CN106038575B - Fat-soluble vitamin for injection II powder-injection composition and preparation method - Google Patents
Fat-soluble vitamin for injection II powder-injection composition and preparation method Download PDFInfo
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Abstract
The present invention relates to fat-soluble vitamin for injection II powder-injection composition and preparation methods.In particular it relates to the composition of fat-soluble vitamin for injection II freeze-drying powder-injections, wherein including the component of following weight proportion：445~595 μ g vitamin As, 2.25~3.00 μ g calciferols, 4.1~5.0mg vitamin Es, 67.5~90.0 μ g vitamin K1s.The invention further relates to the preparation methods of the composition.Composition provided by the invention has excellent effect as used in the description.
Description
Technical field
The invention belongs to technology of pharmaceutical engineering fields, specifically, being related to a kind of liposoluble vitamin preparation and its system
Method, more particularly to a kind of fat-soluble vitamin for injection II powder-injection composition and its preparation method.
Background technology
Vitamin is that humans and animals are to maintain normal physiological function and required a kind of trace organic substance, is given birth in human body
It plays an important role in long, metabolism, growth course, normal growth is unable to when humans and animals are deficient in vitamin, and spy occurs
Anisotropic lesion, i.e., so-called vitamin-deficiency.
Vitamin also known as vitamin, for popular, that is, the substance to sustain life is to maintain human life activity necessary one
Type organic matter is also to maintain the important active substances of health.The content of vitamin in vivo is seldom, but indispensable.
Although the chemical constitution and property of various vitamins are different, they have following common ground：1. vitamin is to tie up life
The form of plain original (previtamin) is present in food.2. vitamin is not the constituent for constituting body tissue and cell,
It will not generate energy, its effect mainly participates in the adjusting of organism metabolism.3. most of vitamin, body cannot close
At or synthetic quantity it is insufficient, the needs of body cannot be met, it is necessary to frequently by being obtained in food.4. human body is to the needs of vitamin
Very little is measured, daily requirement is often calculated with milligram (mg) or microgram (μ g), but once shortage will cause corresponding hypovitaminosis
Disease damages health.Vitamin is different from carbohydrate, fat and 3 big substance of protein, in natural food
Minor proportion is only accounted for, but it is required for human body.Some vitamins such as B6 and K can be synthesized by the bacterium in animal intestinal tract, be closed
The needs of animal can be met at amount.Tryptophan transfer can be become niacin (a kind of B family vitamin) by zooblast, but production quantity is not applied
It needs；For vitamin C in addition to primate (including mankind) and cavy, other animals can itself synthesis.Plant and majority are micro-
Biology oneself can synthesize vitamin, it is not necessary to by external supply.Many vitamins are the component parts of prothetic group or coenzyme.
Vitamin is certain a small amount of organic compounds necessary to humans and animals nutrition, growth, to the metabolism of body,
Growth, development, health have effect of the utmost importance.If certain vitamin of long-term lacking will cause physiological function obstacle and occur
Certain disease.
Vitamin is essential organic compound in body metabolism.Human body like an extremely complex chemical plant,
Constantly carry out various biochemical reactions.Its catalytic action for reacting with enzyme has substantial connection.Enzyme will generate activity, it is necessary to have auxiliary
Enzyme is participated in.Known much vitamins are the ingredients of the coenzyme either coenzyme of enzyme.Therefore, vitamin is to maintain and adjust machine
The important substance of body eubolism.It is believed that best vitamin is in the form of " bioactive substance ", it is present in human body
In tissue.
One of the great discovery for being the discovery that for 20th century of vitamin.1897, Ai Keman (ChrIstIan EIjkman) existed
Java finds that the rice for only eating fine grinding can suffer from athlete's foot, and the brown rice without milling can treat this disease.And it finds that tinea pedis can be controlled
The substance of disease can use water or alcoholic extraction, and this substance was referred to as " water-soluble B " at that time.It proves within 1906 to contain removing protein in food
" cofactor " other than matter, lipid, carbohydrate, inorganic salts and water, amount very little, but it is required for growth of animal.
1911 Casimir Feng Ke (KazImIerzFunk) identify that the substance of athlete's foot can be fought in brown rice is amine (one
Class contains nitrogen compound), it is necessary to sustaining life, so suggesting being named as " VItamIne ".That is VItal (life)
AmIne (amine), the Chinese meaning are " life amine ".Many vitamins are found successively later, their chemical property is different, physiology work(
It can be different, it has been found that many vitamins are not amine-containing, not nitrogenous, but the name of Feng Ke continues use and gets off, only will most
Alphabetical " e " removes afterwards.The vitamin B being originally found turns out to be vitamin B complex later, and purified separation is found, is several
Substance, only property is similar with the distribution in food, and most is coenzyme.Some supply amounts must balance each other, such as vitamin
Otherwise B1, B2 and PP can influence physiological action.Vitamin B complex includes：Pantothenic acid, niacin, biotin, folic acid, vitamin B1
(thiamine), vitamin B2 (riboflavin), pyridoxol (vitamin B6) and cyanocobalamin (vitamin B12).Someone is also by choline, flesh
Alcohol, para-aminobenzoic acid (p-aminobenzoic acid), carnitine, lipoic acid include in B complexs.
As soon as vitamin is a large family, it is currently known more than 20 kinds, people press its deliquescent difference, vitamin
It is divided into water soluble vitamin and liposoluble vitamin two major classes.Liposoluble vitamin includes tetra- kinds of A, D, E, K, water soluble vitamin
Including B family vitamin (B1, B2, B6, B12 etc.) and vitamin C.
For example, the existing fat-soluble vitamin for injection I powder-injection clinically used, typical proportioning is (such as 1 bottle
Amount or half bottle of amount)：310~415 μ g vitamin As, 4.5~6.0 μ g calciferols, 2.9~3.5mg vitamin Es, 90~120 μ g
Vitamin K1；Or its typical proportioning is (such as 2 bottles of amounts or 1 bottle of amount)：690 μ g vitamin As, 10 μ g calciferols, 6.4mg
Vitamin E, 200 μ g vitamin K1s.
