CN106074377A

CN106074377A - A kind of stable vitamin K2submicron emulsion and preparation method thereof

Info

Publication number: CN106074377A
Application number: CN201610489774.4A
Authority: CN
Inventors: 陈杰鹏; 段丽丽; 邱雪莲; 洪琳; 陈鸿锐; 纪烨瑜; 蔡桂珠; 陈煜藩; 胡留松; 许志锴; 叶红林; 黄晓莹
Original assignee: Sungen Bioscience Co ltd
Current assignee: Sungen Bioscience Co ltd
Priority date: 2016-06-24
Filing date: 2016-06-24
Publication date: 2016-11-09
Also published as: CN110496101A

Abstract

A kind of vitamin K₂Submicron emulsion, including having by described vitamin K₂Following each component of the percetage by weight of the gross weight meter of submicron emulsion: vitamin K₂0.0005%～1%, oil 1.0%～10%, phosphatidase 0 .1%～1.2%, emulsifying agent 0.5%～2.3%, antifreezing agent 0.5%～3.0% and water, wherein emulsifying agent is other emulsifying agents beyond phospholipid.Described vitamin K₂Submicron emulsion sterilization stability and freeze-thaw stability are good, and have the expection effect duration of even as high as more than 2 years.

Description

A kind of stable vitamin K2Submicron emulsion and preparation method thereof

Technical field

The application relates to field of pharmaceutical preparations, is specifically related to a kind of stable vitamin K₂Submicron emulsion and preparation method thereof with And the pharmaceutical applications of above-mentioned submicron emulsion.

Background technology

Osteoporosis is a kind of chronic, gradual dysostosis disease, and the reaction of its principal disease is the most complete for part The bone mass of portion's skeleton reduces, and with bigger risk of bone fracture.Most old people, postmenopausal women can suffer from sclerotin Osteoporosis, faces the threat that chronic pain, fracture are even disabled, causes quality of life to be reduced, and is also required to undertake huge simultaneously Cost.

Calcium is the important composition material of sclerotin, in order to pre-preventing bone rarefaction, increasing people starts attention and replenishes the calcium. But, the scientific research institution of American-European countries once carried out repeatedly replenishing the calcium and healthy large-scale clinical trials, found to replenish the calcium merely also The incidence rate of osteoporosis and fracture can not be reduced, constipation, calculus, articular cartilage calcification, bony spur hypertrophy, bone can be caused on the contrary The untoward reaction such as arthritis and cardiovascular and cerebrovascular vessel obstruction.

There are some researches show there are two kinds of different whereabouts after calcium ion entrance is internal: one is deposited on correct position, than Such as skeleton, tooth etc.；Two positions being deposited on mistake, such as articular cartilage, heart and brain arteries, gallbladder and kidney etc..Mistake The calcareous meeting of deposition further results in the calcification of place site tissue and organ.The calcification of articular cartilage can cause vertebra, lumbar vertebra, The damage of the big Minor articulus such as elbow, knee joint, causes the diseases such as serious osteoarthritis, scapulohumeral periarthritis, and severe patient can cause bony spur and pass The destruction in joint chamber.Arterial vascular calcification can cause stricture of artery, thromboembolism, myocardial infarction and apoplexy.Gallbladder and the calcium of kidney Change the normal physiological function that then can affect internal organs, but also other secondary diseases can be caused.Many old peoples often face simultaneously Face the multiple health problems such as osteoporosis, arteriosclerosis and Senior osteoarthritis, it is desirable to have a preferable Therapeutic Method, both Osteoporosis symptoms can be improved, be not result in again or increase the weight of the disease such as arteriosclerosis and arthritis, and vitamin K just can solve Certainly these problems.

For many years, the mankind are confined to the effect of vitamin K to maintain normal clotting mechanism aspect always, but along with 1960 Year has scholar to find vitamin K₂Also participate in the effect of human body bone metabolism, after particularly " vitamin K dependent protein " is found, this Plant understanding and be just changed (Nelsestuen, G.L., et al. (2000) .Vitamin K-dependent proteins.Vitamins&Hormones 58:355-389.).Vitamin K is the coenzyme of gamma-glutamic acid carboxylase, can be by solidifying The former glutaminic acid residue carboxylation waiting albumen of hemase becomes gamma-carboxylation glutamic acid (γ-carboxyglutamate, Gla), generates Gla Comprise albumen, i.e. vitamin K dependent protein.Having multiple Gla to comprise albumen in body, they are distributed in different organ, tissue, Having of having now been found that is following several:

(1) coagulation factors (II, VII, IX, X) and anticoagulant protein (C, S, Z), they are synthesized by liver, coagulate at blood Play an important role during Gu.

(2) Bone Gla protein (Osteocalcin), is the noncollagen protein secreted by osteoblast, and during bone formation Play a significant role.

(3) substrate GLA albumen (Matrix Gla protein, MGP), this albumen is present in multiple bodily tissue, The main effect playing suppression calcification, this cartilage and particularly evident at arterial blood tube wall of acting on.

(4) growth inhibited specific proteins 6 (Growth-arrest-specific gene-6 protein, GAS6), by Damage response is secreted by leukocyte and endotheliocyte, it is possible to helps cell survival, breed, migrate and adhere to.

(5) in addition also having the Gla albumen (PRGP) of proline rich, cross-film Gla albumen (TMG) etc., they are really Cut function the most unknown.

Due to the Gla of vitamin K and body, to comprise albumen closely bound up, and these protein all play important physiology Function, therefore vitamin K has multiple pharmacological effect.

Prevention and treatment hemorrhage

The thrombin that liver initially synthesizes is inactive precursor, it is necessary to modifies through translation and processing and just has work Property.This process needs vitamin K family member as cofactor.When human body or animal be deficient in vitamin K or take in vitamin K During antagonist such as coumarin or warfarin, in blood plasma, thrombin can reduce accordingly, promotes that the ability of blood coagulation significantly declines, solidifying The blood time will be obviously prolonged, and bleeding even occurs.Although vitamin K can promote blood coagulation, but can't affect blood Proper flow.Research finds, the clotting mechanism effect of vitamin K simply just can play under human body occurs hemorrhage situation, When the cytokine i.e. comprised when the cell organized or be stimulated of damage is exposed to blood plasma, just initially enter normal blood coagulation Process, plays anastalsis.

" growing pain " of child can be improved

Child, is referred to as " growing pain " it sometimes appear that double lower limb intermittence pain of recurrent exerbation at growth and development stage.Day This child is because from little edible rich in vitamin K₂Natto, suffer the probability of " growing pain " to be far smaller than the youngster of other countries Virgin.Research shows, the bone density at " growing pain " children with pain position is substantially less than normal children, vitimin supplement K₂Can make Virgin bone density is higher, and skeleton is strongr, thus prevents the appearance of " growing pain ".

