CN104337829B - The one bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion - Google Patents
The one bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion Download PDFInfo
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- CN104337829B CN104337829B CN201410430836.5A CN201410430836A CN104337829B CN 104337829 B CN104337829 B CN 104337829B CN 201410430836 A CN201410430836 A CN 201410430836A CN 104337829 B CN104337829 B CN 104337829B
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- A61K31/51—Thiamines, e.g. vitamin B1
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
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- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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Abstract
The invention discloses a kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion.Fat-soluble A, D, E, K are wrapped in fat micro emulsion of the grain size less than 120nm by said preparation, are then mixed with water soluble vitamins such as B family vitamin, vitamin C, folic acid, niacinamide, and freeze-drying excipients are added and redissolve auxiliary agent, are lyophilized.The present invention according to the above formula and preparation method exploitation at the novel freeze-dried formulation containing 13 kinds of vitamin, it is simple for process, the stability of vitamin can be improved, reduce drug decompose and decomposition product caused by side effect；It efficiently solves the problems, such as that fat-soluble and water soluble vitamin is molten altogether, while can ensure the abundant dissolving of pharmaceutical compounds, avoid insoluble matter side effect caused by body and injure.
Description
Technical field
The invention belongs to medical drugs technical field, be related to a kind of prevention and treatment vitamin-deficiency pharmaceutical preparation and
Preparation method.It is exactly a kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion.The novel formulation is using special
Prescription and technique cleverly combine water-soluble and liposoluble vitamin, form single freeze-drying compound molten altogether.It can be with
Improve vitamin stability, reduce drug decomposition and decomposition product caused by side effect；Effectively solve it is fat-soluble and
Water soluble vitamin is total to molten problem, caused by eliminating the extraction repeatedly-mixing possibility of traditional 2 bottled preparations when in use
Pollution risk；The abundant dissolving that can ensure pharmaceutical compounds simultaneously avoids insoluble matter side effect caused by body and injures.
It is suitable for multivitamin to lack and parenteral nutrition clinical application.
Background technology
Total parenteral nutrition (Total Parenteral Nutrition, TPN) support be suitable for patient cannot or
In the case of cannot cmpletely being absorbed nourishment by gastrointestinal tract, pass through venous access input glucose, amino acid, Fat Emulsion, electricity
The intravenous nutrition liquids such as Xie Zhi, trace element, vitamin make the supplement of these nutriments that can reach one kind of relatively satisfactory degree
Method.Clinically it is mainly used for the treatment of following diseases：Gastrointestinal fistula, short intestines synthesis card, renal failure, large-area burns,
Serious wound, infection, acute pancreatitis etc.；It is also used for the auxiliary treatment of following disease：Major operation peri-operation period, work of breathing
Energy failure, patients with severe brain injury early stage, bone-marrow transplantation, malignant tumor patient, cannot normally take the photograph long-time assisted mechanical ventilator
The newborn of danger again etc. of food.
Vitamin is necessary to maintaining body normal function, often by the small molecule organic compound of food supply.
Vitamin neither constitutes body tissue ingredient, and also oxygenolysis does not release energy, but is given birth to by participating in a variety of different physiology
Change process and play a significant role in vivo.Body is few to the daily requirement of vitamin, is often calculated with microgram, normal human
It can be obtained required vitamin by food, but may cause in the case where some special situations or disease occur
Vitamin insufficiency of intake, therefore the nutritional support of vitamin is an essential part in Parenteral nutrition.Vitamin
Type it is very much, configurations are divided into liposoluble vitamin and water soluble vitamin generally according to the difference of its dissolution properties
Two major classes.Liposoluble vitamin includes vitamin A. D. E, K etc.；Water soluble vitamin includes mainly vitamin C and the dimension life of B races
Element, B family vitamin include vitamin B1、B2、PP、B6、B12, folic acid, pantothenic acid, biotin etc..
The chemical constitution of vitamin A is the unsaturated monohydric alcohol containing alicyclic ring, there is A1And A2Two kinds, A1For retinol, A2
For 3-dehydroretinol, beta carotene is provitamin A in plant.Vitamin A, which has, to be promoted growth, maintains epithelial tissue such as
The normal function of skin, conjunctiva, cornea etc., and participate in the synthesis of rhodopsin, enhances retinal photoreceptor power, and when shortage can lead
Cause scheroma；Vitamin A promotes body growth, development, breeding, vitamin A deficiency that will lead by the synthesis of participation steroids
Body growth is caused to stagnate, depauperation.Be grown up daily requirement 250~800 μ g of vitamin A, clinically vitamin A mainly use
In preventing vitamine A deficiency and certain treating for skin disease.
Vitamin D is steroid derivatives, mainly there is vitamin D2And D3Two kinds, D2For ergocalciferol, D3For courage calcium
Change alcohol.Vitamin D is primarily involved in the adjusting of Ca,P metabolism, increases utilization of the body to calcium, phosphorus, promotes bone normal growth.
Be deficient in vitamin D or its active material when, for children since osteogenic action obstacle may occur in which rickets, it is soft that bone then occurs in adult
Change disease.Be grown up daily requirement vitamin D 5 μ g, 10 μ g of children, pregnant woman and nursing women's daily requirement.Clinically vitamin D master
It is used to prevent rickets, malacosteon, senile osteoporosis etc..
Vitamin E is also known as tocopherol, is the derivative of benzene a pair of horses going side by side dihydropyran in chemical constitution.Vitamin E to oxygen extremely
Sensitivity is easily aoxidized, therefore can play antioxidation from Oxidative demage with some important compounds in protective, can
To maintain the integrity and stability of the organelle of cell membrane；Vitamin E can also be to Green Tea Extract to human body harm, be used for
Anti-aging；Vitamin E has antisterility effect.Be grown up 5~150mg of daily requirement vitamin E.Clinically vitamin E is used for
Treat the ancillary drug of infertility, habitual abortion, muscular dystrophy and artery sclerosis etc..
Vitamin K is the derivative of 2-MNQ, naturally occurring to have K1And K2Two kinds, be fat-soluble, people
Work synthesizes K3And K4For water-soluble substances.Vitamin K is mainly related with blood coagulation, can promote prothrombin, the conjunction of IV, IX and X
It is reduced at the these types of coagulation factor in blood when, shortage, cruor time extending, subcutaneous, muscle and hemorrhage of gastrointestinal tract occurs；
Vitamin K can also increase enterocinesia, have relieving spasm and pain effect.Be grown up 20~100mg of daily requirement vitamin K.Clinically
Vitamin K is mainly used for sweet-clover disease and the bleeding caused by vitamin K deficiency, as obstructive jaundice, hepatic sclerosis,
Take patient, the premature etc. of broad-spectrum antibiotic for a long time.
Vitamin C is also known as ascorbic acid, is easily aoxidized, and heat is easily destroyed in neutral or alkaline solution.Vitamin
C participates in the hydroxylation reaction of substance in vivo metabolism by the form of confactor, can promote collagen synthesis, cholesterol conversion and
The metabolism of aromatic series aliphatic acid leads to scurvy if lacking；Vitamin C also by participating in redox reaction, plays anti-
Oxygen free radical injury promotes antibody tormation and promotes the effect of hematopoiesis；In addition, vitamin C can prevent nitrosamine from synthesizing and promote
It is decomposed, therefore has certain protective effect on cancer risk.Be grown up 30~500mg of daily requirement vitamin C.Clinically vitamin C is used
In the auxiliary of scurvy, the treatment of methemoglobinemia and various acute and chronic infectious diseases, wound, anaphylactia etc.
Help treatment.
Vitamin B1Also known as thiamine, heat is highly vulnerable to breakage in neutral and alkaline solution, and oxidant or reducing agent all may be used
So that it is inactivated.Vitamin B1Play an important role in glycometabolism, if lacking can cause energy supply insufficient, influence cardiac muscle,
The function of skeletal muscle and nervous system forms athlete's foot；In addition, vitamin B1The synthesis of acetylcholine can be also influenced, when shortage
Acetylcholine synthesis is reduced, and decomposition increases, so that cholinergic nerve is affected, lead to nerve impulse conduction obstacle, influence stomach and intestine,
Myocardial function.Adult's daily requirement vitamin B10.5~20mg.Clinic is mainly used for preventing vitamin B1Deficiency disease and multiple
The auxiliary treatment of nerve inflammation, peripheral neuritis, facial palsy, indigestion etc..