Further for example, the existing fat-soluble vitamin for injection II powder-injection clinically used, typical proportioning for (such as
1 bottle of amount or half bottle of amount)：445~595 μ g vitamin As, 2.25~3.00 μ g calciferols, 4.1~5.0mg vitamin Es, 67.5
~90.0 μ g vitamin K1s；Or its typical proportioning is (such as 1 bottle of amount or half bottle of amount)：495 μ g vitamin As, 2.5 μ g dimension lifes
Plain D2,4.55mg vitamin E, 75 μ g vitamin K1s；Or its typical proportioning is (such as 2 bottles of amounts or 1 bottle of amount)：990 μ g dimensions
Raw element A, 5 μ g calciferols, 9.1mg vitamin Es, 150 μ g vitamin K1s.
Parenteral alimentation (Parenteral nutrItIon, PN) is widely used in treatment and the average of operation periods patient of a variety of diseases
Nutritional support, vitamin as metabolism important confactor, be the main component of parenteral alimentation.Clinical main use
It cannot be fed in due to operation, large-area burns, fracture and other wounds, seriousness infectious disease and comatose state etc.,
The patient that need to parenterally absorb nourishment.
Vitamin A, calciferol, vitamin E, vitamin K1 are that body maintains liposoluble necessary to eubolism and function
Property vitamin.Vitamin A is the neccessary composition for promoting growth, keeps the visual process of retina, has and maintains human cell membrane steady
Fixed effect will cause body to stop growing after shortage, yctalopia, xerophthalmia and keratomalacia.Calciferol can form bone group
It knits, increases the absorption of calcium and phosphorus, malacosteon is formed after shortage.Vitamin E has intracellular antioxidation, is oxygen radical
Scavenger makes after shortage erythrocyte membrane destroy and haemolysis, skeletal muscle and muscular degeneration of heart.Vitamin K1 can form factor, dimension
It is normal to hold blood clotting function, prothrombin deficiency bleeding is caused after shortage.
The liposoluble vitamin preparation listed at present is the injection or lyophilized preparation of above-mentioned four kinds of liposoluble vitamins.
It must add it in fat milk transfusion bottle and apply when clinically being used due to poorly water-soluble this preparation, so patient complies with
Property is poor；And it is clinically often shared with water soluble vitamin injection, and water soluble vitamin injection is sterile water-soluble
Liquid when with liposoluble vitamin compatibility, also needs that the laggard row vein instillation of Fat Emulsion is added, therefore Clinical practice is more inconvenient.
It is the solubility problem for solving liposoluble vitamin in the prior art, it will usually larger amount of tween is added, such as
The amount of tween is 5 times of the amount of vitamin E or more even up to 10 times or more in Tween 80 and/or polysorbas20, such as prescription.
It is not soluble in water that CN1903207A solves above-mentioned liposoluble vitamin preparation by being properly joined into polyoxyethylene sorbitan monoleate and mannitol
The problem of, but experiments have shown that its redissolved with water after solution clarity unsatisfactory (visible foreign matters and particulate determination do not conform to
Lattice).CN101366712B then by being added Tween 80, polysorbas20, ethyl alcohol, glycine, cysteine hydrochloride, bisulfite simultaneously
The solubilizer such as sodium, EDTA-2Na, mannitol solve the problems, such as this, and the supplementary product kind being added is obviously too many, this not only increases
Preparation cost, and quality control is made to become more difficult, the interaction between each component is also difficult to control completely；And
And addition supplementary product kind cause the chance of unknown adverse reaction it is also more (such as Tween-20 have certain haemolysis
Property), these solubilizer or cosolvent is used for a long time in patient, can cause a series of adverse reaction such as allergy, renal toxicity, Nervous toxicity
Property, Cardiovascular Toxicity etc.；So this is nor a good selection.
Therefore, the note for having new method to prepare with excellent properties for example with superior solubility performance is still expected in this field
It penetrates and uses liposoluble vitamin II powder-injection compositions, and especially expect in these powder-injection compositions there is a small amount of tween to add
Dosage.
Invention content
Present invention aims at providing, a kind of injection with excellent properties for example with superior solubility performance is fat-soluble
Vitamin II powder-injection compositions, and especially expect that there is a small amount of tween additive amount in these powder-injection compositions.This hair
A person of good sense significantly decreases surprisingly it has been found that when the injectable using combination is auxiliary material with carbohydrate in powder injection composition
Tween amount can also obtain the powder injection composition haveing excellent performance.It finds and is accomplished the present invention is based on this.
For this purpose, first aspect present invention provides the composition of fat-soluble vitamin for injection II freeze-drying powder-injections,
Wherein include the component of following weight proportion：
445~595 μ g vitamin As,
2.25~3.00 μ g calciferols,
4.1~5.0mg vitamin Es,
67.5~90.0 μ g vitamin K1s.
The composition of any embodiment according to a first aspect of the present invention, wherein further including Tween 80.In an embodiment party
In case, the weight ratio of vitamin E and Tween 80 is 1：0.2~2, such as weight ratio is 1：0.5~1.5, such as weight ratio is 1：
0.5~1.0.
The composition of any embodiment according to a first aspect of the present invention, wherein further including lactose and maltose.At one
In embodiment, the weight ratio of lactose and maltose is 1：0.2~1, such as weight ratio is 1：0.2~0.8, such as weight ratio is
1：0.2~0.5.In one embodiment, the weight ratio of vitamin E and lactose is 1：10~50, such as weight ratio is 1：15
~30, such as weight ratio is 1：15~20.It has been unexpectedly discovered that when the sugar combined using the present invention, substantially reduce
The amount of Tween 80 in composition can obtain the freeze-dried powder composition with excellent properties.
The composition of any embodiment according to a first aspect of the present invention, wherein including the component of following weight proportion：
445~595 μ g vitamin As,
2.25~3.00 μ g calciferols,
4.1~5.0mg vitamin Es,
67.5~90.0 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.2~2, such as weight ratio is 1：0.5~1.5,
Such as weight ratio is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：10~50, such as weight ratio is 1：15~30, for example, it is heavy
Amount is than being 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~1, such as weight ratio is 1：0.2~0.8, such as
Weight ratio is 1：0.2~0.5.