Prevention of arterial hardening, organ calcification and arthritis

Calcium in food will not deposit to skeleton and tooth after entering human body completely, understands some and deposits to arterial blood The soft tissue at pipe, cardiac valve, articular cartilage or other positions, causes the diseases such as arterial sclerosis, organ calcification, arthritis Sick.Vitimin supplement K₂After, it can improve the content of Bone Gla protein, strengthens itself and Ca²⁺Binding ability, reduce in blood vessel, pass The calcareous content of the error location depositions such as joint chamber, anti-hemostatic tube, joint and other organ calcifications, prevention of arterial hardening, organ calcium Change and arthritis.

Auxiliary treatment and prophylaxis of cancer

In vitro study all shows, vitamin K can show antitumaous effect (K₁And K₂It is all), test cell line result shows, dimension Raw element K is inhibited to multiple cancerous cell, and vitamin K₂ID50 less than K₁, to the inhibitory action of tumor cell more By force, but to normal medullary cell almost without effect.Researcher takes vitamin K to liver cancer patient₂, significantly improve existence Rate, compared to matched group, takes vitamin K₂The cancer metastasis rate of group is lower.It addition, suffer from promyelocytic leukemia Patient takes vitamin K₂, in conjunction with other treatment, promyelocyte is wholly absent after two months；Suffers from myeloproliferative disorder comprehensive Levy the clothes for patients vitamin K of (MDS easily develops into acute myeloid leukemia)₂Rear marrow germinal cell number reduces, platelet count Amount increases, and still shows good curative effect after stopping myelosuppresive therapy.

There is now invention vitamin K and other vitamin are added to (CN 1073826) in beverage or are prepared as powdery group Compound (CN 1212080C) is used for nutritional supplementation, but these inventions are only capable of, to human body vitimin supplement K, to play treatment The effect of osteoporosis.Sai Sifumeier etc. disclose a kind of for treating and preventing bone, cartilage and cardiovascular system phase The vitamin K of related disorders₂Medicine and nutraceuticals, but the dosage form of its design is tablet or capsule (CN 101534807A).Due to vitamin K₂Compare vitamin K₁Therapeutic effect more preferable, and the vitamin K of body picked-up₁Need to be converted into K₂Rear competence exertion effect (Okano T, Shimomura Y, Yamane M, et al.Conversion of phylloquinone(vitamin K1)into menaquinone-4(vitamin K2)in mice:two possible routes for menaquinone-4accumulation incerebra of mice.J Biol Chem.2008；283: 11270-11279), vitamin K is the most directly used₂Can there is faster and better therapeutic effect.At present, it has been used for Prevent or treat osteoporotic vitamin K₂Medicine (Menatetrenone soft capsule) and health product listing, dosage form It is soft capsule or tablet.

Due to vitamin K₂Being fat-soluble medicine, its dissolubility in water is the least, and after oral administration, gastrointestinal absorption is relatively Difference, bioavailability is low.Therefore, though vitamin K₂Having good pharmacological action, its curative effect clinically also is difficult to reach Expected value.Additionally, vitamin K₂Mainly extracting from natto or prepared by fermentable, synthetic is extremely difficult. Therefore need a kind of higher dosage form of bioavailability of exploitation badly, both can guarantee that medicine can reach desired concn in vivo, and again could Economize in raw materials, reduce cost.

In order to increase the clinical efficacy of lipophilic compound, researchers have attempted multiple increase gastrointestinal absorption and raising The method of bioavailability.Submicron emulsion (submicron emulsion) can improve the oral life of medicine from the following aspects Thing availability:

(1) by being insoluble in the medicine dissolution of water or being solubilized in oil phase and be then prepared as O/W type submicron emulsion, medicine can be improved The dissolubility of thing, increase medicine dispersion, be more beneficial for medicine absorption (Araya, H., et al. (2005). " The novel formulation design of O/W microemulsion for improving the gastrointestinal absorption of poorly water soluble compounds."International journal of pharmaceutics 305(1):61-74.)；

(2) drug encapsulation is administered in submicron emulsion, the drug degradation sensitive to the enzyme in digestive tract can be avoided, improve Gastrointestinal tract stability (Crauste-Manciet, S., et al., the Cefpodoxime-proxetil protection of medicine from intestinal lumen hydrolysis by oil-in-water submicron emulsions.International journal of pharmaceutics,1998.165(1):p.97-106.)。

(3) submicron emulsion surface has hydrophilic so that it is be easier to enter the hydrated sheath of enteric cavity mucosa, and medicine can directly and stomach Intestinal epithelial cell contact, thus beneficially medicine absorption (Zhang Zhengquan, Lu Bin. microemulsion drug-supplying system research overview. middle traditional Chinese medical science Medicine industry magazine, 2001.32 (3): p.139-142)；

(4) lipid in microemulsion can occur degradation of lipid under pancreatin and bile effect, and re-assemble becomes the breast that particle diameter is less Drip, thus increase the contact area of medicine and intestinal epithelial cell, add medicine in gastrointestinal transhipment and medicine cross-film Absorption and transport efficiency (Zangenberg, N.H., et al., A dynamic in vitro lipolysis model:II: Evaluation of the model.European Journal of Pharmaceutical Sciences,2001.14 (3):p.237-244.)；

(5) some surfactant in microemulsion can suppress P-glycoprotein in gastrointestinal mucosa to act on the outer row of medicine, increases Add absorption (Cornaire, G., et al., the Impact of excipients on the absorption of P-of medicine glycoprotein substrates in vitro and in vivo.International journal of pharmaceutics,2004.278(1):p.119-131.)。

(6) submicron emulsion is directly entered lymph circulation after being absorbed, and can avoid first pass effect (Araya, H., the et of liver al.(2005)."The novel formulation design of O/W microemulsion for improving the gastrointestinal absorption of poorly water soluble compounds." International journal of pharmaceutics 305(1):61-74.)

Therefore, by vitamin K₂Exploitation is submicron emulsion, can improve its oral administration biaavailability, have compared to other dosage form Preferably prevention or therapeutic effect.

Additionally, from the point of view of patient compliance angle, compared to tablet or capsule, oral submicron emulsion is taken more square Just, the crowd of child, old man and dysphagia it is particularly suited for.The equipment preparing Emulsion has high pressure homogenizer, microjet instrument, glue Body mills etc., particle diameter is less, particle diameter narrow distribution, exterior quality are excellent, the Emulsion of good stability to use the said equipment all to can get Product.It is applicable to industrialized great production.

Generally speaking, oral submicron emulsion has tablet, the irreplaceable advantage of capsule, but by vitamin K₂Exploitation is mouth Take submicron emulsion, still have two problems to need to solve:

(1) freeze-thaw stability of submicron emulsion is improved.Fat emulsion injection or medicine carrying type submicron emulsion are storing and transportation Middle freezing can cause structural deterioration, profit lamination occurs so that it is lost efficacy, so submicron emulsion requires that storage temperature is not less than 0 ℃.But most of China area winter temperature is below 0 DEG C, transport and the preservation condition of preparation are the harshest.Although lyophilizing Technology can solve problems to a certain extent, but lyophilizing complex process, relatively costly.

