropyl alcohol-n-heptane solution (2:1) and dissolves and dilute, make concentration be respectively every 1ml containing 0.02,0.04,0.1, the reference substance solution of 0.2mg.Precision measures in the each 50ml injection liquid of reference substance solution chromatography and records chromatogram, according to the content of lysophosphatide in 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 measures this product 1ml, puts in 10ml measuring bottle, adds isopropyl alcohol-n-heptane solution (2:1) and is diluted to scale, shakes up, and to obtain final product.
Algoscopy: precision measures need testing solution 50ml, injection liquid chromatography, records chromatogram, by lysophosphatide content in regression equation calculation test sample.In every 1ml, must not cross 1.2mg containing lysophosphatide.
(8) content: each vitamin, glycerol and triglyceride content are all undertaken by assay method mentioned above.
(9) bacterial endotoxin, aseptic: all check latter stage with investigation before stability keeps sample by the method for two regulations of Chinese Pharmacopoeia version in 2010.
2, investigate sample
Tri-crowdes of II-101, the II-102, the II-103 that above in preparation example, prepare, 10ml/ bottle, sealing by fusing is (this comprises identical with commercially available product) in 10ml Clear glass bottles and jars.
3, study on the stability method
(1) accelerated test: by the requirement of Chinese Pharmacopoeia two annex XI X C of version in 2010 " crude drug and pharmaceutical preparation stability test guideline ", Emulsion directly adopts the condition of 30 DEG C ± 2 DEG C of temperature to test.
(2) 6 ± 2 DEG C of long term tests (keeping sample referred to as 6 DEG C): sample is placed under the temperature conditions of 6 ± 2 DEG C, placed 30 months, in 0 month, June, December, sampling and measuring 18 months, 24 months, 30 months time.
(3) 16 ± 4 DEG C of long term tests (keeping sample referred to as 16 DEG C): sample is placed under the temperature conditions of 16 ± 4 DEG C, placed 30 months, in 0 month, June, December, sampling and measuring 18 months, 24 months, 30 months time.
4, study on the stability result of the test
II-101, II-102, tri-crowdes of II-103 measure the index of each sample under accelerated test, 6 ± 2 DEG C of long term tests, three kinds of experimental conditions of 16 ± 4 DEG C of long term tests in different time points, result is shown in respectively following table 3 ~ table 11.
Table 3: accelerated test result (sample lot number: II-101)
| The investigation time (moon) | 0 | 3 | 6 |
| Appearance luster | Qualified | Qualified | Qualified |
| Layering/breaking | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| Breast grain | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | Conform with the regulations |
In upper table, for Four Vitamins content, the concentration that represents them with " qualified " all, in 95% ~ 105% scope of the theoretical labelled amount of this formula, also has similar meaning while below having similar statement in result of the test.
Table 4: accelerated test result (sample lot number: II-102)
| The investigation time (moon) | 0 | 3 | 6 |
| Appearance luster | Qualified | Qualified | Qualified |
| Layering/breaking | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| Breast grain | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | Conform with the regulations |
Table 5: accelerated test result (sample lot number: II-103)
| The investigation time (moon) | 0 | 3 | 6 |
| Appearance luster | Qualified | Qualified | Qualified |
| Layering/breaking | Be showed no | Be showed no | Be showed no |
| PH value | 7.5~8.5 | 7.5~8.5 | 7.5~8.5 |
| Breast grain | Qualified | Qualified | Qualified |
| FFA(mmol/L) | 2.0~4.5 | 2.0~4.5 | 2.0~4.5 |
| Peroxide value | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | Conform with the regulations |
Table 6: long term test (6 DEG C keep sample) result (sample lot number: II-101)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/breaking | 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 |
| 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 | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | -- | Conform with the regulations |
Table 7: long term test (6 DEG C keep sample) result (sample lot number: II-102)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/breaking | 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 |
| 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 | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | -- | Conform with the regulations |
Table 8: long term test (6 DEG C keep sample) result (sample lot number: II-103)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/breaking | 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 |
| 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 | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | -- | Conform with the regulations |
Table 9: long term test (16 DEG C keep sample) result (sample lot number: II-101)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Qualified | Qualified | Qualified | Qualified |
| Layering/breaking | 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 |
| 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 | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | -- | Conform with the regulations |
Table 10: long term test (16 DEG C keep sample) result (sample lot number: II-102)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Milky emulsion | Milky emulsion | Milky emulsion | Milky emulsion |
| Layering/breaking | 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 |
| 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 | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | -- | Conform with the regulations |
Table 11: long term test (16 DEG C keep sample) result (sample lot number: II-103)
| The investigation time (moon) | 0 | 12 | 24 | 30 |
| Appearance luster | Milky emulsion | Milky emulsion | Milky emulsion | Milky emulsion |
| Layering/breaking | 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 |
| 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 | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 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 | Conform with the regulations | -- | -- | Conform with the regulations |
| Aseptic | Conform with the regulations | -- | -- | Conform with the regulations |
In supplementary test, also having investigated according to said method I-101, I-102 sample and preparation example 3 and 4 that preparation example 1 of the present invention obtains obtains samples and keeps sample and stability result that 16 DEG C keep sample under two kinds of conditions at 6 DEG C, result shows substantially that with above, for the coming to the same thing of the table 6 ~ table 11 of sample II-101, II-102, II-103 tri-samples, these samples still meet general drug standard regulation place 30 months under two kinds of conditions that keep sample after.