The composition of any embodiment according to a first aspect of the present invention, also adds ethyl alcohol in preparation process.One
In a embodiment, the ethyl alcohol is 95% ethyl alcohol.In one embodiment, the weight ratio of vitamin E and ethyl alcohol is 1：3~
6, such as weight ratio is 1：4~5.In one embodiment, the freeze-drying that the ethyl alcohol is prepared in powder-injection composition
It is removed in journey.
The composition of any embodiment according to a first aspect of the present invention, also adds water for injection in preparation process.
In one embodiment, the ratio of water for injection and vitamin A is 1ml：445~595 μ g.In one embodiment, described
Water for injection is substantially removed in freezing dry process prepared by powder-injection composition.
The composition of any embodiment according to a first aspect of the present invention, also adds acid-base accommodation in preparation process
Agent.In one embodiment, the acid-base modifier is selected from 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
The composition of any embodiment according to a first aspect of the present invention, wherein further including acid-base modifier.In a reality
It applies in scheme, the acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, biphosphate
Potassium, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof.In one embodiment, the acid-base modifier
It is hydrochloric acid solution either sodium hydroxide solution such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
It is well known that freeze-drying powder-injection (the often referred to simply as freeze-dried powder obtained through cryogenic freezing-vacuum drying
Agent or freeze-dried powder), it is that the dissolving of each material solvent (being typically to use water dissolution) is configured to a solution, so first
After so that the solution is carried out cryogenic freezing, then substantially anhydrous (the typically water of one kind for being vacuumized, distilling, being dried and obtained
Content is less than 8%, is especially generally lower than 7%, is especially generally lower than powdered object or block 5%).Therefore, this is solid
The acid-base value of body lyophilized products usually adjusts the pH value of solution to control by process for preparation；Or can by prescription adjust so that
The pH value that the solid lyophilized products of acquisition control the dissolving/dilution under defined dissolving/dilute strength (is referred to herein as controlled to control
The acid-base value of solid lyophilized products processed)；Latter means generally more generally use, such as many freeze drying powder injections contained in pharmacopeia
The acid-base value of product is controlled by this method, and the acid-base value that this mode controls product usually can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.It is equally applicable to the present invention, according to first party of the present invention
Freeze drying powder injection composition described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make freezing
Amount of the pH value of liquid before drying in 6.0~8.0 ranges, for example, the solution pH value in 6.5~7.5 ranges
Amount, for example, the solution amount of the pH value in 6.8~7.2 ranges.
The composition of any embodiment according to a first aspect of the present invention, is packed by cillin bottle.
The composition of any embodiment according to a first aspect of the present invention, wherein moisture are less than 10%, preferably shorter than
8%, preferably shorter than 7%, more preferably less than 5%.
The composition of any embodiment according to a first aspect of the present invention, wherein including the component of following weight proportion：
460~550 μ g vitamin As,
2.25~2.75 μ g calciferols,
4.2~4.8mg vitamin Es,
70~85 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
The composition of any embodiment according to a first aspect of the present invention, wherein including the component of following weight proportion：
480~510 μ g vitamin As,
2.3~2.7 μ g calciferols,
4.4~4.7mg vitamin Es,
70~80 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
The composition of any embodiment according to a first aspect of the present invention, wherein including the component of following weight proportion：
495 μ g vitamin As,
2.5 μ g calciferols,
4.55mg vitamin E,
75 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
The composition of any embodiment according to a first aspect of the present invention, wherein the vitamin A is selected from vitamin A or dimension
Raw element A palmitates.It is converted to vitamin A meter in its inventory using Retinol Palmitate.
The composition of any embodiment according to a first aspect of the present invention is substantially prepared according to following method
's：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
Further, second aspect of the present invention, which provides, prepares fat-soluble vitamin for injection II freeze-drying powder-injections
Fat-soluble vitamin for injection II freeze-drying powder-injections described in composition such as first aspect present invention any embodiment
Composition method, the composition includes the component of following weight proportion：
445~595 μ g vitamin As,
2.25~3.00 μ g calciferols,
4.1~5.0mg vitamin Es,
67.5~90.0 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.2~2, such as weight ratio is 1：0.5~1.5,
Such as weight ratio is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：10~50, such as weight ratio is 1：15~30, for example, it is heavy
Amount is than being 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~1, such as weight ratio is 1：0.2~0.8, such as
Weight ratio is 1：0.2~0.5；
This approach includes the following steps：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
The method of any embodiment according to a second aspect of the present invention, wherein including following weight proportion in the composition
Component：
445~595 μ g vitamin As,
2.25~3.00 μ g calciferols,
4.1~5.0mg vitamin Es,
67.5~90.0 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.2~2, such as weight ratio is 1：0.5~1.5,
Such as weight ratio is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：10~50, such as weight ratio is 1：15~30, for example, it is heavy
Amount is than being 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~1, such as weight ratio is 1：0.2~0.8, such as
Weight ratio is 1：0.2~0.5.
The method of any embodiment according to a second aspect of the present invention, the ethyl alcohol are 95% ethyl alcohol.In an embodiment party
In case, the weight ratio of vitamin E and ethyl alcohol is 1：3~6, such as weight ratio is 1：4~5.In one embodiment, the second
Alcohol is removed in freezing dry process prepared by powder-injection composition.
The ratio of the method for any embodiment according to a second aspect of the present invention, water for injection and vitamin A is 1ml：445~
595μg.In one embodiment, the water for injection in freezing dry process prepared by powder-injection composition substantially by
It removes.
The method of any embodiment according to a second aspect of the present invention, the acid-base modifier are selected from sodium hydroxide, hydrogen
Potassium oxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its group
It closes.In one embodiment, the acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solutions
Or 1M sodium hydroxide solutions.
