CN105997869A - Vitamin K1 micelle injection and preparation method thereof - Google Patents
Vitamin K1 micelle injection and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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Abstract
The invention discloses a vitamin K1 micelle injection and a preparation method thereof, and belongs to the field of micelle injection and preparation thereof. The invention discloses a vitamin K1 micelle for the first time. The vitamin K1 micelle is prepared from vitamin K1, cholate, phospholipid, a pH regulator and water for injection. The preparation method of the vitamin K1 micelle injection comprises the steps that an organic solvent freezing and drying method is adopted, a mixed micelle composed of phospholipid and cholate is adopted as a carrier, and the vitamin K1 is entrapped in hydrophobic nuclei of the mixed micelle. Due to the fact that the vitamin K1 is not dissolved into water, the solubility of the vitamin K1 in water is remarkably improved through the cholate/phospholipid mixed micelle preparation technology, polysorbate-80 and propylene glycol are not added into the vitamin K1 micelle injection, only phospholipid and cholate named as physiological excipient are adopted as auxiliary materials, and compared with vitamin K1 injections on sale currently, the preparation can reduce adverse drug effect and improve the clinic application safety.
Description
Technical field
The present invention relates to the preparation method of described vitamin K1 micelle injection, belong to micelle ejection preparation and preparation field thereof.
Background technology
Vitamin K1 is the liquid of a kind of yellow extremely orange-yellow clear viscous, and odorless or almost odorless are met light and easily decomposed；Index of refraction: 1.525～1.528；In chloroform, ether or vegetable oil readily soluble, the most molten, insoluble in water；Its chemical name is: the mixture of the trans and cis-isomer of 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecene base)-1,4-naphthalenedione；Its molecular formula: C31H46O2；Molecular weight: 450.71, structural formula is:
Vitamin K is clot-promoting factor active medicine, and its effect mainly participates in liver synthesis prothrombin, VII, IX, X.Under having vitamin K to participate in, the γ-hydroxylating of the glutaminic acid residue of above-mentioned thrombin can be made, and activate as energy and Ca2+In conjunction with the thrombin with blood coagulation activity, thus play hemostasis effect.Vitamin K is one group of menadione derivant, wherein vitamin K1It it is the natural type vitamin K class medicine obtained from plant Herba Medicaginis.Vitamin K deficiency can cause these thrombin dyssynthesis or exceptions, clinical visible bleeding tendency and prolonged prothrombin.Vitamin K1For fat-soluble, rely on bile after being administered orally and absorb, food 6～onset in 12 hours；Injecting onset in 1～2 hour, within 3～6 hours, haemostatic effect is obvious, and after 12～14 hours, prothrombin time recovers normal.It, at intrahepatic metabolism, is discharged through kidney and bile.
The shortage of vitamin K1 can cause blood not solidify, and mostly is neonate because vitamin K1 lacks hemorrhage patient in clinic.Neonate 1～2 day diet of birth is limited, the intake of vitamin K is few, in breast milk, vitamin content is low, in addition aseptic in intestinal, affects the synthesis of vitamin K, cause vitamin K deficiency, liver is not mature enough, and liver synthesis prothrombin, the process of VII, IX, X are obstructed, cruor time extending, causing hemorrhage, this disease is hemorrhagic disease of the newborn.The generation of hemorrhagic disease of the newborn (HDN) and avitaminous relation is just described as far back as nineteen fifty-two Dam etc..Three kinds can be divided into: Early onset hemorrhage, typical case hemorrhage, delayed according to disease time.Be deficient in vitamin in body when neonate is just born K1, Pure breast feeding time longer neonate can lack to serious vitamin K1 in fast development: children's can occur typical after birth for first week or occur delayed hemorrhage in 2 months, and both of these case morbidity is anxious, easily cause intracranial hemorrhage to damage, disability rate height, mortality rate are the highest.The sickness rate of China is up to 0.5～2%, and the sickness rate of Area in Yantai Region is up to 9.03%, and China is the hotspot of Vitamin K Deficiency Bleeding disease.Medical research shows, neonate birth gives vitamin K1 can prevent vitamin K1 shortage property hemorrhage.The route of administration of vitamin K1 also affects drug effect.Oral vitamin K1 is only capable of preventing typical case's hemorrhage, invalid to delayed hemorrhage, Longhan find vitamin K1 with sustainable more than 2 months of 2mg intramuscular injection drug effect, oral relatively poor.2000, Hengxian County of China is conventional in promoting neonate birth 24h applied vitamin K1 intramuscular injection once, and result of study shows: baby's vitamin K deficiency number of hospitalized significantly reduces, and vitamin K deficiency patient declines.It addition, because human liver can synthesize thrombinogen, hepatic disfunction person or surgery large operation person, be both needed to give a certain amount of vitamin K1 and can prevent hemorrhage.