(2) oxidation of drug degradation problem.Due to vitamin K₂Naphthoquinone core on connect and have multiple isoprene structures, it is The double bond of first isoprene structures of neighbouring naphthoquinone core is the most oxidized, and the catalysis of illumination or metal ion also can promote this oxygen Change the generation of reaction, by vitamin K₂After being prepared as submicron emulsion, its effect duration is the shortest, it is impossible to realize the purpose of list marketing.

Described on end, need a kind of stable vitamin K of exploitation badly₂Submicron emulsion, this submicron emulsion has good physically stable Property and chemical stability, it is possible to tolerance freeze thawing, and medicine can make its active component content maintain regulation within a certain period of time More than standard.

Summary of the invention

One purpose of the application is to provide a kind of vitamin K₂Submicron emulsion.

The application is also an object that offer one prepares said vitamin K₂The method of submicron emulsion.

A further object of the application is to provide said vitamin K₂Submicron emulsion is used for treating hemorrhage, prevention in preparation Close with treatment osteoporosis, pre-child-resistant " growing pain ", prevention old people's angiosteosis, prevention cardiovascular and cerebrovascular disease, prevention Purposes in the sick medicine treating and preventing cancer with arthritis or auxiliary of joint.

Specifically, the application provides a kind of vitamin K₂Submicron emulsion, including by described vitamin K₂The gross weight meter of submicron emulsion Each component of following percetage by weight:

Vitamin K₂0.0005%～0.5%,

Oil 1.0%～10%,

Phosphatidase 0 .1%～1.2%,

Emulsifying agent 0.5%～2.3%

Antifreezing agent 0.5%～3.0%,

And water；

Wherein emulsifying agent is other emulsifying agents beyond phospholipid.

In above or other embodiments, the percetage by weight of phospholipid can be 0.3%～0.8%.

In above or other embodiments, the percetage by weight of emulsifying agent can be 1.0%～1.6%.

In above or other embodiments, the percetage by weight of antifreezing agent can be 0.5%～2.0%.

In above or other embodiments, described vitamin K₂Submicron emulsion can also include by described vitamin K₂Sub-micro The correctives that percetage by weight is 0.02%～5.0% of the gross weight meter of breast.

In above or other embodiments, described vitamin K₂Submicron emulsion can also include the gross weight by described submicron emulsion The percetage by weight of gauge is 0.001%～1%, the stabilizer of preferably 0.001%～0.015%.

In above or other embodiments, described Menaquinone K6 can selected from MK-4, MK-5, MK-6, MK-7, MK-8 and One or more of in MK-9, it is understood to one skilled in the art that numeral 4-9 represents the side chain isoprene of Menaquinone K6 The quantity of group.Wherein, Menaquinone K6 used herein be extract from natto gained series compound and can be commercial Obtain or prepare voluntarily, such as, can be purchased by the Kappa Bioscience of Norway, Jin Ying bio tech ltd, Taiwan etc. ?；If prepared voluntarily, in described natto fermentation, extracting method can be found in such as document: Wu Yuanfeng etc., and microbial method produces dimension Raw element K2 (MK), science and technology circular, 2004,20 (5): 428-433).

In above or other embodiments, described oil can be selected from soybean oil, Semen Maydis oil, Oleum Camelliae, olive oil, Cortex cocois radicis One or more of in oil, fish oil, safflower oil, Oleum sesami and medium chain triglyceride, it is preferable that described oil can be soybean oil With the mixture of medium chain triglyceride, it is highly preferred that described oil can be weight ratio be 1:0.8～1:1.5 soybean oil and in The mixture of chain triglyceride.Preferably, medicine vitamin K₂It is 1:1～1:20000 (w/w), preferably 1:50 with the ratio of oil ～1:5000 (w/w).Wherein, used herein to oil be commercial products.

In above or other embodiments, described phospholipid can be selected from soybean lecithin (SPC), Ovum Gallus domesticus Flavus lecithin (EPC), hydrogenated soya phosphatide (HSPC), DOPC (DOPC), DOPE (DOPE), two palm fibres Palmitic acid phosphatidyl choline (DPPC), DPPE (DPPE), distearoyl phosphatidylcholine (DSPC), two hard Acyl PHOSPHATIDYL ETHANOLAMINE (DSPE), DSPG (DSPG), dimyristoyl phosphatidyl choline (DMPC), two Myristoyl PHOSPHATIDYL ETHANOLAMINE (DMPE), DLPC (DLPC) and two lauroyl PHOSPHATIDYL ETHANOLAMINE (DLPE) one or more of in.Wherein, used herein to phospholipid be commercial products.Wherein, in this application, phosphorus Fat can have the strongest emulsification, good biocompatibility as amphoteric emulsifier, it is easy to and enterocyte fusion, so After be ingested, there is good Nutrition.

In above or other embodiments, described emulsifying agent can be selected from F68 F87, pluronic F108, general Lang Nike F127, pluronic P124, PLURONICS F87 (Pluronic F68), poloxamer 237 (Pluronic F-87), Pluronic/Lutrol F 108 (Pluronic F-108), poloxamer188 (Pluronic F-127), CREMOPHORE EL (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), Cremophor RH60 (Cremophor RH60), polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween60), polyoxyethylene sorbitan monoleate (Tween 80), Polyethylene Glycol 12 hydroxy stearic acid ester (solutol HS 15) and poly-second two One or more of in alcohol 1000 vitamin e succinate (TPGS).Wherein, used herein to emulsifying agent be commercial Product.

Inventor it was unexpectedly observed that mentioned emulsifier and being used in combination of phospholipid obtain extraordinary emulsifying effectiveness, and Mentioned emulsifier has the effect of suppression P-glycoprotein mostly, it is possible to promote the enterocyte absorption to submicron emulsion.

In above or other embodiments, described antifreezing agent can be selected from glucose, xylose, fructose, sucrose, Fructus Hordei Germinatus Sugar, lactose, galactose, trehalose, mannitol, xylitol, maltol, propylene glycol, glycerol, PEG200, PEG300, PEG400, One or more of in PEG600, PEG1000, PEG2000, PEG4000 and PEG6000.

Inventor is it was unexpectedly observed that remain to the state before recovering freeze thawing, grain after adding the submicron emulsion experience freeze thawing of antifreezing agent Footpath change is less than 5%.

In above or other embodiments, described can be with water as purified water.