It is well known that freeze-drying powder-injection (the often referred to simply as freeze-dried powder obtained through cryogenic freezing-vacuum drying
Agent or freeze-dried powder), it is that the dissolving of each material solvent (being typically to use water dissolution) is configured to a solution, so first
After so that the solution is carried out cryogenic freezing, then substantially anhydrous (the typically water of one kind for being vacuumized, distilling, being dried and obtained
Content is less than 8%, is especially generally lower than 7%, is especially generally lower than powdered object or block 5%).Therefore, this is solid
The acid-base value of body lyophilized products usually adjusts the pH value of solution to control by process for preparation；Or can by prescription adjust so that
The pH value that the solid lyophilized products of acquisition control the dissolving/dilution under defined dissolving/dilute strength (is referred to herein as controlled to control
The acid-base value of solid lyophilized products processed)；Latter means generally more generally use, such as many freeze drying powder injections contained in pharmacopeia
The acid-base value of product is controlled by this method, and the acid-base value that this mode controls product usually can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.It is equally applicable to the present invention, according to first party of the present invention
Freeze drying powder injection composition described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make freezing
Amount of the pH value of liquid before drying in 6.0~8.0 ranges, for example, the solution pH value in 6.5~7.5 ranges
Amount, for example, the solution amount of the pH value in 6.8~7.2 ranges.
The method of any embodiment according to a second aspect of the present invention, obtained by composition by cillin bottle seal wrap
Dress.
The method of any embodiment according to a second aspect of the present invention, obtained by composition in moisture be less than
10%, preferably shorter than 8%, preferably shorter than 7%, more preferably less than 5%.
The method of any embodiment according to a second aspect of the present invention, obtained by composition in match comprising following weight
The component of ratio：
460~550 μ g vitamin As,
2.25~2.75 μ g calciferols,
4.2~4.8mg vitamin Es,
70~85 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
The method of any embodiment according to a second aspect of the present invention, obtained by composition in match comprising following weight
The component of ratio：
480~510 μ g vitamin As,
2.3~2.7 μ g calciferols,
4.4~4.7mg vitamin Es,
70~80 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
The method of any embodiment according to a second aspect of the present invention, obtained by composition in match comprising following weight
The component of ratio：
495 μ g vitamin As,
2.5 μ g calciferols,
4.55mg vitamin E,
75 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
The method of any embodiment according to a second aspect of the present invention, wherein the vitamin A is selected from vitamin A or dimension life
Plain A palmitates.It is converted to vitamin A meter in its inventory using Retinol Palmitate.
In the above-mentioned preparation method of the invention the step of, although the specific steps of its description are in certain details or language
Step different from description and described in the preparation example of following detailed description part, however, people in the art
Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.
The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary
When offering expressed meaning and the inconsistent present invention, it is subject to the statement of the present invention.In addition, the various terms that use of the present invention and
Phrase has that well known to a person skilled in the art general senses, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
Subject to the meaning stated.
The preparation process of freeze-drying powder-injection is well known to those skilled in the art pharmaceutical technology, such as following freeze-drying song
Two kinds of schematical freeze-drying curves shown in line A and freeze-drying curve B：
It prepares below in the specific example in freeze-drying powder-injection, if not otherwise specified, freeze-drying used is bent
Line is freeze-drying curve A.
Water content in freeze-drying powder-injection is generally 8% hereinafter, preferably shorter than 7%, more preferably less than 5%.Water
Sub-control system can be controlled by suitably adjusting freeze-drying program.Moisture in the freeze-drying powder-injection can be according to many
Known method measures, such as dry weight-loss method.
In the present invention, for the pH value of regulating liquid medicine if necessary, pH appropriate can be added into composition and adjust
Agent or acid-base modifier.Although the present inventor is only with the strong acid or strong base solution such as sodium hydrate aqueous solution for not having buffer capacity
It is adjusted with aqueous hydrochloric acid solution, however, it will be appreciated by those skilled in the art that if with this pH adjusting agent for not having buffer capacity
Processing can meet the pH requirements of system, then the pH adjusting agent with buffer capacity will be better able to realize the object of the invention, therefore
These buffers are not only able to adjust pH value, and can stablize pH value.Therefore any pH adjusting agent listed by the present invention or combinations thereof
It is included in spirit and scope of the invention.
When preparing freeze drying powder injection of the present invention, in prepared liquid, solid content be for 1~20% (w/v), it is excellent
Select 2~15% (w/v), such as 2~8%, such as 8~15%, such as 4~10%.Since freeze drying powder injection is typically in tubulose
It is freeze-dried to obtain in cillin bottle, those skilled in the art understand that this product is obtaining finished product or even using for doctor
Before, a round pie is typically each presented, although lecture is fewer than the volume of original aqueous solution (slightly in the volume theory of the cake
Reduce), however usually this diminution will not usually narrow down to raw water liquor capacity 50%, it will usually in raw water liquor capacity
It between 80-120%, is more typically between the 90-100% of raw water liquor capacity, and original can be observed out of finished product cillin bottle
(main body pie remains in the liquid level trace in bottle wall to aqueous solution liquid level trace after being reduced because of freeze-drying, even if the jelly in cillin bottle
Dry product is in powdered due to a variety of causes reason such as colliding, and still can usually retain original liquid level trace), trace accordingly
Mark can also estimate the aqueous solution volume of the freeze-dried composition before freeze-drying.Therefore, although it is provided by the invention
It is a kind of substantially anhydrous freeze-drying powder-injection, however still can substantially estimates it according to the powder-injection when preparing,
Medicine liquid volume at least before freeze-drying starts, according to the drying final product in the volume estimated and cillin bottle
Weight can also be calculated when preparing freeze drying powder injection of the present invention, the content of the solid content in prepared liquid.Therefore, root
According to the freeze drying powder injection of first aspect present invention, the solid content of the liquid when preparing is 1~20% (w/v), preferably 2
~15% (w/v), such as 2~8%, such as 8~15%, such as 4~10%.
In the present invention, symbol %, according to its used context, can have skilled addressee readily understands that
Meaning.Such as when referring to solid content, the percentage (w/v, such as g/100ml) of the symbolic indication weight/volume；Example again
Such as in " water content " in referring to freeze-drying powder-injection, for example, water content 8% hereinafter, at this time symbol % indicate weight
The percentage (w/w, g/100g) of amount/weight.In general, when solid disperses in a liquid, % indicates weight/volume percentage
Number；When solid disperses in solids or liquid disperses (such as water content of powder needle) in solids, % indicates w/w
Percentage.In other cases, unless otherwise noted, symbol % indicates w/w percentage.