Vitamin K 1 injection is one of clinical commonly used drug, on May 31,1 day to 2011 January in 2004, national drug adverse reaction monitoring center case report data base there is vitamin K 1 injection serious adverse reaction/event to report 893 examples, wherein anaphylactic shock 328 example (accounting for 36.7%), severe allergic reaction is the untoward reaction that vitamin K1 highlights the most, and December in 2011 State Food and Drug Administration on the 26th issues bulletin and reminds the severe allergic reaction paying close attention to vitamin K 1 injection.
There is serious untoward reaction in the vitamin K 1 injection used clinically at present, its untoward reaction may be relevant containing cosolvent tween 80, propylene glycol etc. with injection to have researcher to think.Therefore, it is necessary to while a kind of novel form of exploitation makes vitamin K1 dissolubility increase, the generation of its untoward reaction is reduced or avoided.Cholate/lecithin mixed micelle (BS/PC MMS) is the colloid solution system being abroad widely used in insoluble drug solubilising, is successfully used for, the solubilising of the medicine such as paclitaxel, diazepam, lorazepam.Great many of experiments confirms that cholate/lecithin mixed micelle system is possible not only to significantly improve the dissolubility of insoluble drug, additionally it is possible to improve curative effect of medication, is a kind of biocompatibility solvent, is referred to as " physiology excipient ".
Although existing cholate/lecithin mixed micelle system wide variety of technology enlightenment in prior art, but being applied in combination and unexpectedly of the material of different activities and different cholate/lecithin.Owing to character such as stability, onset time, circulation time, bioavailability and the toxic and side effects etc. in vivo of cholate/lecithin mixed micelle system form the most closely related with it, and the composition of cholate/lecithin mixed micelle system is the most closely related with pharmaceutical properties to be encapsulated, therefore, the cholate/lecithin mixed micelle system selecting which type of composition to form the vitamin K1 with better quality is problem urgently to be resolved hurrily.
In order to form the cholate/lecithin mixed micelle system of colory vitamin K1, it is important that find can the most compatible with vitamin K1 thus it is well encapsulated and improve its bioavailability cholate/lecithin, in order to form the cholate/lecithin mixed micelle system of colory vitamin K1.
It is an object of the invention to overcome the slightly solubility of vitamin K1, the shortcomings such as oral administration biaavailability is low, and intravenously administrable side effect is big, preparation one can be greatly improved its bioavailability and low cost, preparation technology is simple, is suitable to industrialized production, safely and effectively vitamin K1 micelle injection.
Summary of the invention
The technical problem to be solved is to provide the preparation method of a kind of vitamin K1 micelle injection.
For solving above-mentioned technical problem, the technical solution used in the present invention is:
First the present invention discloses a kind of vitamin K1 micelle injection, including following component: vitamin K1, cholate, phospholipid, pH adjusting agent and water for injection.
The weight percentage of each component is: vitamin K1 0.5～5%, cholate 2～15%, phosphatidase 3～20%, pH adjusting agent trace, surplus is water for injection.
Preferably, the weight percentage of each component is: vitamin K1 0.9%, cholate 5.1%, phosphatidase 6 .6%, pH adjusting agent trace, and surplus is water for injection.
Wherein, described cholate be in NaGC, Bile Salts, Glycodeoxrycholic acid, Calculus Bovis NaTDC, glycochenodeoxycholate sodium, Calculus Bovis chenodeoxy cholic acid sodium any one or any two kinds according to arbitrary proportion composition mixture, preferably NaGC；Described phospholipid be soybean lecithin, Ovum Gallus domesticus Flavus lecithin any one or two kinds according to the mixture of arbitrary proportion composition, preferably soya lecithin.
The invention also discloses the preparation method of a kind of described vitamin K1 micelle injection, comprise the following steps:
(1) weigh each component according to described proportioning, vitamin K1, cholate, phospholipid are added in organic solvent, stirring, it is dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with pH adjusting agent regulation pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Wherein, step (1) described organic solvent selected from 2-methyl-2-propanol, 2-methyl-2-butanol, any one or two kinds according to arbitrary proportion or any one mixture with different proportion water composition；The mixture that most preferably 2-methyl-2-propanol and water form according to volume ratio 4:1；
Step (1) is counted according to g/ml, vitamin K1, cholate, the gross mass of phospholipid: solvent=1:10-30, preferably 1:20；
In step (3) pH adjusting agent selected from hydrochloric acid, acetic acid, citric acid any one or two kinds according to arbitrary proportion, preferably hydrochloric acid.
Vitamin K1 micelle injection particle diameter prepared by the present invention is 1-50nm, and envelop rate is 60%-96%.