Vitamin B2Also known as riboflavin, it is heat-resisting, stablize in neutral or acid solution, but easily by alkali and ultraviolet damage.
Vitamin B2Active form in vivo is FMN and FAD, and FMN and FAD are the prothetic groups of various flavo-enzymes, in biological oxidation process
In can play pass hydrogen effect, vitamin B2When shortage, cheilitis, glossitis, angular stomatitis, scrotitis, seborrhea and eye may occur in which
Conjunctivitis etc..Adult's daily requirement vitamin B20.5~20mg.
Vitamin B6It is the derivative of pyridine including pyridoxol, pyridoxal and pyridoxamine, it is sensitive to light, alkali, heat,
It is rapid at high temperature to destroy.Adult's daily requirement vitamin B60.5~10mg.Clinically B6It is mainly used for treating nervous centralis
Vomiting, anaemia, Neuroleptic Leukocytopenia etc. caused by Agitation and peripheral neuritis, drug and gestation etc..
Vitamin B12Also known as cobalamin, light sensitive, oxidant or reducing agent easily make its destruction.Vitamin B12It is
The coenzyme of transmethylase participates in homocysteine in endochylema and methylates, when shortage influence methionine metabolism and choline,
The synthesis of the important substances such as creatine, moreover it is possible to cause the tetrahydrofolic acid to dissociate in vivo to lack, generate megaloblastic anemia, cause
Neural myelin sheath degeneration degeneration, intelelectual deterioration etc..Adult's daily requirement vitamin B121~10 μ g.Clinically vitamin B12Mainly
For treating pernicious anaemia and megaloblastic anemia, neuritis, neuratorphy etc..
Nicotinic acid has two kinds of niacin and niacinamide in nature, belongs to the derivative of pyridine.Nicotinic acid is coenzyme
Component part, hydrogen effect of passing is played in biological oxidation process, when shortage can cause bark favus, clinical manifestation to be that body is naked
It blows by symmetry dermatitis at dew position.Be grown up 12~17mg of daily requirement nicotinic acid.It is clinically used for prevention bark favus, also can be used
In peripheral vessel spasm, Buerger's disease, the retinitis, hypertension, angina pectoris, hyperlipidemia and atherosclerosis
Deng.
Pantothenic acid is also known as pantothenic acid, plays an important role during sugar, fat and protein metabolism, daily requirement pantothenic acid of being grown up
2~20mg.The hydrogenation products of pantothenic acid are panthenol, and panthenol can reinforce normal skin hydration function, can improve dry, coarse, de-
Bits, antipruritic and treatment multiple dermatosis (such as atopic dermatitis, psoriasis, psoriasis and contact dermatitis).
Folic acid is also known as pteroylglutamic acid, easily decomposes destroy in an acidic solution.Folic acid purine, pyrimidine synthesis in lifting
Act on, when shortage DNA synthesis be suppressed, the cell cycle can be caused to stop at the S phases, red blood cell is reached maturity by shadow
It rings, megaloblastic anemia occurs.Be grown up 100~400 μ g of daily requirement folic acid.Clinically folic acid is red for treating huge children
The auxiliary treatment of cellulous anemia, alpastic anemia and leukopenia.
Biology is known as α-biotin and β-biotin, the destructible in alkaline solution, and oxidant and high temperature can make its mistake
It is living.Biotin is the coenzyme of carboxylase, and the carboxylation reaction participated in is significant to the metabolism of sugar, fat etc..It is easy when shortage
Geroderma lesion occurs, weight loss, burnout is drowsy, courbature, nausea etc..Adult's daily requirement biotin 10~100
μg。
Numerous studies confirm to need 13 kinds of vitamin, wherein 9 kinds of water soluble vitamin, fat-soluble dimension in intravenous nutrition liquid
Raw 4 kinds of element, but since liposoluble vitamin is not soluble in water, when preparation, need to make using special auxiliary material or technology
Two biostearins are present in same system.Also, since the most of physicochemical properties of vitamins ingredient are unstable, multipair light, heat,
The sensitivities such as oxygen, metal ion, soda acid, therefore be also required to keep the stability of product using special dosage form.Currently, both at home and abroad
The mode that addition solubilizer (tween, phospholipid) is all made of comprising two class Cernevit-12s listed is fat-soluble to increase
The solubility of vitamin, dosage form have freeze drying powder injection and concentrated solution for injection, are used after being required to dilution.
Shi Niweita is unique freeze drying powder injection for including two biostearins of current domestic listing, is given birth to containing 12 kinds of dimensions
Element (is free of vitamin K), and mixed micelle solubilising is formed with 2.25% soybean lecithin and 2.8% glycocholic acid.The principle of its solubilising
It is：Soybean lecithin and glycocholic acid are to have hydrophilic and hydrophobic grouping compound, the soybean phosphorus after more than critical micelle concentration
Fat and glycocholic acid can be alternately arranged to form the micella that hydrophilic radical flocks together to dampening, hydrophobic C-H bond, vitamin
Molecule is solubilized with its non-polar group insertion micella hydrocarbon core.It can be seen that there is no wrapped vitamin to micella completely
Envelope, Micellar Solubilization is to form solubilizer-drug dynamic aggregating body, the aggregation have unstability, when injection dilution agent or
Person mixes with other nutrient solutions may cause micella to disintegrate, and then injection muddiness occurs, generate the feelings such as suspended matter or precipitation
Condition is unfavorable for the stability of product.
" adult's multivitamin injection (INFUVITE ADULT) " is the 13 kinds of vitamin injections listed in the U.S.,
To avoid interaction of the vitamin under water environment using the form of two bottles of packing.Wherein, bottle 1 containing vitamin A. D. E,
K, vitamin B1、B2、B6, niacinamide and Dexpanthenol, using 1.4% Tween 80 solubilising, solubilized principle is also Micellar Solubilization.Bottle
2 contain vitamin B12, biotin and folic acid, use 30% propylene glycol for solvent.It is found in prolonged application, Tween 80 has one
Fixed pharmacological action and toxicity, most outstanding is haemocylolysis, in addition has inhibiting effect to heart, under blood pressure can be caused slight
Drop, moreover it is possible to induce human lymphocyte Sister Chromatid Exchange Frequency and increase, and damage dna replicate template, have it is mutagenic can
It can property.Therefore, Tweens are unsuitable as the solubilizer of intravenous administration formulation.Also, the kind is made using two bottles of packing
With when need to extract-mix repeatedly, bring inconvenience to clinical application, increase the possibility of pollution.
CN101491499 provides a kind of composite liposome for injection containing 12 vitamins and preparation method thereof, the patent
In, be initially formed liposome, then the hot mixt of two biostearins is carried out at the same time encapsulating, the grain size of liposome between 150nm~
Between 200nm.But the preparation process of liposome is more complex, and organic examination such as chloroform is introduced in the preparation of liposome
Agent is unfavorable for the safety of product.In addition, lipid weight is not easily controlled, vitamin is easy to happen leakage.
CN1989975 provides a kind of preparation method of 12 kinds of composite vitamin injections, and the purpose of the patent is to provide
A kind of 12 kinds of composite vitamin injections at low cost, simple for process, the main innovation point of said preparation is by solubilising appropriate
Agent and cosolvent dissolve fat-soluble and water-soluble two kinds of vitamin respectively, then so that two biostearins is incorporated in by activated carbon adsorption
Together.Although this method can be such that two classes are combined together from the vitamin to dissolve each other, due to the addition meeting of activated carbon
It is substantially reduced the content of main ingredient, and activated carbon is sensitive to the variation of temperature and pH value, there is no assurance that this preparation is in clinic
It can be completely dissolved when use, property is stablized.
Patent about Compsoite vitamin injection also has CN101297680, CN101433547 etc., main component,
Preparation characteristic and as follows with the comparison of this patent：
Patent No. CN101297680, main component are 9 kinds of vitamins, and the form in aqueous solution is emulsion droplet, and dosage form is special
Point：Emulsion containing 1% edible oil, 2% Tween 80,0.7% span 85, drinks for poultry；Advantage：It can appoint with water
Meaning is not stratified, do not precipitate than mixing, easy to operate；Disadvantage：Tween, sapn of addition etc. are more toxic, and be easy to cause haemolysis.