It is well known to those skilled in the art when preparing the liquid of the present invention, for example, about miillpore filter of 0.45um can be used
Coarse filtration filtering is carried out, before liquid is filled in cillin bottle, for example, about 0.22 μm of miillpore filter can be used to carry out essence
Filtration filter is with degerming, it may be necessary to which filtering is multiple.
Freeze drying powder injection according to the present invention is freeze-drying powder-injection.In one embodiment, the freeze-drying
Powder-injection is single-dose preparations (such as XiLin bottled powder-injection), the amount of reactive compound in per unit dosage, to tie up life
Plain A meters, can be such as, but not limited to about 200 μ g, about 250 μ g, about 300 μ g, about 345 μ g, about 400 μ g, about 450 μ g, about 500 μ
g。
Freeze drying powder injection according to the present invention, is redissolved with water for injection, typically redissolves the time in 30 seconds, preferably
In 20 seconds, more preferably in 15 seconds.
Freeze drying powder injection according to the present invention is made of water and contains the solution of 200 μ g vitamin As in every 1ml and in
Method under state's pharmacopeia annex VI H of version two in 2010 measures, and the pH value of the solution is 6.0~8.0.In an embodiment party
In case, pH value is 6.5~7.5.
Freeze drying powder injection provided by the invention can preserve at least 18 months at 20 DEG C or less dryings, can meet one
As freeze-drying powder-injection Storage Requirement.
Present composition fat-soluble vitamin for injection is one of indispensable component part of parenteral nutrition, to full
The foot adult physiological requirements to fat-soluble A, calciferol, vitamin E, vitamin K1 daily.
This product can provide the liposoluble vitamin of daily physiological requirements, including vitamin A, calciferol, vitamin E, dimension
Raw element K1.Vitamin A can promote the synthesis or regeneration of rhodopsin in eyeball, maintain twenty-twenty vision, prevent yctalopia, in maintenance
Skin is grown and differentiation, improves immunity and the resistance to disease.Vitamin D increases calcium and phosphorus in enteral absorption, to adjust
The eubolism institute for saving calcium and phosphorus is required, promotes the normal growth of tooth and bone.Vitamin E has anti-oxidation function, protection
The integrality of red blood cell participates in the biosynthesis of DNA, immunity of organisms is improved, with fecundity and Sperm specific enzyme
It is related.Vitamin K participates in the synthesis of factor, participates in the oxidation-reduction process in histocyte, increases the bullet of musculature
Property.
Specific implementation mode
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general
And/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art that
But the present invention is still described in detail as far as possible herein.Following embodiment further illustrates the present invention, rather than limits this hair
It is bright.The made only formal but not substantive equivalent transformation of any design according to the present invention is regarded as the present invention
Technical solution scope.
It is if not otherwise indicated, when preparing powder-injection use with a batch of bulk pharmaceutical chemicals and auxiliary material in following example.
In following example, the pH adjusting agent (in the present invention that is, acid-base modifier) used, unless otherwise noted,
It is 1M sodium hydroxide solutions or 1M hydrochloric acid solutions, dosage is prepared molten before making freeze-drying when making to prepare powder-injection
The pH value of liquid is adjusted to a certain regulation value or range.Hereafter preparation process in order to citing purpose, and based on the comparable of each citing
It is made some specific description compared with property, those skilled in the art can therefrom summarize to obtain system of the present invention according to existing knowledge completely
The method of standby freeze drying powder injection.It is prepared in various compositions with liquid below, if not otherwise indicated, every batch of is always with liquid measure
2000ml, but when listing formula, illustrated with the material content in every bottle.It is such as not special when in following instance using to ethyl alcohol
It does not mentionlet alone bright, each means 95% ethyl alcohol.
Embodiment 1：Prepare fat-soluble vitamin for injection (II) composition
Every bottle of weight proportion：
495 μ g vitamin As,
2.5 μ g calciferols,
4.55mg vitamin E,
75 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.75,
The weight ratio of lactose, wherein vitamin E and lactose is 1：18,
The weight ratio of maltose, wherein lactose and maltose is 1：0.35,
The weight ratio of ethyl alcohol, vitamin E and ethyl alcohol is 1：4.5,
Water for injection adds to 1ml in right amount.
Preparation method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
Embodiment 2：Prepare fat-soluble vitamin for injection (II) composition
Every bottle of weight proportion：
480 μ g vitamin As,
2.7 μ g calciferols,
4.4mg vitamin Es,
80 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5,
The weight ratio of lactose, wherein vitamin E and lactose is 1：20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2,
The weight ratio of ethyl alcohol, vitamin E and ethyl alcohol is 1：4,
Water for injection adds to 1ml in right amount.
Preparation method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets and is freeze-dried (freeze-drying curve B) in freeze drier, close plug, i.e.,
?.
Embodiment 3：Prepare fat-soluble vitamin for injection (II) composition
Every bottle of weight proportion：
510 μ g vitamin As,
2.3 μ g calciferols,
4.7mg vitamin Es,
70 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：1,
The weight ratio of lactose, wherein vitamin E and lactose is 1：30,
The weight ratio of maltose, wherein lactose and maltose is 1：0.5,
The weight ratio of ethyl alcohol, vitamin E and ethyl alcohol is 1：5,
Water for injection adds to 1ml in right amount.
Preparation method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
Embodiment 4：Prepare fat-soluble vitamin for injection (II) composition
Every bottle of weight proportion：
550 μ g vitamin As,
2.25 μ g calciferols,
4.8mg vitamin Es,
70 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.75,
The weight ratio of lactose, wherein vitamin E and lactose is 1：25,
The weight ratio of maltose, wherein lactose and maltose is 1：0.8,
The weight ratio of ethyl alcohol, vitamin E and ethyl alcohol is 1：6,
Water for injection adds to 1ml in right amount.
Preparation method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
Embodiment 5：Prepare fat-soluble vitamin for injection (II) composition
Every bottle of weight proportion：
460 μ g vitamin As,
2.75 μ g calciferols,
4.2mg vitamin Es,
85 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.6,
The weight ratio of lactose, wherein vitamin E and lactose is 1：20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.6,
The weight ratio of ethyl alcohol, vitamin E and ethyl alcohol is 1：3,
Water for injection adds to 1ml in right amount.