In above or other embodiments, described correctives can be selected from one or more in sweeting agent and essence Kind；Preferably, described sweeting agent one in sucrose, glucose, stevioside, saccharin sodium, aspartame and xylitol or More kinds of；Described essence is selected from blue berry flavor, Fructus Citri sinensis taste, lemon, honey peach taste, cherry-flavored, strawberry flavor, Fructus Ananadis comosi taste, litchi flavor, awns Fruity, Fructus Melo taste, mixing berry taste, milk, coffee and the essence of cocoa flavored.Therefore, client can according to the hobby of oneself voluntarily Select to like the submicron emulsion of taste.Preferably, described sweeting agent presses described vitamin K₂The weight hundred of the gross weight meter of submicron emulsion Mark can be 0.02%～3%, more preferably 0.025%～0.5%.Preferably, described vitamin K pressed by described essence₂Sub-micro The percetage by weight of the gross weight meter of breast can be 0.05%～1%, more preferably 0.1～0.5%.

In above or other embodiments, described stabilizer can be in antioxidant and metal ion chelation agent One or more of, it is preferable that described stabilizer can be the compositions of antioxidant and metal ion chelation agent.

In above or other embodiments, described antioxidant can selected from tocopherol and ester thereof, vitamin C and Salt, sodium L-ascorbate-2-phosphate, butylated hydroxyarisol, two fourth cresols, propylgallate, histidine, half Guang ammonia One or more of in acid, sulphite, pyrosulfite and bisulfites；Described metal ion chelation agent is selected from second two One or both in amine tetraacethyl disodium and calcio-disodium edetate.

Wherein, the ester of tocopherol refers to the corresponding esters can being commercially available on commonly used in the art and market, such as Tocopherol acetas, tocopheryl nicotinate, tocopherol succinate etc..

Further, ascorbic salt refers to the corresponding salt can being commercially available on commonly used in the art and market, such as calcium Salt, sodium salt etc..

It will be appreciated by those skilled in the art that owing in industrialized production, parameters can not carry out complete precision Control, thus allow that each constituent content lower limit thereon in prescription occurs ± 10% in the range of fluctuate, such as oil in prescription Content be 1%～10%, in actual production, oil content is that 0.9%～11% (w/v) is all it is believed that be capable of the present invention Purpose, be also considered as in the protection domain of present patent application.

On the other hand, the application provides a kind of for preparing vitamin K as above₂The method of submicron emulsion, including such as Lower step:

Weigh the vitamin K of formula ratio₂, oil, phospholipid and emulsifying agent composition oil phase；

The antifreezing agent weighing formula ratio is dissolved in appropriate water composition aqueous phase；Wherein, if there is stabilizer, if stable Agent is fat-soluble, is added in oil phase by the stabilizer of formula ratio, if stabilizer is water miscible, is then added by stabilizer In aqueous phase；

If there is sweeting agent, the sweeting agent of formula ratio is added in aqueous phase；

By oil phase and aqueous phase evacuation respectively, being filled with protective gas, the number of times being preferably filled with protective gas is 3 times；Add Deep fat phase and aqueous phase, so that the material in biphase is all completely dissolved, are preferably heated to 60～65 DEG C, the most under agitation by water It is slowly added into mutually in oil phase, continues stirring, it is preferred to continue stir 10～40 minutes, become uniform Lac Bovis seu Bubali shape, prepare colostrum；

Described colostrum is carried out homogenizing, to obtain the Emulsion of the sub-micro rank that particle diameter is 80～200nm, if there is perfume (or spice) Essence, adds after being diluted with remaining water by the essence of formula ratio, if there is no essence, is directly added into remaining water, to described The gross weight of Emulsion reaches 100%, stirs, and crosses microporous filter membrane, preferably crosses 0.45 μm microporous filter membrane, prepares breast eventually；

By breast subpackage eventually, it is filled with sterilizing after protective gas.

In above or other embodiments, microjet instrument, high pressure dispersing emulsification machine, colloid mill, ball mill and ultrasonic can be used One or more of equipment in ripple biomixer carry out homogenizing to described colostrum.

It will be appreciated by those skilled in the art that homogenizing can use known in the art and conventional operation to enter OK, high pressure dispersing emulsification machine, first step regulation pressure is such as used to regulate to 1000～1400 bars to 400～600 bars, second step；Make Using microjet instrument, first step regulation homogenization pressure is to 4000～8000psi, and second step regulates to 10000～16000psi again；Make With ball mill, 200～400rpm work 10min, suspend 2～5min, circulate 3～6 times；Or use ultrasonic cell-break machine, 200W × 2min, 400W × 6min.

In above or other embodiments, described protective gas can be selected from nitrogen, argon or helium.Further, protection The amount of gas is advisable with full container remaining space.

Wherein, the vitamin K that above-mentioned technique prepares is used₂Oral submicron emulsion, outward appearance is creamy white, and has light blue breast Light, without oil droplet, has no layering；Mean diameter is 90～130nm, and is evenly distributed；At the circulation steam sterilization standing 100 DEG C After the freeze-thaw cycle of 30min and 3-25～40 DEG C, outward appearance and particle diameter do not occur significance to change.

Therefore, the vitamin K of the application₂Submicron emulsion has good sterilization stability and freeze-thaw stability, and easily by oxygen The medicine changed is protected, and the expection effect duration of room temperature storage is even up to by more than 2 years.

The vitamin K of the application₂Submicron emulsion can directly be taken, it is possible to adds and makes to the beverage such as milk, Yoghourt With.

Additionally, inventor is at the vitamin K to the application₂Submicron emulsion carries out finding during the pharmacokinetic studies in rat body, By measuring blood drug level and calculating relevant parameter, compared with commercially available soft capsule (i.e. oil solution), the vitamin K of the application₂Sub- The relative bioavailability of microemulsion is up to 256.27%.

Further, compared with prior art, compared to soft capsule and tablet, the vitamin K of the application of listing₂Submicron emulsion is just Patient medication in dysphagia, it is possible to increase patient medication compliance, and the bioavailability of medicine can be significantly improved；This The vitamin K of application₂Submicron emulsion is resistant to freeze thawing, reduces transport and the condition requirement of storage；Suitably preparation condition Vitamin K is improve with formula combination₂Stability so that effect duration meets regulation.

Additionally, the vitamin K of the application₂Submicron emulsion significantly improves vitamin K₂Curative effect and stability, for extensive patients Provide safer, effective, stable preparation, and simple process is ripe, it is simple to industrialized production.

Accompanying drawing explanation

Fig. 1 is the structural representation of vitamin K, and wherein A is vitamin K₁；B is vitamin K₂, wherein n is 7.

Fig. 2 is the vitamin K of the application₂The outside drawing of submicron emulsion 26.

Fig. 3 is the vitamin K of the application₂The particle size distribution figure of submicron emulsion 26.

Fig. 4 is respectively by the vitamin K of the application₂Submicron emulsion 26 and oil solution gavage give the Drug-time curve after rat.

Detailed description of the invention

Describe presently filed embodiment below by embodiment, it will be appreciated by the person skilled in the art that these The enforcement technical scheme that specific embodiment only indicates that to reach the purpose of the application and selects, is not to technical scheme Limit.According to teachings of the present application, it is obvious in conjunction with prior art to the improvement of technical scheme, belongs to the application The scope of protection.