Below to the each main quality index amplitude of variation of II-101, II-102, II-103 tri-samples long term test under two kinds of holding conditions (30 months poor with 0 month numerical value, take absolute value) as a comparison, result is respectively in table 12 ~ 14, being presented at two kinds of stability keeps sample under 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 the difference of investigating two kinds of holding conditions and substantially cannot determine two kinds of methods.
Table 12: the 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 DEG C of 30 monthly variation amplitudes that keep sample | 16 DEG C 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: the 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 DEG C of 30 monthly variation amplitudes that keep sample | 16 DEG C 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: the 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 DEG C of 30 monthly variation amplitudes that keep sample | 16 DEG C 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 to be better applied to clinical.
Claims (1)
1. dispose the method for emulsion-type injection, the method is included in preserves described emulsion-type injection under the condition that covers 12 ~ 20 DEG C of temperature ranges and reaches 1.5 ~ 3 years, and the every 10ml of described emulsion-type injection comprises:
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,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml.
2. according to the method for claim 1, the method is included in preserves described emulsion-type injection under the condition that covers 12 ~ 20 DEG C of temperature ranges and reaches 1.5 ~ 2.5 years.
3. according to the method for claim 1, the method is included in preserves described emulsion-type injection under the condition that covers 12 ~ 20 DEG C of temperature ranges and reaches 1.5 years or 2.5 years.
4. according to the method for claim 1, the method is included in preserves described emulsion-type injection under the condition that covers 12 ~ 20 DEG C of temperature ranges and reaches 2 years.
5. according to the process of claim 1 wherein that the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69 ~ 0.99mg,
Vitamin D2: 5 ~ 10 μ g,
Vitamin E: 5.8 ~ 10.0mg,
Vitamin K1: 0.15 ~ 0.2mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml.
6. according to the process of claim 1 wherein that the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69mg,
Vitamin D2: 10 μ g,
Vitamin E: 6.4mg,
Vitamin K1: 0.2mg,
Injection soybean oil: 1g,
Injection lecithin: 0.12g,
Glycerol: 0.22g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml.
7. according to the process of claim 1 wherein that the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.99mg,
Vitamin D2: 5 μ g,
Vitamin E: 9.1mg,
Vitamin K1: 0.15mg,
Injection soybean oil: 1g,
Injection lecithin: 0.12g,
Glycerol: 0.22g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml.
8. according to the method for claim 1 to 7 any one, wherein said vitamin A is to join in described injection with the form of vitamin A palmitate.
9. according to the method for claim 1 to 7 any one, wherein said vitamin A is to join in described injection with the form of vitamin A palmitate, and it is, and the amount that is converted to vitamin A is calculated.
10. according to the process of claim 1 wherein that the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.62 ~ 1.19mg,
Vitamin D2: 4.5 ~ 12 μ g,
Vitamin E: 6.4 ~ 10mg,
Vitamin K1: 0.135 ~ 0.24mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69 ~ 0.99mg,
Vitamin D2: 5 ~ 10 μ g,
Vitamin E: 6.4 ~ 9.1mg,
Vitamin K1: 0.15 ~ 0.2mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml.
The method of 11. storage medicine box products, the method is included under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserves the process that described medicine box product reaches 1.5 ~ 3 years; Described medicine box product comprises at least one vial, be sealed in emulsion-type injection in described vial, pack the box of described vial and recorded the information detail file of the method for disposing described emulsion-type injection, wherein
In described information detail file, record under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserved the information that described emulsion-type injection reaches 1.5 ~ 3 years;
The every 10ml of described emulsion-type injection comprises:
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,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69 ~ 0.99mg,
Vitamin D2: 5 ~ 10 μ g,
Vitamin E: 5.8 ~ 10.0mg,
Vitamin K1: 0.15 ~ 0.2mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69mg,
Vitamin D2: 10 μ g,
Vitamin E: 6.4mg,
Vitamin K1: 0.2mg,
Injection soybean oil: 1g,
Injection lecithin: 0.12g,
Glycerol: 0.22g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.99mg,
Vitamin D2: 5 μ g,
Vitamin E: 9.1mg,
Vitamin K1: 0.15mg,
Injection soybean oil: 1g,
Injection lecithin: 0.12g,
Glycerol: 0.22g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.62 ~ 1.19mg,
Vitamin D2: 4.5 ~ 12 μ g,
Vitamin E: 6.4 ~ 10mg,
Vitamin K1: 0.135 ~ 0.24mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69 ~ 0.99mg,
Vitamin D2: 5 ~ 10 μ g,
Vitamin E: 6.4 ~ 9.1mg,
Vitamin K1: 0.15 ~ 0.2mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml.