Patent No. CN101491499, main component are 12 kinds of vitamins, and the form in aqueous solution is liposome, dosage form
Feature：Lipidosome freeze-dried preparation containing soybean lecithin and glycocholic acid；Advantage：The complete encapsulating for realizing vitamin, avoids point
Solution, improves stability；Disadvantage：The organic reagents such as chloroform are introduced in the preparation of liposome, are unfavorable for the safety of product
Property.
Patent No. CN101433547, main component are 12 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Using glycocholic acid and lecithin as solubilizer, pass through the powder-injection of activated carbon adsorption；Advantage：It is simple for process, it is easy to operate；
Disadvantage：The activated carbon of addition can be substantially reduced the content of main ingredient, and activated carbon is sensitive to the variation of temperature and pH value, cannot
Ensure this preparation and can be completely dissolved in Clinical practice, property is stablized.
Patent No. CN1843362, main component are 9 kinds of vitamins, and the form in aqueous solution is micella, formulation characteristic：
Using Tween 80 as the lyophilized preparation of cosolvent；Advantage：Water content is low, not oxidizable, and stability is good, and single bottle dress avoids repeatedly matching
Liquid pollutes caused by operating；Disadvantage：Tween 80 has certain toxicity, such as：Haemocylolysis has inhibiting effect to heart.
Patent No. CN1843327, main component are 9 kinds of vitamins, and the form in aqueous solution is micella, formulation characteristic：
Using cholic acid substance and phosphatide as the lyophilized preparation of solubilizer；Advantage：It is simple for process, it is easy to operate；Disadvantage：Vitamin type
And content is few.
Patent No. CN1989975, main component are 12 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Using 2.25% phosphatide as solubilizer, 2.4% sodium taurocholate is cosolvent, activated carbon is adsorbent lyophilized preparation；Advantage：At
This is low, simple for process；Disadvantage：The addition of activated carbon can be substantially reduced the content of main ingredient, and activated carbon is to temperature and pH value
Variation is sensitive, it cannot be guaranteed that this preparation can be completely dissolved in Clinical practice, property is stablized.
Patent No. CN1879648, main component are 13 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Using Tween 80 as the lyophilized preparation of solubilizer；Advantage：Stability is good, easy to use；Disadvantage：The tween toxicity of addition compared with
Greatly, it be easy to cause haemolysis.
Patent No. CN101711769, main component are 12 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Using 3.8%~5.0% poly yamanashi esters as the lyophilized preparation of cosolvent；Advantage：Stability is good；Disadvantage：Poly yamanashi esters have
There is certain toxicity, is unfavorable for the safety of preparation.
Patent No. CN103006683, main component are 12 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Using 1.0%~6.0% polyoxyethylene sorbitan monoleate as the lyophilized preparation of cosolvent；Advantage：Without glycocholic acid, can be clinically used for sweet
The excessively high crowd of ammonia cholic acid；Disadvantage：Poly yamanashi esters have certain toxicity, do not utilize the safety of preparation.
Patent No. CN102652744, main component are 13 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Include the injection of two bottles, bottle 1 contains Tween 80, propylene glycol or ethyl alcohol；Advantage：Improve stability；Disadvantage：It spits
Temperature 80 etc. have certain toxicity, influence the safety of injection.
Patent No. CN101073580, main component are 13 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Include the injection of two bottles, bottle 1 is using 1.4% Tween 80 as cosolvent；Advantage：Product is Aqueous injection agent, surely
It is qualitative good；Disadvantage：1. extraction-the mixing repeatedly of two bottled preparations when in use may pollute；2. Tween 80 has certain
Toxicity, such as：Haemocylolysis has inhibiting effect to heart.
Patent No. CN101181289, main component are 13 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Two dosage forms, liposoluble vitamin Tweens solubilizer (Tween 80,20, by 100:1~20:1 ratio cooperation)；Advantage：
Direct injection, without redissolving, stability is good；Disadvantage：1. two dress preparations may pollute when in use；2. Tween 80 has
There is certain toxicity, such as：Haemocylolysis has inhibiting effect to heart.
Patent No. CN102526089, main component are 13 kinds of vitamins, and the form in aqueous solution is micella, and dosage form is special
Point：Using glycocholic acid and soybean lecithin as solubilizer, pass through the injection or freeze drying powder injection of activated carbon adsorption；Advantage：It is free of
Harmful antioxidant and preservative；Disadvantage：1. containing glycocholic acid, clinic is not useable for the excessively high crowd of glycocholic acid；
2. activated carbon adsorption is unfavorable for preparation stabilization and long-term preservation.
The present invention, main component are 13 kinds of multi-vitamins, and the form in aqueous solution is fat micro emulsion, formulation characteristic：It is single
Branch dosage form, the lyophilized preparation being made of vegetable oil, phospholipid emulsifier, assistant for emulsifying agent；Advantage：1. efficiently solve it is fat-soluble and
Water soluble vitamin is total to molten problem, eliminates traditional 2 bottled preparations pollution risk caused by possibility when in use；2. comparing
Traditional Micellar Solubilization uses fat micro emulsion to wrap up so that the dissolubility of vitamin in water greatly improves, and improves load medicine
Amount and the stability of preparation, safety；3. increasing the safety of preparation without solubilizer such as tweens, glycocholic acid is free of, is faced
Bed can be used for the excessively high crowd of glycocholic acid；4. water content is low after freeze-drying, it is not easy to be aoxidized, is conducive to storage.Disadvantage：Nothing.
This patent is shown in Table 1 with the comparative situation for having listed composite vitamin injection both at home and abroad, as can be seen from Table 1 originally
Invent the 13 kinds of multi-vitamins lyophilized preparations of a kind of injection provided has many innovative points for other preparations：
(1) liposoluble vitamin is wrapped in fat micro emulsion of the grain size less than 120nm, compares traditional Micellar Solubilization, makes
It is wrapped up with fat micro emulsion so that the dissolubility of vitamin in water greatly improves, and improves the stability of drugloading rate and preparation.
(2) the key component vegetable oil of fat micro emulsion and lecithin are natural products, not only nontoxic, without side-effects, still
The nutrition and energy supplement substance that patient is common, easily absorbs, and liposoluble vitamin can be dissolved well, it avoids using big
The solubilizer such as dosage tween, propylene glycol cause adverse reaction, improve drug effect and safety；
(3) contain 13 kinds of vitamins, 9 kinds be water soluble vitamin, 4 kinds be liposoluble vitamin, vitamin A wide selection of colours and designs,
Dosage is suitable；And the domestic uniquely injection Shi Niweita containing two biostearins only includes 12 kinds of vitamins at present；
(4) easy to use, it avoids and is completed with liquid medicine contamination caused by liquid in multi-pass operation using traditional 2 bottled preparations,
Improve the stability of preparation；
(5) water content is low after this product freeze-drying, is not easy to be aoxidized, and is conducive to the long-distance transport of formulation products and long-term holding, fills
The advantage of fat micro emulsion drug carrying system is waved in distribution, is extended the action time of drug in vivo, is reduced its toxic side effect, improves biology
Availability.
Wherein it is important that 13 kinds of multi-vitamins lyophilized preparations of injection provided by the invention are without tween, third
The solubilizer such as glycol, the present invention in liposoluble vitamin be directly dissolved in vegetable oil, without adding solubilizer, avoid similar
Patent CN1879648, CN101073580, CN102652744, CN101181289, CN102526089 and home products：It applies
Ni Weita, external product：Adult's multivitamin injection (INFUVITE ADULT), adult's multivitamin injection
(M.I.V.ADULT) security risk present in such as, while glycocholic acid is free of, it can be clinically used for the excessively high people of glycocholic acid
Group, expands Clinical practice range.