In the examples below, used raw material be city available from product.

Embodiment 1 vitamin K₂Submicron emulsion 1 and 2 (without antifreezing agent and stabilizer)

Vitamin K₂The composition of submicron emulsion 1 and 2 is as shown in table 1.

Table 1

Preparation method:

Weigh the vitamin K of formula ratio₂, MCT (MCT Oil), SPC (soybean lecithin), RH₄₀(polyoxy Ethylene hydrogenation Oleum Ricini) or F68 (Pluronic F68) composition oil phase；

The sucrose pipetting formula ratio adds in appropriate purified water as aqueous phase；Biphase evacuation, inflated with nitrogen respectively, repeatedly 3 times, it is heated to 60 DEG C by biphase, after biphase middle material is completely dissolved, under conditions of magnetic agitation, aqueous phase is slowly added to In oil phase, continue stirring 20min, become uniform Lac Bovis seu Bubali shape, prepare colostrum；With microjet instrument 14000psi homogenizing 4 times, with To the Emulsion of the sub-micro rank that particle diameter is 80～200nm, add the mixing slurry fruity flavor of formula ratio, be supplemented to by purified water 100%, stir, cross the microporous filter membrane of 0.45 μm, prepare breast eventually；

Being sub-packed in brown cillin bottle by breast at end, inflated with nitrogen, jump a queue, aluminium lid seals, sterilizing under 100 DEG C of flowing steams 30min, cold water spray makes preparation be rapidly decreased to room temperature, obtains vitamin K₂Submicron emulsion 1 or 2.

Wherein, Menaquinone K6 is purchased from Shuan Jun bio tech ltd, Guangdong, and MCT has purchased from north Asia, Tieling medicinal oil Limit company, SPC is purchased from Man bio tech ltd, Jiangsu, and RH40 is purchased from the upper sea-freight grand chemical industry limited public affairs of pharmaceutical adjunct technology Department, F68 is purchased from Pumex chemical industry, and sucrose is purchased from Zhengzhou Ming Xin chemical products company limited, and mixing slurry fruity flavor is purchased from Shanghai gram Lun Na essence and flavoring agent company limited.

Embodiment 2 vitamin K₂Submicron emulsion 3 and 4 (containing antifreezing agent but without stabilizer)

Vitamin K₂The composition of submicron emulsion 3 and 4 is as shown in table 2.

Table 2

Preparation method:

Weigh the vitamin K of formula ratio₂、MCT、SPC、RH₄₀Or F68 forms oil phase；

Pipette the glycerol of formula ratio, sucrose adds in appropriate purified water as aqueous phase；Biphase evacuation, nitrogen charging respectively Gas, 3 times repeatedly, and it is heated to 60 DEG C.After biphase middle material is completely dissolved, under conditions of magnetic agitation, aqueous phase is slow Join in oil phase, continue stirring 20min, become uniform Lac Bovis seu Bubali shape, prepare colostrum；With microjet instrument 14000psi homogenizing 4 times After, to obtain the Emulsion of the sub-micro rank that particle diameter is 80～200nm, add the mixing slurry fruity flavor of formula ratio, use purified water It is supplemented to 100%, stirs, cross the microporous filter membrane of 0.45 μm, prepare breast eventually；

Being sub-packed in brown cillin bottle by breast at end, inflated with nitrogen, jump a queue, aluminium lid seals, sterilizing under 100 DEG C of flowing steams 30min, cold water spray makes preparation be rapidly decreased to room temperature, obtains vitamin K₂Submicron emulsion.

Wherein, vitamin K₂、MCT、SPC、RH₄₀, F68, sucrose, mixing slurry fruity flavor same as in Example 1, and glycerol Purchased from Suichang Glycerin Plant, Zhejiang Prov..

Embodiment 3-dimensional raw element K₂The sterilization stability of submicron emulsion 1-4 is investigated and freeze-thaw stability is investigated

Under 100 DEG C of flowing steams of DIYU as described in embodiment 1 or 2, sterilizing 30min and cold water spray make preparation be rapidly decreased to Room temperature is to test the sterilization stability of submicron emulsion, vitamin K₂Change of size before and after the sterilizing of submicron emulsion 1-4 is as shown in table 3:

Table 3

Wherein, M.D. represents that mean diameter, P.I. represent particle size distribution.

As can be seen from Table 3, vitamin K₂Particle diameter before and after submicron emulsion 1-4 sterilizing is held essentially constant, and its sterilizing is described Have good stability.

Take the vitamin K prepared₂The some bottles of submicron emulsion 1-4, freezing 48h under the conditions of-20 DEG C, then 40 DEG C of acceleration Under the conditions of place 48h as a circulation, altogether circulation 3 times, often complete one circulation survey primary particle size, result is as shown in table 4.

Table 4

Freezing-thawing test result shows, is not added with the vitamin K of antifreezing agent₂Just divide after a submicron emulsion 1-2 freeze-thaw cycle of experience Layer, and added the vitamin K of antifreezing agent₂Submicron emulsion 3-4 can withstand freezing-thawing test, experiences particle diameter after 3 freeze-thaw cycle Change, less than 5%, illustrates vitamin K₂The freeze-thaw stability of submicron emulsion 3-4 is good.

Additionally, except by vitamin K₂Emulsifying agent in submicron emulsion 3 changes the poloxamer 237 of 0.1% respectively into (Pluronic F-87), Pluronic/Lutrol F 108 (Pluronic F-108), poloxamer188 (Pluronic F-127), polyoxy In ethylene 35 Oleum Ricini (Cremophor EL) and Cremophor RH60 (Cremophor RH 60) each and The polysorbate 20 (Tween 20) of 1.2%, polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), poly-Pyrusussuriensis Ester 80 ((Tween 80), Polyethylene Glycol 12 hydroxy stearic acid ester (solutol HS 15) and polyethylene glycol 1000 vitamin E amber Beyond each in amber acid esters (TPGS), according to the vitamin K in embodiment 2₂The formula of submicron emulsion 3 and preparation method prepare Corresponding vitamin K₂Submicron emulsion, carries out test as implied above, obtain basically identical result of the test, i.e. sterilization stability and Freeze-thaw stability is good.

Except by vitamin K₂Antifreezing agent in submicron emulsion 3 changes the Fructus Vitis viniferae with 0.5% or the percetage by weight of 2% into Sugar, xylose, fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylitol, maltol, propylene glycol, One or more in PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000 and PEG6000 In addition, according to the vitamin K in embodiment 2₂The formula of submicron emulsion 3 and preparation method prepare corresponding vitamin K₂Submicron emulsion, enters The test that row is as implied above, obtains basically identical result of the test, i.e. sterilization stability and freeze-thaw stability good.

Embodiment 4 vitamin K₂Submicron emulsion 5-7 (containing single fat soluble antioxidants)

Vitamin K₂The composition of submicron emulsion 5-7 is as shown in table 5.