Preparation method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
Embodiment 6：Prepare fat-soluble vitamin for injection (II) composition
Every bottle of weight proportion：
445 μ g vitamin As,
3.00 μ g calciferols,
4.1mg vitamin Es,
90.0 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：9,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15,
The weight ratio of maltose, wherein lactose and maltose is 1：0.4,
The weight ratio of ethyl alcohol, vitamin E and ethyl alcohol is 1：4,
Water for injection adds to 1ml in right amount.
Preparation method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
Embodiment 7：Prepare fat-soluble vitamin for injection (II) composition
Every bottle of weight proportion：
595 μ g vitamin As,
2.25 μ g calciferols,
5.0mg vitamin Es,
67.5 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.8,
The weight ratio of lactose, wherein vitamin E and lactose is 1：18,
The weight ratio of maltose, wherein lactose and maltose is 1：0.5,
The weight ratio of ethyl alcohol, vitamin E and ethyl alcohol is 1：5,
Water for injection adds to 1ml in right amount.
Preparation method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, stirred
Uniformly, it is stood at a temperature of 5~10 DEG C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution
In, it stirs to clarify, 4 hours is stood at a temperature of 2~8 DEG C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering uses acid-base modifier
The pH value 6.8~7.2 for adjusting solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
Embodiment 8：Prepare fat-soluble vitamin for injection composition
The formula and preparation method of embodiment 1-7 are respectively referred to, the difference is that both lactose therein and maltose are changed into
The mannitol of amount obtains 7 powder injection compositions.
Embodiment 9：Prepare fat-soluble vitamin for injection composition
The formula and preparation method of embodiment 1-7 are respectively referred to, the difference is that not 2~8 after being stirred to clarify in step (3)
It handles under DEG C low temperature and directly carries out subsequent processing, obtain 7 powder injection compositions.
Embodiment 101：Powder needle is prepared according to formula and preparation method described in CN101606939B (200910089635.2) embodiment 3
Agent.
Embodiment 102：Powder needle is prepared according to formula and preparation method described in CN102526075B (201010575712.8) embodiment 2
Agent.
Embodiment 103：According to CN102499939B (201110387660.6) specification [0053] to [0057] section and
[0065] powder-injection is prepared to [0069] section formula and preparation method.
Embodiment 104：Powder needle is prepared according to formula and preparation method described in CN102525959B (201210010878.4) embodiment 1
Agent.
Embodiment 105：Powder needle is prepared according to formula and preparation method described in CN102657662B (201210113282.7) embodiment 1
Agent.
Embodiment 106：Powder needle is prepared according to formula and preparation method described in CN102657663B (201210113285.0) embodiment 1
Agent.
Embodiment 107：According to formula described in CN103520186B (201310488987.1) embodiment 1 and embodiment 2 and make
Method prepares powder-injection.
Test example 1：Physical property is investigated
Various vitamins not readily dissolve in water in fat-soluble vitamin for injection powder-injection, therefore insoluble in powder-injection
The monitoring of property particle is very important quality monitoring index.Version in 2015《Chinese Pharmacopoeia》Four page 114 record " 0903
In particulate matter inspection technique ", " the first method (light blockage method) " provided may be conveniently used insoluble in measurement powder-injection
Particle, this index are also the evaluation deliquescent leading indicator of product.In the light blockage method, standard regulation " contains 10um and 10um
Above particle number is no more than 6000；Particle number containing 25um and 25um or more is no more than 600 ".In view of 10um's or more
Particle would generally be relatively more, thus can increasingly focus in the present invention 10um with particle and evaluate with this physics of product
Performance is especially its dissolubility.
Detection method：4 bottles of every batch of fat-soluble vitamin for injection powder-injection sample is taken, every bottle adds microparticles water 10ml
Dissolving merges solution, is detected on particulate determination instrument (light blockage method) after standing 2 minutes or appropriate time de-bubbled.
After testing, whole powder-injection of 1~embodiment of embodiment 9 and embodiment 101~107 are detected according to the above method,
As a result the particle number of the particle number and 25um and 25um or more that show their 10um and 10um or more meets above-mentioned standard rule
It is fixed.
Study on the stability：Make whole powder-injection of 1~embodiment of embodiment 9 and embodiment 101~107 be protected from light, it is cloudy
The dry place of airing preserves 18 months, for every a collection of powder-injection, measures its at 0 month " particle number of 10um and 10um or more ", with
And " particle number of 10um and 10um or more " at 18 months, it is calculated as follows particle number and increases percentage：
Particle number increases percentage=[(- 0 month particle number of 18 months particle numbers) 0 month particle number of ÷] × 100%
As a result：The whole powder-injection particle numbers of 1~embodiment of embodiment 7 increase percentage in 35~61% ranges, example
It is 44% as 1 particle number of embodiment increases percentage；Whole powder needles of 8~embodiment of embodiment 9 and embodiment 101~107
Agent particle number increase percentage in 144~247% ranges, such as embodiment 8 and embodiment 9 whole powder-injection particle numbers
Increase percentage in 178~203% ranges, such as the powder-injection particle number with reference to obtained by 1 method of embodiment of embodiment 9 increases
Percentage is 196%.The above result shows that powder-injection of the present invention has excellent physical stability.
Test example 2：Quality investigation
1, character：This product is the freeze-drying block or powder of white or off-white color.
2, differentiate：In the chromatogram recorded under assay item, test solution vitamin E peak, vitamin K1 peak, dimension
The retention time at the raw element peaks A and calciferol peak should be consistent with the retention time of the main peak of corresponding reference substance solution.
3. acid-base value inspection：5 bottles of this product, every bottle plus water 2ml dissolvings is taken to set in 15ml beakers, mixing, pH after calibration
It is measured on meter.The pH value of test sample should be in 6.5~7.5 ranges.
4, the clarity and color of solution：Precision measures turbidity standard stock solution 1.5ml, sets in 100ml volumetric flasks, adds water
It is diluted to 100ml, is shaken up, is set in 1cm absorption cells, on ultraviolet specrophotometer at 550nm wavelength, slit 1.0nm, with purifying
Water measures absorbance as blank.Absorbance is in 0.12~0.15 range to get required turbidity standard stoste.