As in recent years, clinically the adverse reaction caused by auxiliary material is more and more, such as neat two medicines event, traditional Chinese medicine
The problems such as anaphylaxis event and plasticiser phthalate pollution drug event that middle Tween 80 causes, auxiliary material is to medicine
The influence of product safety also increasingly causes the attention of Drug Administration department.Zhang Haiyan etc. is published in《Shaanxi Chinese medicine》On paper
《The Safety Situation of injections in common use solubilizing auxiliary materials》In point out：It will appear allergic reaction when Tween 80 part and intramuscular injection, separately
There is serious adverse reaction, the vitamin E intravenous injection such as tween 80 is lethal for newborn.Tween 80 is commonly used for indissoluble
The solubilizer or emulsifier of property drug, such as：Intravenous anesthetics Etomidate (Fu Erli), antineoplastic Etoposide (sufficient leaf
Second glucoside) and docetaxel, vitamin K1 injection, allergic reaction happen occasionally, be mainly shown as low blood pressure, bronchus convulsion
Contraction, flush, fash, expiratory dyspnea, increased heart rate, fever, shiver with cold.Above-mentioned adverse reaction is common in rapid intravenous infusion,
Can by taking antihistamine, steroid hormone class medicine is eased.Wang Xiaoxuan etc. is published in《Chinese Pharmacological is miscellaneous with toxicology
Will (Chinese Journal of Pharmacology and Toxicology)》On paper《Tween-80 induces people's leaching
Bar cell sister chromosomes monomer exchanges and the damage to DNA》In point out：Can seriously it press down as a concentration of 1mg/mL of Tween-80
Cell Proliferation processed and division can also damage DNA replication dna template, while have obvious haemocylolysis.Herein it has also been found that tween-
80 may also have mutagenesis or carcinogenesis.Wang Yunting etc. is published in《CHINA JOURNAL OF CHINESE MATERIA MEDICA》On paper《Injection and medicine
With polyoxyethylene sorbitan monooleate (Tween-80) anaphylactoid reaction comparative studies》In point out：Tween-80 dosage increases
When big, it will form larger micella, had an impact to drug release, absorption, distribution etc..In addition Tween-80 has in addition to itself
Have outside certain cause anaphylactoid, can also cause allergy with factors such as unstable quality after injection compatibility, as storage time is long
Tween oxidation deterioration can cause sensitization to improve in injection afterwards.There has been anaphylactoid reaction caused by Tween-80 in the country
Certain research, but the molecular biology mechanism to cause allergic reaction is not clear at present, needs by further studying tween
Mechanism of action prevents the adverse reaction clinically occurred in vivo and in vitro.Yang Rui etc. is published in for 2012《Pharmaceutical Analysis magazine》
On paper《Influence of the pharmaceutic adjuvant to drug safety》In analyze polyoxyethylene sorbitan monoleate for will produce malicious secondary make when injecting
With the reason of one of：Polyoxyethylene sorbitan monoleate is common emulsifier, due to its excellent emulsifiability in pharmaceutical preparation especially
It is widely used in injection, due to raw materials for production used by part of the manufacturer-the purity of oleic acid is relatively low, so
The polyoxyethylene sorbitan monoleate coloration produced by it is poor, and colour of solution item requirement of the Chinese Pharmacopoeia to polyoxyethylene sorbitan monoleate is not achieved,
So producer is added to this process of decolourizing in the final step of production technology, i.e., in polyoxyethylene sorbitan monoleate finished product in post synthesis
A certain amount of hydrogen peroxide bleaching is added so that product colour meets the requirement of Chinese Pharmacopoeia.Hydrogen peroxide is commonly called as hydrogen peroxide,
It can be decomposed into water and oxygen under conditions of agitation and illumination, there is extremely strong oxidisability and corrosivity, thus be widely used as
Bleaching agent and disinfectant.3% hydrogen peroxide is used as the disinfectant of wound, abscess in medical treatment, have purification the surface of a wound, anti-corrosion,
The effects that deodorization, sterilization, disinfection.If be used in drug, especially in injection, harm will be difficult to estimate.Yu Yufa
Table exists《Criminal technique》Paper《Inject hydrogen peroxide causing death 1》In point out：Hydrogen peroxide is pushed away as cavity disinfectant
Note treatment, as a result may cause patient allergy it is even possible that patient dies instantly.Remaining hydrogen peroxide is tight in Tween 80
Its safety as pharmaceutic adjuvant, the especially injection containing Tween 80 are threatened again.Also, the existing pharmacopeia in China is made
For pharmaceutic adjuvant, solubilizer and emulsifier etc. record, and compared with 2005 editions pharmacopeia, quality standard has improved, reduce with Europe,
U.S., day etc. existing pharmacopeia gap, but still uncharged injection stage Tween 80.Therefore it needs to find harmless and energy
Solve the problems, such as that fat-soluble and water soluble vitamin is molten altogether, to improve quality and peace containing 13 kinds of multi-vitamins ejection preparations
Quan Xing, this is the problem that 13 kinds of multi-vitamins ejection preparations that the current quality of production is stablized have to solution, but up to now
It is not resolved.
For the drawbacks described above of the prior art, the present invention provides a kind of 13 kinds of multi-vitamins of novel injection to be lyophilized
Preparation, specially：By fat-soluble A, D, E, K be wrapped in grain size less than 120nm fat micro emulsion in, then again with it is water-soluble
Property vitamin, freeze-drying excipients and redissolve that auxiliary agent is freeze-dried mixed forms, can injection for intravenous by dilution after redissolution.Fat micro emulsion is
It is given birth to using the vegetable oil (main component is fatty acid triglycercide) of science dosage, phospholipid emulsifier, assistant for emulsifying agent and fat-soluble dimension
Element is prepared.Wherein, solvent of the vegetable oil as liposoluble vitamin, have good Drug loading capacity, phospholipid emulsifier and
Assistant for emulsifying agent is then regularly arranged in droplet surface and forms emulsifying film, prevents droplet coalescence.Primary emulsion phosphatide is from egg
A kind of amphoteric compound of the natural phospholipid extracted in yellow or soybean, scientific name are glycerolphosphocholine di fatty acid ester,
Phosphatidyl choline part is hydrophilic, fatty acid glycerine ester moiety oleophylic, and under surface tension effects, oil droplet is directed toward at lipophilic end, hydrophilic
End is outwardly formed small orbicule, will carry medicine oil drop and is wrapped in core, forms stable oil droplet.The stability and phosphorus of fat micro emulsion
The concentration of fat in the solution has a much relations, the formation of fat micro emulsion must phosphatide reach minimum at micellar concentration more than, if
The fat micro emulsion grain size that dosage less (for example the dosage of common fats emulsion is 1%~3%) is formed is larger, and increases emulsifier
Dosage can be such that grain size reduces, and increase the stability of system, as lecithin lipid concentration is adjusted to 5~30%, and with as helping emulsification
The polyethyleneglycol derivative of agent is combined, then can form grain size and be less than the fat micro emulsion of 120nm, while can ensure vitamin
It is effectively wrapped in fat micro emulsion, improves the stability of fat micro emulsion.The 13 kinds of multi-vitamins of injection prepared due to this patent
Lyophilized preparation needs to it requires fat micro emulsion filtration sterilization into that the average grain diameter of fat micro emulsion need to be less than 120nm before freeze-drying, and
And its particle diameter distribution 99% should be less than 220nm or near 220nm, and the injection prepared in patent family CN 102552293
It is 160~210nm with the average particle size distribution of multi-vitamins Submicron Emulsion, most of grain sizes are 180~210nm, refer to this specially
Table 1,4,7,10 and 13 in profit, the Submicron Emulsion grain size prepared according to the method for this patent is larger, and corresponding distribution is also wider, works as warp
10% or more Submicron Emulsion is had when the membrane filtration degerming for crossing 0.22um to be filtered, and can influence vitamin in Submicron Emulsion in this way
Content, while stringent quality control can not be carried out to vitamin.
So mostly important is a little that this patent additionally provides a kind of fat micro emulsion system for preparing and can be applied to filtration sterilization
Standby formula and method.This patent has carried out stringent particle size and distribution when preparing 13 kinds of vitamin liposoluble lyophilized preparations
Control is found：When average grain diameter is 191.7nm, particle diameter distribution can only achieve 75% and be less than less than 228.8nm, 99%
413.3nm, it is seen that attached drawing 1 can be seen by filter membrane by being only less than 75% emulsion；When average grain diameter is 184.7nm,
Particle diameter distribution can only achieve 75% and be less than 219.7nm, 99% less than 391.1nm, it is seen that only 75% emulsion can pass through filter
Film is shown in attached drawing 2；When average grain diameter is 165.9nm, particle diameter distribution can only achieve 90% and be less than less than 253.3nm, 99%
380.7nm, it is seen that attached drawing 3 can be seen by filter membrane by being only less than 90% emulsion；It can be seen that patent CN 102552293
There is at least 20% emulsion cannot be by the filter membrane of 220nm in the injection multi-vitamins Submicron Emulsion of middle preparation, this can not
Meet the requirement of filtration sterilization.