Table 5

Preparation method:

Weigh the vitamin K of formula ratio₂、MCT、SPC、RH₄₀, vitamin E or sodium L-ascorbate-2-phosphate or gallic acid third Ester composition oil phase；

Weigh the glycerol of formula ratio, sucrose adds appropriate purified water composition aqueous phase；

Biphase evacuation, inflated with nitrogen respectively, 3 times repeatedly, and it is heated to 60 DEG C.After biphase middle material is completely dissolved, Under conditions of magnetic agitation, aqueous phase is slowly added in oil phase, continues stirring 20min, become uniform Lac Bovis seu Bubali shape, at the beginning of preparing Breast；After microjet instrument 14000psi homogenizing 4 times, to obtain the Emulsion of the sub-micro rank that particle diameter is 80～200nm, add formula The mixing slurry fruity flavor of amount, is supplemented to 100% by purified water, stirs, cross the microporous filter membrane of 0.45 μm, prepare breast eventually；

Wherein, vitamin K₂、MCT、SPC、RH₄₀, F68, sucrose, mixing slurry fruity flavor, glycerol same as in Example 2, And vitamin E is purchased from the traditional Chinese medicines group limited public affairs of chemical reagent purchased from BASF vitamin company limited, sodium L-ascorbate-2-phosphate Department, and propylgallate is purchased from Hunan Er Kang pharmaceutcal corporation, Ltd.

Embodiment 5 vitamin K₂Submicron emulsion 8-10 (containing single water soluble antioxidants)

Vitamin K₂The composition of submicron emulsion 8-10 is as shown in table 6.

Table 6

Preparation method:

Weigh the vitamin K of formula ratio₂、MCT、SPC、RH₄₀Composition oil phase；

Weigh the glycerol of formula ratio, sucrose, sodium pyrosulfite or histidine or vitamin C adds appropriate purified water composition water Phase；

Wherein, vitamin K₂、MCT、SPC、RH₄₀, sucrose, mixing slurry fruity flavor, glycerol same as in Example 2 and burnt Sodium sulfite is purchased from Hunan Er Kang pharmaceutcal corporation, Ltd, histidine and vitamin C purchased from Chemical Reagent Co., Ltd., Sinopharm Group.

Embodiment 6 vitamin K₂Submicron emulsion 11-12 (adds single metal ion chelation agent)

Vitamin K₂The composition of submicron emulsion 11-12 is as shown in table 7.

Table 7

Preparation method:

Weigh the glycerol of formula ratio, sucrose, CaNa₂EDTA or Na₂EDTA adds appropriate purified water composition aqueous phase；

Wherein, vitamin K₂、MCT、SPC、RH₄₀, sucrose, mixing slurry fruity flavor, glycerol same as in Example 2, and CaNa₂EDTA and Na₂EDTA is purchased from Cologne, Sichuan pharmaceutcal corporation, Ltd.

Embodiment 7 vitamin K₂Submicron emulsion 13-17 (interpolation combination of stabilizers)

Vitamin K₂The composition of submicron emulsion 13-17 is as shown in table 8.

Table 8

Preparation method:

Weigh the vitamin K of formula ratio₂、MCT、SPC、RH₄₀And vitamin E or sodium L-ascorbate-2-phosphate (if present) Composition oil phase；

Weigh the glycerol of formula ratio, sucrose, CaNa₂EDTA and sodium pyrosulfite or cysteine or vitamin C are (if deposited ) add appropriate purified water composition aqueous phase；

Wherein, the material used in the present embodiment is identical with the source of the same substance in embodiment 5-8.

Embodiment 8 vitamin K₂The sterilization stability of submicron emulsion 5-17 is investigated and freeze-thaw stability is investigated

Investigate vitamin K as described in Example 3₂Change of size before and after the sterilizing of submicron emulsion 5-17, result such as table 9 institute Show.

Table 9

Investigate vitamin K as described in Example 4₂The freeze-thaw stability of submicron emulsion 5-17, result is as shown in table 10.

Table 10

Result shows, vitamin K₂Sterilization stability and the freeze-thaw stability of submicron emulsion 5-17 are good.

Embodiment 9 classical isothermal method prediction vitamin K₂The effect duration of submicron emulsion 3-17

By the vitamin K after subpackage₂Submicron emulsion 3-17 is respectively placed in the constant temperature oven of 70,80,90,100 DEG C, according to setting Sample under fixed time point, measure drug level at each temperature over time, try to achieve the drug degradation order of reaction and Reaction rate constant K under each test temperature, then according to Arrhenius equation, maps to 1/T with lgK, and medicine is tried to achieve in extrapolation Speed constant K298 at room temperature, thus calculates at room temperature medicament contg and is reduced to the time needed for qualified (90%) limit, I.e. room temperature storage effect duration, it was predicted that the results are shown in Table 11:

Table 11

As shown in Table 11, use single antioxidant or metal ion chelation agent can improve the chemical stability of medicine, And can be by 1.5-3 times of the extension of validity of submicron emulsion to blank group (not adding the experimental group of any antioxidant)；It is used in combination Antioxidant and metal ion chelation agent are capable of more preferable antioxidant effect, and can by the extension of validity of submicron emulsion extremely More than 2 years, it is more than 20 times of blank group, such that it is able to realize the industrialization of this submicron emulsion.

Embodiment 10 vitamin K₂Submicron emulsion 18-23 (uses other oil solutions, phospholipid, additional emulsifiers)

Vitamin K₂The composition of submicron emulsion 18-23 is as shown in table 12.

Table 12

Preparation method:

Weigh the vitamin K of formula ratio₂, MCT/ soybean oil/Semen Maydis oil (if present), SPC/HSPC/DSPC is (if deposited ), RH₄₀/ F68/TPGS (if present), vitamin E composition oil phase；

Weigh the glycerol of formula ratio, sucrose, CaNa₂EDTA adds appropriate purified water composition aqueous phase；

Wherein, Menaquinone K6, MCT, SPC, RH40, F68, sucrose, mixing slurry fruity flavor, glycerol, vitamin E, CaNa2EDTA is identical with the source of the same substance of embodiment above, and soybean oil, Semen Maydis oil are purchased from benefit sea (Taizhou) grain and oil Industrial Co., Ltd, HSPC, DSPC and TPGS are purchased from BASF Corp. of Germany.

Test vitamin K as described in Example 3₂Change of size before and after submicron emulsion 18-23 sterilizing, result such as table 13 institute Show.

Table 13

Test vitamin K as described in Example 4₂The freeze-thaw stability of submicron emulsion 18-23, result is as shown in table 14.

Table 14

Result shows, vitamin K₂Sterilization stability and the freeze-thaw stability of submicron emulsion 18-23 are good.

Test vitamin K as described in Example 9₂The prediction effect duration of submicron emulsion 18-23, result is as shown in Table 15.