Turbidity standard stoste 2.5ml is taken, is set in 100ml volumetric flasks, is diluted with water to scale to get No. 0.5 turbidity standard
Liquid.
5 bottles of this product, every bottle plus water 2ml dissolvings is taken to shake up, it is turbid with No. 0.5 under 1000lx illumination on clarity detecting apparatus
Degree titer is compared, and test solution turbidity must not cross No. 0.5 turbidity standard, and (the first method can not accurately judge the two
Clarity difference when, the second method of using instead is measured and is judged with its measurement result).Take the confession under clarity check item
Test sample solution 5ml is set in 5ml standard colorimetric bottles, must not be deeper compared with Sunset Yellow FCF standard color solution under white background.
Test solution is clarified；The color of solution has no deeper compared with Sunset Yellow FCF standard color solution, then is judged to " meet
Regulation ".
5, loss on drying：It takes and is dried under reduced pressure at 60 DEG C to the empty weighing bottle of constant weight, accurately weighed bottle weight (W1) is added into bottle
Test sample (weighs test sample about 1g), weighs (W2).Using phosphorus pentoxide as drier, subtract for 60 DEG C in electric vacunm drying case
It press dry dry 4 hours, weighs (W3).Test sample less loss weight must not cross 1.5%, then be judged to " meeting regulation ".
6 pyrogens：
The preparation of test solution：2 bottles of this product is taken, every bottle adds sodium chloride injection 5ml to be dissolved in same beaker respectively,
Mixing, as test solution.
Measuring method：Applicable rabbit 3 is taken, its normal body temperature is measured within 15 minutes, warm is slowly injected from ear vein
To about 38 DEG C of test solutions (dosage slowly injects 0.5ml by rabbit weight per 1kg), then its body was measured every 30 minutes
Temperature 1 time is surveyed 6 times, once normal body temperature, as the raising temperature of the rabbit body temperature is subtracted with highest in 6 body temperature altogether.Such as 3
There is 1 body temperature to increase 0.6 DEG C in rabbit or be higher than 0.6 DEG C, or 3 rabbit body temperatures increase summations up to 1.3 DEG C or are higher than 1.3 DEG C,
5 rabbit retrials, inspection method should be separately taken to be same as above.When rabbit heating is negative value, in terms of 0 DEG C.
As a result judge：
In 3 rabbit of preliminary examination, body temperature raising is below 0.6 DEG C, and 3 rabbit body temperatures increase summation and are less than 1.3
℃；Or in 5 rabbit of retrial, body temperature increases 0.6 DEG C or the rabbit higher than 0.6 DEG C is no more than 1, and preliminary examination, retrial
The body temperature for merging 8 rabbit increases summation as 3.5 DEG C or is less than 3.5 DEG C, judges that the pyrogen test of test sample meets regulation.
In 3 rabbit of preliminary examination, it is more than 1 that body temperature, which increases 0.6 DEG C or the rabbit higher than 0.6 DEG C,；Or 5 in retrial
In rabbit, it is more than 1 that body temperature, which increases 0.6 DEG C or the rabbit higher than 0.6 DEG C,；Or merge the body temperature liter of 8 rabbit in preliminary examination, retrial
High summation is more than 3.5 DEG C, judges that the pyrogen test of test sample is against regulation.
7, the assay of vitamin E, vitamin K1 and vitamin A
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica, with methanol/ethanol
(40：60) it is mobile phase, Detection wavelength 270nm, number of theoretical plate is calculated by vitamin A peak should be not less than 2000, vitamin K1 peak
1.5 are should be greater than with the separating degree at vitamin E peak and vitamin A peak.
The preparation of vitamin A reference substance stock solution：Retinol Palmitate about 50mg is taken, it is accurately weighed, set 50ml measuring bottles
In, add absolute ethyl alcohol appropriate, ultrasound makes dissolving and is diluted to scale, shakes up to get (every gram of vitamin A reference substance stock solution (1)
Retinol Palmitate is equivalent to 0.5457g vitamin As), vitamin A reference substance stock solution (2) is obtained with legal system.
The preparation of vitamin K1 reference substance stock solution：Vitamin K1 about 37.5mg is taken, it is accurately weighed, it sets in 50ml measuring bottles,
Add absolute ethyl alcohol to dissolve and be diluted to scale, shakes up to get vitamin K1 reference substance stock solution (1), with legal system and obtain vitamin K1
Reference substance stock solution (2).
The preparation of reference substance solution：Vitamin E reference substance about 45mg is taken, it is accurately weighed, it sets in 50ml measuring bottles, precision is added
Vitamin A reference substance stock solution (1) 5ml, vitamin K1 reference substance stock solution (1) 1ml, add absolute ethyl alcohol to dissolve and are diluted to quarter
Degree, shakes up to get reference substance solution (1), reference substance solution (2) is obtained with legal system.(facing with brand-new)
It is prepared by test solution：The content (being approximately equivalent to vitamin E 9.1mg) under content uniformity item is taken, it is accurately weighed,
It sets in 10ml measuring bottles, be dissolved in water and be diluted to scale, shake up to get test solution (1), with legal system and obtain test solution
(2)。
Measuring method：Reference substance solution and each 10 μ l of test solution are taken, liquid chromatograph is injected separately into, records chromatogram,
By external standard method with calculated by peak area to get.For each component target of each product, (pass through preparation in theoretical labelled amount
Inventory in the process can be calculated) 90~110% ranges in be qualified.
8, the assay of calciferol
Chromatographic condition and system suitability：It is filler with octadecylsilane bonding silane, with methanol：Acetonitrile：
Ethyl alcohol：Water (20：60：15：5) it is mobile phase, Detection wavelength 265nm, number of theoretical plate is calculated by calciferol peak to be not less than
2000, flow velocity：1.0ml/min.