Therefore, this patent is innovated for this problem on pharmaceutical formulation and preparation method, has been prepared a series of
Different-grain diameter size and the fat micro emulsion of distribution, such as：Average grain diameter is the emulsion of 154.7nm, and particle diameter distribution can only achieve 90%
It is less than 334.2nm less than 229.7nm, 99%, it is seen that attached drawing 4 can be seen by filter membrane by being only less than 90% emulsion；It is average
Grain size is the emulsion of 146.0nm, and particle diameter distribution can only achieve 90% and be less than 209.5nm, 99% less than 293.6nm, it is seen that only
There is 90% emulsion that can see attached drawing 5 by filter membrane；Average grain diameter is the emulsion of 139.5nm, and particle diameter distribution can only achieve
90% is less than 204.4nm, 99% less than 293.1nm, it is seen that only 90% emulsion can be shown in attached drawing 6 by filter membrane；Average grain
Diameter is the emulsion of 121.1nm, and particle diameter distribution can reach 90% and be less than 178.2nm, 99% less than 256.9nm, it is seen that have and be more than
90% emulsion can be shown in attached drawing 7 by filter membrane.Average grain diameter is the emulsion of 91.1nm, and it is small that particle diameter distribution can reach 90%
It is less than 229.5nm in 145.1nm, 99%, it is seen that have at least 90% or even 99% emulsion that can see attached drawing 9 by filter membrane；It is flat
The emulsion that equal grain size is 87.8nm, particle diameter distribution can reach 90% and be less than 142.9nm, 99% less than 232.0nm, it is seen that have
Nearly 99% emulsion can be shown in attached drawing 11 by filter membrane；Average grain diameter is the emulsion of 75.5nm, and particle diameter distribution can reach 90%
It is less than 186.5nm less than 119.2nm, 99%, it is seen that attached drawing 13 can be seen by filter membrane by having more than 99% emulsion；Average grain
Diameter is the emulsion of 68.7nm, and particle diameter distribution can reach 90% and be less than 110.4nm, 99% less than 176.7nm, it is seen that have at least
99% or even 100% emulsion can be shown in attached drawing 15 by filter membrane；Average grain diameter is the emulsion of 48.7nm, particle diameter distribution energy
Reach 90% and be less than 73.5nm, 99% less than 108.8nm, it is seen that has 100% emulsion that can see attached drawing 17 by filter membrane.This
Patent according to these screenings finally prepare can with 100% by the emulsion of filtration sterilization, this be also exactly this patent innovation it
One.In addition, this patent wraps up liposoluble vitamin using fat micro emulsion, preferably resolve in same system water soluble vitamin with
The molten problem altogether of liposoluble vitamin, while without cosolvents such as tweens, providing the safety of preparation, and fat micro emulsion grain size
It is small, it is evenly distributed, stability is good, non-stimulated to vein, and clinical application is safer, this is also exactly the two of the innovation of this patent.
Table 1 has listed composite vitamin injection situation (the representative kind in part) both at home and abroad
Invention content
The present invention provides one bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion of one kind and preparation method thereof, novel formulation
Water-soluble and liposoluble vitamin is cleverly combined using special prescription and technique, it is multiple to form single freeze-drying molten altogether
Side.The novel multivitamin lyophilized preparation efficiently solves the problems, such as that fat-soluble and water soluble vitamin is molten altogether, improves dimension
The stability of raw element, reduce drug decomposition and decomposition product caused by side effect；Traditional 2 bottled preparations are eliminated to exist
Pollution risk caused by possibility when use；The abundant dissolving that can ensure pharmaceutical compounds simultaneously, avoids insoluble matter to body
Caused by side effect injure.Particularly suitable for multivitamin lack and cannot be through the vitamin for the patient that alimentary canal is normally fed
Parenteral supplement.
An object of the present invention is to provide a kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion, it can
Avoid reducing its pharmacological toxicity using cosolvents such as tweens, but can with the water for injection of arbitrary proportion, water, NaCL solution,
Glucose solution, blank Fat Emulsion or the mixing of other aqueous solutions, without occurring precipitating or crystallization, it may also be used for glycocholic acid
Excessively high crowd.
It is micro- that second object of the present invention is to provide a kind of compound 13 kinds of vitamin fat can be directly used for filtration sterilization
Breast, preparation process is easy, reliable, and convenient for industrialization, the fat micro emulsion grain size prepared is small, is distributed, while making medicament contg
It is more controllable, improve the stability of drug and auxiliary material.Safer, stable, effective freeze-dried emulsion is provided for many patients.
The present invention is achieved through the following technical solutions：
A kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion, which is characterized in that the lyophilized preparation is using emulsification
Technology is wrapped in liposoluble vitamin in fat micro emulsion, and then fat micro emulsion and water soluble vitamin, freeze-drying excipients, redissolution are auxiliary
Auxiliary agent is prepared by mixing into lyophilized preparation, and the average grain diameter of wherein fat micro emulsion is answered<120nm, it is best<100nm, particle diameter distribution 99%<
220nm is more advantageous to filtration sterilization, and grain size is basically unchanged after the lyophilized preparation prepared redissolves.
A kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion, which is characterized in that the liposoluble vitamin
For vitamin A. D. E, K.
A kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion, which is characterized in that the water soluble vitamin
For vitamin C and vitamin B1、B2、B6、B12, niacinamide, panthenol, folic acid, biotin.
A kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion, which is characterized in that 1000 bottles of unit formulations are made
The weight proportion theoretical amount of required each component can be：
The weight proportion theoretical amount of each component is preferably：
The weight proportion theoretical amount of each component is preferably：
A kind of bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion, which is characterized in that
The phospholipid emulsifier, Ke Yishi：Egg yolk lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soybean
Any one of lecithin, artificial synthesized lecithin or mixture.
The polyethyleneglycol derivative, Ke Yishi：Polyethylene glycol-cephalin derivative, polyethylene glycol-cholesterol are spread out
Biology, polyethylene glycol-two-fatty acid glycerine ester derivant, polyethylene glycol-aliphatic ester derivatives, polyethylene glycol-fatty amine
Any one of derivative, polyethylene glycol-fatty alcohol derivative or mixture.
The freeze-drying excipients are：Mannitol, sorbic acid, lactose, sucrose, dextran, gelatin, monosaccharide are (such as：Portugal
Grape sugar, fructose etc.) or polysaccharide is (such as：Starch, cellulose etc.), amino acids (such as glycine, alanine, histidine, arginine
Deng) or oligopeptides in it is one or more.
The redissolution auxiliary agent is：Polyethylene glycol-400, polyethylene glycol -600, polyethylene glycol-1000, polyethylene glycol -
1500 or polyethylene glycol-4000 it is one or more.
The preparation method of the one bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion, steps are as follows：
Step 1：By the vitamin A of recipe quantity, vitamin D3, vitamin E, vitamin K1With the injection soybean of recipe quantity
Oil mixing, is added the polyethyleneglycol derivative of the lecithin and recipe quantity of recipe quantity, is heated to 30~70 DEG C under nitrogen protection
Form oil mixture；
Step 2：The enuatrol, PLURONICS F87 and water for injection of recipe quantity are mixed at 30~80 DEG C, formed
Aqueous mixture；
Step 3：The oil mixture that the aqueous mixture that step 2 obtains is obtained with step 1 is carried out under nitrogen protection
Mixing, then at 30~80 DEG C, under the conditions of 5000~50000r/min after 5~30min of high speed dispersion, with 0.1mol/L NaOH
Or HCL adjusts pH to 6.0~9.0, homogeneous is carried out under the conditions of pressure is 90~210MPa 5~15 times, and it is micro- to obtain uniform fat
Breast；
Step 4：By the water soluble vitamin of recipe quantity：Vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin
B12, niacinamide, panthenol, biotin, folic acid, freeze drying protectant and redissolve auxiliary agent, be dissolved in water for injection, adjust pH value about 4~
Water soluble vitamin solution is made in 7,0.22um filtering with microporous membrane；
Step 5：Step 3 gained fat microemulsion solution is uniformly mixed with step 4 gained water soluble vitamin solution, 0.22um
Nitrogen-sealed is led in filtering with microporous membrane degerming；
Step 6：Every bottle of 2mL or 5mL are divided in cillin bottle, 2~18h of pre-freeze at -20~-60 DEG C, at -20~-45 DEG C
Primary distillation 4~60h, 0~40 DEG C of 1~30h of secondary distillation, take out, and lead to nitrogen and seal bottle, you can.