Table 15

Additionally, inventor other it was found that, use MCT and the Semen sojae atricolor with 1% or 10% percetage by weight Mixture soybean oil and the mixture of MCT of 1:0.8 and 1:1.5 (the such as weight ratio be) of oil, or other oil are such as Oleum Camelliae, Fructus Canarii albi Oil, Oleum Cocois, fish oil, safflower oil, Oleum sesami etc. or a combination thereof are as vitamin K₂The oil phase of submicron emulsion 18, can get basic Consistent result of the test, i.e. sterilization stability, freeze-thaw stability are good, it was predicted that effect duration ＞ 2 years.

Use other phospholipid such as Ovum Gallus domesticus Flavus lecithin of the percetage by weight with 0.1%, 0.3%, 0.8% or 1.2% (EPC), DOPC (DOPC), DOPE (DOPE), dipalmitoyl phosphatidyl choline (DPPC), DPPE (DPPE), DSPE (DSPE), distearoylphosphatidyl are sweet Oil (DSPG), dimyristoyl phosphatidyl choline (DMPC), DMPEA (DMPE), two lauroyl phospholipid One in phatidylcholine (DLPC), two lauroyl PHOSPHATIDYL ETHANOLAMINE (DLPE) etc. or its any mixture are as vitamin K₂Sub- The phospholipid of microemulsion 18, available basically identical result of the test, i.e. sterilization stability, freeze-thaw stability are good, it was predicted that effect duration ＞ 2 years.

Use and there is other emulsifying agents of percetage by weight such as F68 F87 of 0.5%, 1%, 1.6% or 2.3%, general Lang Nike F108, pluronic F127, pluronic P124, PLURONICS F87 (Pluronic F-68), poloxamer 237 (Pluronic F-87), Pluronic/Lutrol F 108 (Pluronic F-108), poloxamer188 (Pluronic F-127), polyoxy Ethylene 35 Oleum Ricini (Cremophor EL), Cremophor RH60 (Cremophor RH 60), polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polyoxyethylene sorbitan monoleate ((Tween 80), poly- One or two kinds of in ethylene glycol 12 hydroxy stearic acid ester (solutol HS 15) replaces RH40 or TPGS as this vitamin K₂The emulsifying agent of submicron emulsion 18, it is possible to obtain basically identical result of the test, i.e. sterilization stability, freeze-thaw stability well, in advance Survey effect duration ＞ 2 years.

Embodiment 11 vitamin K₂Submicron emulsion 24-26 (other medicine carrying concentration)

Vitamin K₂The composition of submicron emulsion 24-26 is as shown in table 16.

Table 16

Preparation method:

Weigh the vitamin K of formula ratio₂、MCT、SPC、RH₄₀, vitamin E composition oil phase；

Wherein, vitamin K₂、MCT、SPC、RH₄₀, F68, sucrose, mixing slurry fruity flavor, glycerol, vitamin E, CaNa₂EDTA is identical with the source of the same substance of embodiment above.

Test vitamin K as described in Example 3₂Change of size before and after submicron emulsion 24-26 sterilizing, result such as table 17 institute Show.

Table 17

Test vitamin K as described in Example 4₂The freeze-thaw stability of submicron emulsion 24-26, result is as shown in table 18.

Table 18

Result shows, vitamin K₂Sterilization stability and the freeze-thaw stability of submicron emulsion 24-26 are good.

Test vitamin K as described in Example 9₂The prediction effect duration of submicron emulsion 24-26, result is as shown in table 19.

Table 19

From result, different medicine carrying concentration on the physical stability of submicron emulsion without impact, in the concentration that research relates to In the range of, the chemical stability of the biggest submicron emulsion of drug level is the best, it was predicted that effect duration the longest.

Embodiment 12 vitamin K₂The stability study (accelerated test) of submicron emulsion 13-16

According to " chemicals stability study technological guidance's principle ", accelerated test is carried out under the conditions of extraordinary, mesh Be to investigate stability of drug products by accelerating the Chemical Physics pace of change of medicine in commercially available back, to medicine in transport, protect Can be potentially encountered during depositing of short duration extraordinary under the conditions of stability be simulated investigating, and preliminary forecasting sample is in regulation Storage requirement under long-time stability.

Take vitamin K₂Submicron emulsion 13-16 sample, is placed in the growth cabinet of 40 DEG C ± 2 DEG C, respectively at 0,3,6,9, 12,18,24 samplings at the end of month, detect outward appearance, content and particle diameter.Result is as shown in table 20.

Table 20

Result shows, vitamin K₂The extended storage stability of submicron emulsion 13-16 is good.

Embodiment 12 vitamin K₂The pharmacokinetic studies of submicron emulsion 26

Submicron emulsion: vitamin K produced above₂Submicron emulsion 26, wherein vitamin K₂The outward appearance of submicron emulsion 26 as in figure 2 it is shown, And particle size distribution figure is as shown in Figure 3.

Vitamin K₂The preparation of oral oil solution: weigh vitamin K₂5.0mg, adds soybean oil 5g, stirs molten under room temperature Solve.

Dosage regimen and sample collection method: 6 male Wistar rats are randomly divided into two groups, after fasting 12h, according to The dosage gastric infusion of 1mg/kg, A group gavage vitamin K₂Submicron emulsion 16, B group gavage vitamin K₂Oral oil solution.In After administration 0.083,0.25,0.5,0.75,1,1.5,2,4,8,12h eye socket take blood in anticoagulant heparin pipe, 4500rpm is centrifuged 10min separated plasma, gained plasma sample keeps in Dark Place stand-by in-20 DEG C of freezings.

Plasma sample processing method: rat plasma freezing kept in Dark Place takes out, room temperature is melted.Precision pipettes 100 μ L Blood plasma, in 1.5mL centrifuge tube, adds inner mark solution (TN, 10.0 μ g/mL) 50 μ L, methanol 100 μ L and normal hexane 600 μ L, whirlpool Being centrifuged 10min in 10000rpm after rotation 5min mixed extraction, pipette normal hexane layer 500 μ L, nitrogen volatilizes solvent.Residue is with 50 μ L flows phased soln, and vortex 1min mixes, and is centrifuged 10min in 10000rpm, takes 20 μ L sample introductions.Experiment omnidistance lucifuge operation.

Chromatographic condition: use Hypersil BDS C18 (200mm × 4.6mm, 5 μm, Dalian Yi Lite) chromatographic column, flowing Being methanol-isopropanol (80:20, v/v) mutually, column temperature is 35 DEG C, and flow velocity is 1.0mL/min, and detection wavelength is 249nm, sample size It is 20 μ L.

Record by test preparation mean blood plasma concentration as shown in Figure 4, from result, vitamin K₂The life of submicron emulsion 26 Thing availability is far superior to oral oil solution, and pharmacokinetic parameters is shown in Table 21:

Table 21 vitamin K₂Submicron emulsion 26 and vitamin K₂The pharmacokinetic parameters result (n=3) that oral oil solution absorbs

Pharmacokinetic studies result shows, vitamin K₂The bioavailability of submicron emulsion 26 is substantially better than oil solution, the most raw Thing availability is 256.27%.