12. according to the method for claim 11, and wherein said vitamin A is to join in described injection with the form of vitamin A palmitate.
13. according to the method for claim 11, and wherein said vitamin A is to join in described injection with the form of vitamin A palmitate, and it is, and the amount that is converted to vitamin A is calculated.
14. according to the method for claim 11, and the method for the described emulsion-type injection of disposal of recording in wherein said information detail file provides with written form.
15. according to the method for claim 11, has recorded under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserve the information that described emulsion-type injection reaches 1.5 ~ 2.5 years in wherein said information detail file.
16. according to the method for claim 11, has recorded the information of preserving described emulsion-type injection under the condition of 12 ~ 20 DEG C of temperature ranges and reach 1.5 years or 2.5 years covering in wherein said information detail file.
17. according to the method for claim 11, has recorded under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserve the information that described emulsion-type injection reaches 2 years in wherein said information detail file.
18. according to the method for claim 11, and wherein said information detail file is to be printed on described box inwall and/or outer wall; Or described information detail file is be printed on independent paper and be placed in described box; Or described information detail file is to be printed on label paper, described label paper is pasted on described vial or is pasted on described box inwall and/or outer wall.
19. according to the method for claim 11-18 any one, and it is 5 ~ 20ml that the each middle subpackage of wherein said vial has the amount of described emulsion-type injection.
The method of 20. storage emulsion-type injection, the method is included under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserves the process that described emulsion-type injection reaches 1.5 ~ 3 years, wherein:
The every 10ml of described emulsion-type injection comprises:
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,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69 ~ 0.99mg,
Vitamin D2: 5 ~ 10 μ g,
Vitamin E: 5.8 ~ 10.0mg,
Vitamin K1: 0.15 ~ 0.2mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69mg,
Vitamin D2: 10 μ g,
Vitamin E: 6.4mg,
Vitamin K1: 0.2mg,
Injection soybean oil: 1g,
Injection lecithin: 0.12g,
Glycerol: 0.22g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.99mg,
Vitamin D2: 5 μ g,
Vitamin E: 9.1mg,
Vitamin K1: 0.15mg,
Injection soybean oil: 1g,
Injection lecithin: 0.12g,
Glycerol: 0.22g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.62 ~ 1.19mg,
Vitamin D2: 4.5 ~ 12 μ g,
Vitamin E: 6.4 ~ 10mg,
Vitamin K1: 0.135 ~ 0.24mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0
Water for injection: appropriate, add to 10ml;
Or the every 10ml of described emulsion-type injection comprises:
Vitamin A: 0.69 ~ 0.99mg,
Vitamin D2: 5 ~ 10 μ g,
Vitamin E: 6.4 ~ 9.1mg,
Vitamin K1: 0.15 ~ 0.2mg,
Injection soybean oil: 0.8 ~ 1.2g,
Injection lecithin: 0.1 ~ 0.14g,
Glycerol: 0.2 ~ 0.24g,
Sodium hydroxide: appropriate, adjust pH is 6.5 ~ 9.0,
Water for injection: appropriate, add to 10ml.
21. according to the method for claim 20, and wherein said vitamin A is to join in described injection with the form of vitamin A palmitate.
22. according to the method for claim 20, and wherein said vitamin A is to join in described injection with the form of vitamin A palmitate, and it is, and the amount that is converted to vitamin A is calculated.
23. according to the method for claim 20, and the method is included under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserves the process that described emulsion-type injection reaches 1.5 ~ 2.5 years.
24. according to the method for claim 20, and the method is included in the process of preserving described emulsion-type injection under the condition of 12 ~ 20 DEG C of temperature ranges and reach 1.5 years or 2.5 years that covers.
25. according to the method for claim 20, and the method is included under the condition that covers 12 ~ 20 DEG C of temperature ranges and preserves the process that described emulsion-type injection reaches 2 years.
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| 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 |
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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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| 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 |
Non-Patent Citations (5)
| Title |
|---|
| 崔屹.脂溶性维生素注射液.《消化系统疾病合理用药》.山东科学技术出版社,2010,(第1版),323. * |
| 曾韶辉.脂溶性维生素注射液(II)与常用临床输液配伍的稳定性考察.《医学新知杂志》.2006,第16卷(第3期),150-152. |
| 王广银.脂溶性维生素注射液(II).《临床用药指导》.山东大学出版社,2010,(第1版),327-328. * |
| 田野.脂溶性维生素注射液.《移植药物手册》.人民卫生出版社,2011,(第1版),349. * |
| 脂溶性维生素注射液(II)与常用临床输液配伍的稳定性考察;曾韶辉;《医学新知杂志》;20061231;第16卷(第3期);150-152 * |
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