(vitamin injection that meets provided is mainly used for non-bowel nutritional administration, is also used for needing intravenously administrable
Other situations.These situations include：Surgical operation is burnt extensively, fracture and other wounds, treating severe infectious diseases and stupor shape
Condition.These situations make internal metabolic demand that very big change occur and so that histotrophic nutrition is lost in turn.The lyophilized preparation provided needs
It is used after redissolving, double solvents used can be the infusion of glucose sugar, physiological saline etc..)
Four, it illustrates
Fig. 1 is the grain size distribution that average grain diameter is 191.7nm fat micro emulsions；
Fig. 2 is the grain size distribution that average grain diameter is 184.7nm fat micro emulsions；
Fig. 3 is the grain size distribution that average grain diameter is 165.9nm fat micro emulsions；
Fig. 4 is the grain size distribution that average grain diameter is 154.7nm fat micro emulsions；
Fig. 5 is the grain size distribution that average grain diameter is 146.0nm fat micro emulsions；
Fig. 6 is the grain size distribution that average grain diameter is 139.5nm fat micro emulsions；
Fig. 7 is the grain size distribution that average grain diameter is 121.1nm fat micro emulsions；
Fig. 8 is the grain size distribution that average grain diameter is 100.0nm fat micro emulsions；
Fig. 9 is the grain size distribution that average grain diameter is 91.1nm fat micro emulsions；
Figure 10 is the grain size distribution that average grain diameter is 92.8nm fat micro emulsions；
Figure 11 is the grain size distribution that average grain diameter is 87.8nm fat micro emulsions；
Figure 12 is the grain size distribution that average grain diameter is 80.1nm fat micro emulsions；
Figure 13 is the grain size distribution that average grain diameter is 75.5nm fat micro emulsions；
Figure 14 is the grain size distribution that average grain diameter is 71.8nm fat micro emulsions；
Figure 15 is the grain size distribution that average grain diameter is 68.7nm fat micro emulsions；
Figure 16 is the grain size distribution that average grain diameter is 55.7nm fat micro emulsions；
Figure 17 is the grain size distribution that average grain diameter is 48.7nm fat micro emulsions
Five, the preparation embodiment of the bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion
The dosage of various auxiliary materials in the pharmaceutical formulation of the compound 13 kinds of vitamin freeze-dried preparations of a present invention couple bottled fat micro emulsion
Range and preparation process are verified.It elaborates to the present invention with reference to embodiment, but is not limited only to following reality
Example.
One, the preparation embodiment of the bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion
The bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion prepared by 1 different ratio phospholipid emulsifier content of example
1.1 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear egg yolk lecithin that recipe quantity is added to be dissolved continues after stirring and dissolving extremely dissolves at addition
Poloxamer and polyethylene glycol-the cephalin derivative just measured continue to form oil phase mixing after stirring and dissolving is clarified to solution
Object.Meanwhile the enuatrol of recipe quantity and water for injection dissolves into formation aqueous mixture completely in 60 DEG C of water-baths, then by water
Phase mixture, which is slowly added into oil mixture, forms colostrum, and then colostrum is placed in high-speed shearing machine under 14000rpm
10min is sheared, is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 10 times, obtain grain size and be less than
The fat micro emulsion of 120 nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity mannitol, glycine and polyethylene glycol -600 is added, is adjusted with 10% sodium hydroxide solution
PH value is to 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 5mL is divided in cillin bottle, and condition is：At -50 DEG C
Pre-freeze drains 22 hours at 14 hours, -35 DEG C, 10 DEG C of lyophilizations 2 hours finished product, then nitrogen charging, roll lid, packaging.
1.2 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear soybean lecithin that recipe quantity is added to be dissolved continues after stirring and dissolving extremely dissolves at addition
Poloxamer and polyethylene glycol-the cephalin derivative just measured continue to form oil phase mixing after stirring and dissolving is clarified to solution
Object.Meanwhile the enuatrol of recipe quantity and water for injection dissolves into formation aqueous mixture completely in 60 DEG C of water-baths, then by water
Phase mixture, which is slowly added into oil mixture, forms colostrum, and then colostrum is placed in high-speed shearing machine under 14000rpm
10min is sheared, is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 12 times, obtain grain size and be less than
The fat micro emulsion of 120 nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity mannitol, glycine and polyethylene glycol -600 is added, is adjusted with 10% sodium hydroxide solution
PH value is to 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 5mL is divided in cillin bottle, and condition is：At -50 DEG C
Pre-freeze drains 20 hours at 15 hours, -30 DEG C, 20 DEG C of lyophilizations 1 hour finished product, then nitrogen charging, roll lid, packaging.
1.3 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear hydrogenated yolk lecithin that recipe quantity is added to be dissolved continues stirring and dissolving and adds to after dissolving
Enter the poloxamer and polyethylene glycol-cephalin derivative of recipe quantity, it is mixed to continue formation oil phase after stirring and dissolving is clarified to solution
Close object.Meanwhile the enuatrol of recipe quantity and water for injection being dissolved in 60 DEG C of water-baths and form aqueous mixture completely, then will
Aqueous mixture, which is slowly added into oil mixture, forms colostrum, and colostrum is then placed in 14000rpm in high-speed shearing machine
Down cut 10min is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 11 times, it is small to obtain grain size
In the fat micro emulsion of 120nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity mannitol, glycine and polyethylene glycol -600 is added, is adjusted with 10% sodium hydroxide solution
PH value is to 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 5mL is divided in cillin bottle, and condition is：At -55 DEG C
Pre-freeze drains 22 hours at 15 hours, -25 DEG C, 25 DEG C of lyophilizations 2 hours finished product, then nitrogen charging, roll lid, packaging.
The bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion prepared by 2 different ratio frozen-dried protective agent content of example
2.1 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear hydrogenated yolk lecithin that recipe quantity is added to be dissolved continues stirring and dissolving and adds to after dissolving
Enter the poloxamer and polyethylene glycol-cephalin derivative of recipe quantity, it is mixed to continue formation oil phase after stirring and dissolving is clarified to solution
Close object.Meanwhile the enuatrol of recipe quantity and water for injection being dissolved in 60 DEG C of water-baths and form aqueous mixture completely, then will
Aqueous mixture, which is slowly added into oil mixture, forms colostrum, and colostrum is then placed in 14000rpm in high-speed shearing machine
Down cut 10min is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 11 times, it is small to obtain grain size
In the fat micro emulsion of 120nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity mannitol, serine and polyethylene glycol-1000 is added, is adjusted with 10% sodium hydroxide solution
PH values are to 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 2mL is divided in cillin bottle, and condition is：At -60 DEG C
Pre-freeze drains 26 hours at 14 hours, -40 DEG C, 10 DEG C of lyophilizations 2 hours finished product, then nitrogen charging, roll lid, packaging.
2.2 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear soybean lecithin that recipe quantity is added to be dissolved continues after stirring and dissolving extremely dissolves at addition
Poloxamer and polyethylene glycol-the cephalin derivative just measured continue to form oil phase mixing after stirring and dissolving is clarified to solution
Object.Meanwhile the enuatrol of recipe quantity and water for injection dissolves into formation aqueous mixture completely in 60 DEG C of water-baths, then by water
Phase mixture, which is slowly added into oil mixture, forms colostrum, and then colostrum is placed in high-speed shearing machine under 14000rpm
10min is sheared, is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 11 times, obtain grain size and be less than
The fat micro emulsion of 120 nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity lactose, glycine and polyethylene glycol-1000 is added, pH is adjusted with 10% sodium hydroxide solution
It is worth 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 5mL is divided in cillin bottle, and condition is：At -55 DEG C
Pre-freeze drains 25 hours at 14 hours, -25 DEG C, 20 DEG C of lyophilizations 2 hours finished product, then nitrogen charging, roll lid, packaging.