The application includes but not limited to that above example, every any equivalent carried out under the principle of the application spirit are replaced Generation or local improvement, all will be regarded as within the protection domain of the application.

Claims

1. a vitamin K₂Submicron emulsion, including by described vitamin K₂The following percetage by weight of the gross weight meter of submicron emulsion Each component:

Vitamin K₂0.0005%～1%,

Oil 1.0%～10%

Phosphatidase 0 .1%～1.2%,

Emulsifying agent 0.5%～2.3%,

Antifreezing agent 0.5%～3.0%,

And water；

Wherein emulsifying agent is other emulsifying agents beyond phospholipid；

Preferably, by described vitamin K₂The gross weight meter of submicron emulsion, the percetage by weight of phospholipid is 0.3%～0.8%, emulsifying The percetage by weight of agent is 1.0%～1.6%, and the percetage by weight of antifreezing agent is 0.5%～2.0%.

2. vitamin K as claimed in claim 1₂Submicron emulsion, also includes by described vitamin K₂The weight of the gross weight meter of submicron emulsion Amount percent is the correctives of 0.02%～5.0%.

3. vitamin K as claimed in claim 1 or 2₂Submicron emulsion, also includes by described vitamin K₂The gross weight meter of submicron emulsion Percetage by weight be 0.001%～1%, the stabilizer of preferably 0.001%～0.015%.

4. vitamin K as claimed in claim 1₂Submicron emulsion, wherein, described vitamin K₂Selected from MK-4, MK-5, MK-6, MK- 7, one or more of in MK-8 and MK-9；

Described grease separation is from soybean oil, Semen Maydis oil, Oleum Camelliae, olive oil, Oleum Cocois, fish oil, safflower oil, Oleum sesami and medium chain triglyceride three One or more of in ester, it is preferable that described oil is the mixture of soybean oil and medium chain triglyceride, it is highly preferred that described Oil be weight ratio be soybean oil and the mixture of medium chain triglyceride of 1:0.8～1:1.5；

Described phospholipid is selected from soybean lecithin (SPC), Ovum Gallus domesticus Flavus lecithin (EPC), hydrogenated soya phosphatide (HSPC), dioleoyl phospholipid Phatidylcholine (DOPC), DOPE (DOPE), dipalmitoyl phosphatidyl choline (DPPC), two palmityl phosphatidyls Ethanolamine (DPPE), distearoyl phosphatidylcholine (DSPC), DSPE (DSPE), distearyl phospholipid Acyl glycerol (DSPG), dimyristoyl phosphatidyl choline (DMPC), DMPEA (DMPE), two lauroyl One or more of in phosphatidylcholine (DLPC) and two lauroyl PHOSPHATIDYL ETHANOLAMINE (DLPE)；

Described emulsifying agent is selected from F68 F87, pluronic F108, pluronic F127, pluronic P124, poloxamer 188, poloxamer 237, Pluronic/Lutrol F 108, poloxamer188, CREMOPHORE EL, polyoxyethylene 40 hydrogenated castor Oil, Cremophor RH60, polysorbate 20, polysorbate 40, polysorbate 60, polyoxyethylene sorbitan monoleate, Polyethylene Glycol One or more of in 12 hydroxy stearic acid esters and polyethylene glycol 1000 vitamin E succinic acid ester；

Described antifreezing agent is selected from glucose, xylose, fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylose Alcohol, maltol, propylene glycol, glycerol, PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000 and One or more of in PEG6000；And

Described water is purified water.

5. vitamin K as claimed in claim 2₂Submicron emulsion, wherein, described correctives one in sweeting agent and essence Or it is more kinds of；Preferably, described sweeting agent is in sucrose, glucose, stevioside, saccharin sodium, aspartame and xylitol One or more of；Described essence is selected from blue berry flavor, Fructus Citri sinensis taste, lemon, honey peach taste, cherry-flavored, strawberry flavor, Fructus Ananadis comosi taste, litchi Branch taste, Fructus Mangifera Indicae taste, Fructus Melo taste, mixing berry taste, milk, coffee and the essence of cocoa flavored.

Vitamin K the most according to claim 3₂Submicron emulsion, wherein, described stabilizer is selected from antioxidant and metal ion One or more of in chelating agen, it is preferable that described stabilizer is the compositions of antioxidant and metal ion chelation agent；

Preferably, described antioxidant is selected from tocopherol and ester, vitamin C and salt thereof, sodium L-ascorbate-2-phosphate, the tert-butyl group P-hydroxyanisole, two fourth cresols, propylgallate, histidine, cysteine, sulphite, pyrosulfite and Asia One or more of in disulfate；Described metal ion chelation agent is selected from disodiumedetate and ethylenediaminetetraacetic acid One or both in calcium sodium.

7. one kind is used for preparation vitamin K as according to any one of claim 1～6₂The method of submicron emulsion, including walking as follows Rapid:

The antifreezing agent weighing formula ratio is dissolved in appropriate water composition aqueous phase；

Wherein, if there is stabilizer, if stabilizer is fat-soluble, the stabilizer of formula ratio is added in oil phase, as Really stabilizer is water miscible, then added in aqueous phase by stabilizer；

By oil phase and aqueous phase evacuation respectively, being filled with protective gas, the number of times being preferably filled with protective gas is 3 times；Add deep fat Mutually with aqueous phase so that the material in biphase is all completely dissolved, it is preferably heated to 60～65 DEG C, the most under agitation aqueous phase is delayed Slowly join in oil phase, continue stirring, it is preferred to continue stir 10～40 minutes, become uniform Lac Bovis seu Bubali shape, prepare colostrum；

Described colostrum is carried out homogenizing, to obtain the Emulsion of the sub-micro rank that particle diameter is 80～200nm, if there is essence, will The essence of formula ratio adds after diluting with remaining water, if there is no essence, is directly added into remaining water, to described Emulsion Gross weight reaches 100%, stirs, and crosses microporous filter membrane, preferably crosses 0.45 μm microporous filter membrane, prepares breast eventually；

8. method as claimed in claim 7, wherein, with microjet instrument, high pressure dispersing emulsification machine, colloid mill, ball mill and ultrasound wave One or more of equipment in biomixer carry out homogenizing to described colostrum.

9. method as claimed in claim 7, wherein, described protective gas is selected from nitrogen, argon or helium.

10. the vitamin K as according to any one of claim 1-6₂Submicron emulsion or as according to any one of claim 7-9 Method prepare vitamin K₂Submicron emulsion is used for treating hemorrhage, preventing and treat osteoporosis, prevention in preparation Child's " growing pain ", prevention old people's angiosteosis, prevention cardiovascular and cerebrovascular disease, prevention arthrosis and arthritis or auxiliary are controlled Treat and the purposes in the medicine of prophylaxis of cancer.