The preparation of reference substance solution：Calciferol reference substance about 10mg is taken, it is accurately weighed, it sets in 100ml measuring bottles, adds anhydrous
Ethyl alcohol dissolves and is diluted to scale, shakes up；Precision measures solution 5ml and sets in 50ml measuring bottles, and absolute ethyl alcohol is added to be diluted to scale,
It shakes up, then the accurate 5ml that measures is set in 100ml volumetric flasks, is added absolute ethyl alcohol to be diluted to scale, is shaken up, as a contrast product solution
(1), it is made to works solution (2) with method.
Test sample prepares solution：The content (being approximately equivalent to calciferol 5ug) under content uniformity item is taken, it is accurately weighed,
It sets in 10ml measuring bottles, be dissolved in water and be diluted to scale, shake up, test solution is obtained as test solution (1), with legal system
(2)。
Measuring method：Reference substance solution and each 20 μ l of test solution are taken, liquid chromatograph is injected separately into, records chromatogram,
By external standard method with calculated by peak area to get.For the calciferol content of each product, (pass through preparation in theoretical labelled amount
Inventory in the process can be calculated) 90~110% ranges in be qualified.
After testing, whole powder-injection of 1~embodiment of embodiment 9 and embodiment 101~107, according to above-mentioned quality investigation
Method detection, as a result show that whole powder-injection meets the regulation of every quality index.
Study on the stability：Make whole powder-injection of 1~embodiment of embodiment 9 and embodiment 101~107 be protected from light, it is cloudy
The dry place of airing preserves 18 months.For every a collection of powder-injection, each index of its above-mentioned quality investigation at 18 months is measured.As a result
The whole powder-injection of display met the regulation of every quality index at 18 months.The above result shows that powder-injection of the present invention is entirely capable of
Enough meet every quality standard regulation of the product, and there is excellent stability.
Industrial applicability
The above is merely a preferred embodiment of the present invention, and cannot be construed to limit the scope of the present invention with this, all at this
The embodiment for the equivalent deformation and change made in the claimed range of claims of invention is in the present invention
In range claimed.
Claims (14)
1. the composition of fat-soluble vitamin for injection II freeze-drying powder-injections, wherein including the component of following weight proportion：
445 ~ 595 μ g vitamin As,
2.25 ~ 3.00 μ g calciferols,
4.1 ~ 5.0mg vitamin Es,
67.5 ~ 90.0 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~30,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.8；
The composition also adds 95% ethyl alcohol, and the freeze-drying that the ethyl alcohol is prepared in powder-injection composition in preparation process
It is removed in the process, the weight ratio of vitamin E and ethyl alcohol is 1：3~6；
The composition is prepared according to following method：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, is stirred evenly,
It is stood at a temperature of 5 ~ 10 °C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution, is stirred
To clarification, 4 hours are stood at a temperature of 2 ~ 8 °C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering is adjusted with acid-base modifier
The pH value 6.8 ~ 7.2 of solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
2. the weight ratio of the composition of claim 1, wherein vitamin E and lactose is 1：15~20.
3. the weight ratio of the composition of claim 1, wherein lactose and maltose is 1：0.2~0.5.
4. the weight ratio of the composition of claim 1, wherein vitamin E and ethyl alcohol is 1：4~5.
5. the composition of claim 1, wherein the ratio of added water for injection and vitamin A is 1ml：445~595μg.
6. the composition of claim 1, also adds acid-base modifier in preparation process.
7. the composition of claim 6, the acid-base modifier is selected from 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.
8. the composition of claim 1, it is characterised in that：It is packed by cillin bottle.
9. the composition of claim 1, wherein moisture are less than 5%.
10. the composition of claim 1, wherein including the component of following weight proportion：
460 ~ 550 μ g vitamin As,
2.25 ~ 2.75 μ g calciferols,
4.2 ~ 4.8mg vitamin Es,
70 ~ 85 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
11. the composition of claim 1, wherein including the component of following weight proportion：
480 ~ 510 μ g vitamin As,
2.3 ~ 2.7 μ g calciferols,
4.4 ~ 4.7mg vitamin Es,
70 ~ 80 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
12. the composition of claim 1, wherein including the component of following weight proportion：
495 μ g vitamin As,
2.5 μ g calciferols,
4.55mg vitamin E,
75 μ g vitamin K1s,
The weight ratio of Tween 80, wherein vitamin E and Tween 80 is 1：0.5~1.0,
The weight ratio of lactose, wherein vitamin E and lactose is 1：15~20,
The weight ratio of maltose, wherein lactose and maltose is 1：0.2~0.5.
13. the composition of claim 1, the vitamin A is selected from vitamin A or Retinol Palmitate.
14. preparing the composition of claim 1-13 any one of them fat-soluble vitamin for injection II freeze-drying powder-injections
Method,
This approach includes the following steps：
(1) VitAVitE of recipe quantity, vitamin K1 and Tween 80 are uniformly mixed；
(2) calciferol is dissolved with ethyl alcohol, the calciferol dissolved is added in step (1) acquired solution, is stirred evenly,
It is stood at a temperature of 5 ~ 10 °C；
(3) with 80% water for injection solubilized lactose and maltose, which is slowly added into step (2) acquired solution, is stirred
To clarification, 4 hours are stood at a temperature of 2 ~ 8 °C；
(4) 0.1% medical charcoal is added into liquid obtained by step (3), adsorbs 30min, decarbonization filtering is adjusted with acid-base modifier
The pH value 6.8 ~ 7.2 of solution, adds water for injection constant volume, through 0.22 μm of polytetrafluoroethylene (PTFE) filter element filtering degerming；
(5) liquid is dispensed into vial, sets in freeze drier and be freeze-dried, it is close plug to get.
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| CN1561970A (en) * | 2004-04-12 | 2005-01-12 | 沈阳药科大学 | Fat soluble vitamin freeze-drying emulsion and its preparing method |
| CN102552288A (en) * | 2010-12-07 | 2012-07-11 | 北京京卫信康医药科技发展有限公司 | Stable composite fat-soluble vitamin composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1561970A (en) * | 2004-04-12 | 2005-01-12 | 沈阳药科大学 | Fat soluble vitamin freeze-drying emulsion and its preparing method |
| CN102552288A (en) * | 2010-12-07 | 2012-07-11 | 北京京卫信康医药科技发展有限公司 | Stable composite fat-soluble vitamin composition and preparation method thereof |
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