2.3 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear egg yolk lecithin that recipe quantity is added to be dissolved continues after stirring and dissolving extremely dissolves at addition
Poloxamer and polyethylene glycol-the cephalin derivative just measured continue to form oil phase mixing after stirring and dissolving is clarified to solution
Object.Meanwhile the enuatrol of recipe quantity and water for injection dissolves into formation aqueous mixture completely in 60 DEG C of water-baths, then by water
Phase mixture, which is slowly added into oil mixture, forms colostrum, and then colostrum is placed in high-speed shearing machine under 14000rpm
10min is sheared, is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 12 times, obtain grain size and be less than
The fat micro emulsion of 120 nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity lactose, serine and polyethylene glycol-1000 is added, pH is adjusted with 10% sodium hydroxide solution
It is worth 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 2mL is divided in cillin bottle, and condition is：At -50 DEG C
Pre-freeze drains 24 hours at 15 hours, -25 DEG C, 20 DEG C of lyophilizations 2 hours finished product, then nitrogen charging, roll lid, packaging.
3 different ratio of example redissolves the bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion prepared by auxiliary agent content
3.1 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear egg yolk lecithin that recipe quantity is added to be dissolved continues after stirring and dissolving extremely dissolves at addition
Poloxamer and polyethylene glycol-the cephalin derivative just measured continue to form oil phase mixing after stirring and dissolving is clarified to solution
Object.Meanwhile the enuatrol of recipe quantity and water for injection dissolves into formation aqueous mixture completely in 60 DEG C of water-baths, then by water
Phase mixture, which is slowly added into oil mixture, forms colostrum, and then colostrum is placed in high-speed shearing machine under 14000rpm
10min is sheared, is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 12 times, obtain grain size and be less than
The fat micro emulsion of 120 nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity mannitol, serine and polyethylene glycol -200 is added, is adjusted with 10% sodium hydroxide solution
PH value is to 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 5mL is divided in cillin bottle, and condition is：At -50 DEG C
Pre-freeze drains 25 hours at 16 hours, -25 DEG C, 20 DEG C of lyophilizations 3 hours finished product, then nitrogen charging, roll lid, packaging.
3.2 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear egg yolk lecithin that recipe quantity is added to be dissolved continues after stirring and dissolving extremely dissolves at addition
Poloxamer and polyethylene glycol-the cephalin derivative just measured continue to form oil phase mixing after stirring and dissolving is clarified to solution
Object.Meanwhile the enuatrol of recipe quantity and water for injection dissolves into formation aqueous mixture completely in 60 DEG C of water-baths, then by water
Phase mixture, which is slowly added into oil mixture, forms colostrum, and then colostrum is placed in high-speed shearing machine under 14000rpm
10min is sheared, is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 12 times, obtain grain size and be less than
The fat micro emulsion of 120 nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity mannitol, serine and polyethylene glycol-400 is added, is adjusted with 10% sodium hydroxide solution
PH value is to 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 5mL is divided in cillin bottle, and condition is：At -50 DEG C
Pre-freeze drains 22 hours at 15 hours, -25 DEG C, 20 DEG C of lyophilizations 2 hours finished product, then nitrogen charging, roll lid, packaging.
3.3 prescription of example：
Preparation method：
(1) by the vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K under 60 DEG C of water-baths, nitrogen protections
It is dissolved in soybean oil, the completely rear soybean lecithin that recipe quantity is added to be dissolved continues after stirring and dissolving extremely dissolves at addition
Poloxamer and polyethylene glycol-the cephalin derivative just measured continue to form oil phase mixing after stirring and dissolving is clarified to solution
Object.Meanwhile the enuatrol of recipe quantity and water for injection dissolves into formation aqueous mixture completely in 60 DEG C of water-baths, then by water
Phase mixture, which is slowly added into oil mixture, forms colostrum, and then colostrum is placed in high-speed shearing machine under 14000rpm
10min is sheared, is finally placed in high pressure homogenizer under the conditions of pressure is 1250bar and carries out homogeneous 10 times, obtain grain size and be less than
The fat micro emulsion of 120 nm；
(2) by the vitamin C of recipe quantity, vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacinamide, panthenol,
Biotin, folic acid, which are completely dissolved in water for injection, forms clear aqueous solution, then this aqueous solution is added to obtained by step 1
Fat microemulsion solution in, recipe quantity lactose, glycine and polyethylene glycol -600 is added, pH is adjusted with 10% sodium hydroxide solution
It is worth 5~7, then through 0.22 μm of filtering with microporous membrane degerming；
(3) semi-finished product after filtration sterilization are lyophilized, every bottle of 5mL is divided in cillin bottle, and condition is：At -55 DEG C
Pre-freeze drains 22 hours at 13 hours, -30 DEG C, 25 DEG C of lyophilizations 2 hours finished product, then nitrogen charging, roll lid, packaging.
Two, the quality research of the bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion
1 particle diameter distribution of example detects
It is shone the bottled fat micro emulsion compound 13 that above 9 embodiments of grain size/potentiometer detection prepare using dynamic optical
The situation of change of kind vitamin freeze-dried preparation grain size before and after freeze-drying, the results are shown in Table 2.
The compound 13 kinds of vitamin freeze-dried preparations of 2 one bottled fat micro emulsion of the table change of size front and back in freeze-drying
*PdI:Polydispersion index polydispersity indexs (for weighing particle size distribution range)
As shown in Table 2：The grain size that above 9 prescriptions and preparation process obtain meets the requirements, and forward backward averaging grain is lyophilized
Diameter size and particle size distribution range are without significant change, and in addition dried frozen aquatic products appearance character, redissolution situation are more satisfactory, explanation
A bottled compound 13 kinds of vitamin freeze-dried preparations freeze-drying of fat micro emulsion prepared by the present invention is front and back stable.
The compound 13 kinds of vitamin freeze-dried preparations of 2 one bottled fat micro emulsion of example and normal injection and dilution are mixed
The situation of change of solution physical property
It is mixed that the above sample presses 1 ︰ 1 and 1 ︰ 5 with water for injection, water, NaCL solution, glucose solution, blank Fat Emulsion respectively
It closes.It is recovered to emulsion after hydration concussion, 6 hours is placed without crystallization, precipitation, layering or demulsifying phenomenon, illustrates preparation of the present invention
A bottled fat micro emulsion multi-vitamins lyophilized preparation can be molten with water for injection, water, NaCL solution, the glucose of arbitrary proportion
Liquid, blank Fat Emulsion or the mixing of other aqueous solutions, occupation mode are extensive.
The Detection of Stability of the compound 13 kinds of vitamin freeze-dried preparations of 3 one bottled fat micro emulsion of example
It extracts three products in above-mentioned 9 embodiments and places progress in 10 days under the conditions of 60 DEG C of high temperature, illumination 4500Lx
Influence factor experiment investigation, the results are shown in Table 3；6 months under the conditions of 40 DEG C of high temperature, relative humidity 75% ± 5%, accelerated
Experiment investigation the results are shown in Table 4；18 months under the conditions of 25 DEG C of temperature, relative humidity 60% ± 10%, carries out long term test and examine
It examines, detects the variation of every quality index, the results are shown in Table 5.
Influence experiment investigation (60 DEG C of high temperature, the illumination of the compound 13 kinds of vitamin freeze-dried preparations of 3 one bottled fat micro emulsion of table
4500Lx)
Accelerated test (40 DEG C of high temperature, the relative humidity of the compound 13 kinds of vitamin freeze-dried preparations of 4 one bottled fat micro emulsion of table
75% ± 5%)
5 one bottled fat micro emulsion of table compound 13 kinds of vitamin freeze-dried preparation long-time stability (25 DEG C of temperature, relative humidity
60% ± 10%)
Conclusion：
Through influence factor 10 days, accelerate 6 months and be 18 months long-term after, product quality produced by the present invention, which complies with standard, to be wanted
It asks, and every quality index meets quality standard without significant change, illustrates the product quality stability of the present invention very
It is good.
Claims (7)
1. a kind of lyophilized preparation of the compound 13 kinds of vitamin of fat micro emulsion, which is characterized in that the lyophilized preparation uses emulsifying technology handle
Liposoluble vitamin is wrapped in fat micro emulsion, and then fat micro emulsion mixes system with water soluble vitamin, freeze drying protectant, redissolution auxiliary agent
For at lyophilized preparation, the wherein average grain diameter of fat micro emulsion<120nm, particle diameter distribution 99%<220nm is more advantageous to filtration sterilization,
Grain size is basically unchanged after the lyophilized preparation prepared redissolves,
It is characterized in that, the weight proportion that each component needed for 1000 bottles of unit formulations is made is：
Preparation method is as follows：
Step 1：The vitamin A of recipe quantity, vitamine D3, vitamin E, vitamin K1 are mixed with the soybean oil of recipe quantity,
The lecithin of recipe quantity is added under nitrogen protection, the polyethyleneglycol derivative of PLURONICS F87 and recipe quantity is heated to 30~70
DEG C formed oil mixture；
Step 2：The enuatrol of recipe quantity and water for injection are mixed at 30~80 DEG C, form aqueous mixture；
Step 3：The aqueous mixture that step 2 obtains is mixed with the oil mixture that step 1 obtains under nitrogen protection,
Then at 30~80 DEG C, under the conditions of 5000~50000r/min after 5~30min of high speed dispersion, with 0.1mol/L NaOH or HCL
PH to 6.0~9.0 is adjusted, homogeneous is carried out under the conditions of pressure is 90~210MPa 5~15 times, obtains uniform fat micro emulsion；
Step 4：By the water soluble vitamin of recipe quantity：Vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin
B12, niacinamide, panthenol, biotin, folic acid, freeze drying protectant and redissolution auxiliary agent are dissolved in water for injection, adjust pH value 4~7,
Water soluble vitamin solution is made in 0.22um filtering with microporous membrane；
Step 5：Step 3 gained milky solution is uniformly mixed with step 4 gained water soluble vitamin solution, the filter of 0.22um micropores
Nitrogen-sealed is led in membrane filtration degerming；
Step 6：Every bottle of 5mL is divided in cillin bottle, 2~18h of pre-freeze at -20~-60 DEG C, and -20~-45 DEG C distil 4 next time
~60h, 0~40 DEG C of 1~30h of secondary distillation, take out, lead to nitrogen envelope bottle to get.
2. lyophilized preparation described in claim 1, which is characterized in that the weight of each component needed for 1000 bottles of unit formulations is made
Proportioning is：
3. a kind of lyophilized preparation of the compound 13 kinds of vitamin of fat micro emulsion, which is characterized in that the lyophilized preparation uses emulsifying technology handle
Liposoluble vitamin is wrapped in fat micro emulsion, and then fat micro emulsion mixes system with water soluble vitamin, freeze drying protectant, redissolution auxiliary agent
For at lyophilized preparation, the wherein average grain diameter of fat micro emulsion<120nm, particle diameter distribution 99%<220nm is more advantageous to filtration sterilization,
Grain size is basically unchanged after the lyophilized preparation prepared redissolves, and the weight proportion of each component needed for 1000 bottles of unit formulations is made
For：
Preparation method is as follows：
Step 1：The vitamin A of recipe quantity, vitamine D3, vitamin E, vitamin K1 are mixed with the soybean oil of recipe quantity,
The lecithin of recipe quantity is added under nitrogen protection, the polyethyleneglycol derivative of PLURONICS F87 and recipe quantity is heated to 30~70
DEG C formed oil mixture；
Step 2：The enuatrol of recipe quantity and water for injection are mixed at 30~80 DEG C, form aqueous mixture；
Step 3：The aqueous mixture that step 2 obtains is mixed with the oil mixture that step 1 obtains under nitrogen protection,
Then at 30~80 DEG C, under the conditions of 5000~50000r/min after 5~30min of high speed dispersion, with 0.1mol/L NaOH or HCL
PH to 6.0~9.0 is adjusted, homogeneous is carried out under the conditions of pressure is 90~210MPa 5~15 times, obtains uniform fat micro emulsion；
Step 4：By the water soluble vitamin of recipe quantity：Vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin
B12, niacinamide, panthenol, biotin, folic acid, freeze drying protectant and redissolution auxiliary agent, are dissolved in water for injection, adjust pH value 4~7,
Water soluble vitamin solution is made in 0.22um filtering with microporous membrane；
Step 5：Step 3 gained milky solution is uniformly mixed with step 4 gained water soluble vitamin solution, the filter of 0.22um micropores
Nitrogen-sealed is led in membrane filtration degerming；
Step 6：Every bottle of 5mL is divided in cillin bottle, 2~18h of pre-freeze at -20~-60 DEG C, and -20~-45 DEG C distil 4 next time
~60h, 0~40 DEG C of 1~30h of secondary distillation, take out, lead to nitrogen envelope bottle to get.
4. lyophilized preparation described in claim 1, which is characterized in that the lecithin is selected from：Egg yolk lecithin, soybean ovum
Any one of phosphatide, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, artificial synthesized lecithin or mixture.
5. lyophilized preparation described in claim 1, which is characterized in that the polyethyleneglycol derivative is selected from：Polyethylene glycol-
Cephalin derivative, polyethylene glycol-cholesterol derivative, polyethylene glycol-two-fatty acid glycerine ester derivant, polyethylene glycol-fat
Any one of fat acid ester derivant, polyethylene glycol-aliphatic amine derivative, polyethylene glycol-fatty alcohol derivative or mixing
Object.
6. lyophilized preparation described in claim 1, which is characterized in that the freeze drying protectant is selected from：Mannitol, sorbic acid,
Lactose, sucrose, dextran, gelatin, monosaccharide either any one or more of polysaccharide, amino acids or oligopeptides.
7. lyophilized preparation described in claim 1, which is characterized in that the redissolution auxiliary agent is selected from：Polyethylene glycol-400 is gathered
Ethylene glycol -600, polyethylene glycol-1000, polyethylene glycol-1500 or polyethylene glycol-4000 it is any one or more of.
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| CN106821998B (en) * | 2017-03-28 | 2020-03-10 | 深圳万和制药有限公司 | Method for preparing vitamin AD micro-pills and compound amino acid capsule composition thereof |
| CN107115349A (en) * | 2017-05-05 | 2017-09-01 | 宁夏智弘生物科技有限公司 | A kind of vitaminAD E microemulsion injections for animals and preparation method thereof |
| CN110573142B (en) * | 2017-10-25 | 2024-01-16 | 费森尤斯卡比德国有限公司 | All-in-one lyophilized multivitamin emulsion for parenteral use |
| CN109044974A (en) * | 2018-09-06 | 2018-12-21 | 澳汀斯（广州）生物医药科技有限公司 | Coat nano vesicle preparations and its application of vitamin D and vitamin K |
| CN109010292B (en) * | 2018-09-19 | 2020-03-17 | 广州汉光药业股份有限公司 | Multivitamin parenteral nutrient nanosphere freeze-dried injection and preparation method thereof |
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| CN1843362A (en) * | 2006-04-30 | 2006-10-11 | 贵阳云岩西创药物科技开发有限公司 | Composite vitamin injection and its preparation method |
| CN1989975A (en) * | 2005-12-30 | 2007-07-04 | 成都博瑞医药科技开发有限公司 | Method for preparing composite injection of 12 vitamins |
| CN101491499A (en) * | 2009-02-19 | 2009-07-29 | 陶灵刚 | Composite liposome for injection containing 12 vitamins and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1989975A (en) * | 2005-12-30 | 2007-07-04 | 成都博瑞医药科技开发有限公司 | Method for preparing composite injection of 12 vitamins |
| CN1843362A (en) * | 2006-04-30 | 2006-10-11 | 贵阳云岩西创药物科技开发有限公司 | Composite vitamin injection and its preparation method |
| CN101491499A (en) * | 2009-02-19 | 2009-07-29 | 陶灵刚 | Composite liposome for injection containing 12 vitamins and preparation method thereof |
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