Vitamin K1 micelle injection mean diameter, zeta current potential, envelop rate are played important influence by heretofore described cholate, phospholipid, pH adjusting agent, the variety classes of organic solvent and different amounts thereof.Wherein, vitamin K1 and NaGC, vitamin K1 micelle injection quality evaluation prepared by soybean lecithin, 2-methyl-2-propanol and water is preferable；Preferably, vitamin K1 0.9%, cholate 5.1%, phosphatidase 6 .6%, pH adjusting agent trace, surplus be the vitamin K1 micelle injection mean diameter obtained by water for injection be 5.4nm, envelop rate is 85.9%, and quality evaluation is best.Because the particle diameter of vitamin K1 micelle injection is the least, envelop rate is the highest, the targeting of its micelle injection prepared is the best；Unit dosage envelop rate is the biggest, and effect is the best.
Changing cholate, phospholipid, the kind of pH adjusting agent or consumption, or change organic solvent kind, the particle diameter of prepared vitamin K1 micelle injection increases, envelop rate significantly reduces.Such as, in the case of other conditions are all consistent, only change the kind of cholate, phospholipid is soybean lecithin, organic solvent is 2-methyl-2-propanol with water according to volume ratio 4:1, there is notable difference in the quality evaluation of obtained vitamin K1 micelle injection, mean diameter is 12.4nm, and envelop rate is 65.3%.
Technical solution of the present invention compared with prior art, has the advantages that
1. the vitamin K1 micelle injection using this method to prepare has higher envelop rate under conditions of ensureing vitamin K1 stability, can keep internal optimal drug level, and extend the pharmaceutically-active time；Decrease the medicine untoward reaction at Clinical practice simultaneously.
2. this preparation method has simple process, preparation cost is low, technique favorable reproducibility, sample requirement are few, and the prescription of experiment sieving and technique are also scalable to production application, thus the application to industrialization has directive significance.
Detailed description of the invention
Below in conjunction with specific embodiment further describe the present invention, advantages of the present invention and feature will be with describe and apparent.It should be understood that described embodiment is only exemplary, the scope of the present invention is not constituted any restriction.It will be understood by those skilled in the art that and the details of technical solution of the present invention and form can be modified or replace lower without departing from the spirit and scope of the present invention, but these amendments or replacement each fall within protection scope of the present invention.
Embodiment 1
Every bottle of 10mg Han vitamin K1, consisting of of 1000 bottles of vitamin K1 micelle injection:
Specific operation process is as follows:
(1) weigh each component according to described proportioning, vitamin K1, NaGC, soybean lecithin are added 2-methyl-2-propanol with water according in (volume ratio 4:1), stirs, be dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with salt acid for adjusting pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Detection: vitamin K1 micelle injection mean diameter is 5.4nm, and envelop rate is 85.9%.
Embodiment 2
Every bottle of 10mg Han vitamin K1, consisting of of 1000 bottles of vitamin K1 micelle injection:
Specific operation process is as follows:
(1) weigh each component according to described proportioning, vitamin K1, Bile Salts, soybean lecithin are added 2-methyl-2-propanol with water according in (volume ratio 4:1), stirs, be dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with salt acid for adjusting pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Detection: vitamin K1 micelle injection mean diameter is 12.4nm, and envelop rate is 65.3%.
Embodiment 3
Every bottle of 10mg Han vitamin K1, consisting of of 1000 bottles of vitamin K1 micelle injection:
Specific operation process is as follows:
(1) weigh each component according to described proportioning, vitamin K1, NaGC, soybean lecithin are added 2-methyl-2-propanol with water according in (volume ratio 3:1), stirs, be dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with salt acid for adjusting pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Detection: vitamin K1 micelle injection mean diameter is 8.5nm, and envelop rate is 78.3%.
Embodiment 4
Every bottle of 10mg Han vitamin K1, consisting of of 1000 bottles of vitamin K1 micelle injection:
Specific operation process is as follows:
(1) weigh each component according to described proportioning, vitamin K1, NaGC, soybean lecithin are added 2-methyl-2-propanol with water according in (volume ratio 4:1), stirs, be dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with salt acid for adjusting pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Detection: vitamin K1 micelle injection mean diameter is 10.3nm, and envelop rate is 63.8%.
Embodiment 5
Every bottle of 10mg Han vitamin K1, consisting of of 1000 bottles of vitamin K1 micelle injection:
Specific operation process is as follows:
(1) weigh each component according to described proportioning, vitamin K1, NaGC, soybean lecithin are added 2-methyl-2-propanol with water according in (volume ratio 4:1), stirs, be dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with salt acid for adjusting pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Detection: vitamin K1 micelle injection mean diameter is 9.1nm, and envelop rate is 72.3%.
Embodiment 6
Every bottle of 10mg Han vitamin K1, consisting of of 1000 bottles of vitamin K1 micelle injection:
Specific operation process is as follows:
(1) weigh each component according to described proportioning, vitamin K1, NaGC, Ovum Gallus domesticus Flavus lecithin are added 2-methyl-2-propanol with water according in (volume ratio 4:1), stirs, be dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with salt acid for adjusting pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Detection: vitamin K1 micelle injection mean diameter is 8.9nm, and envelop rate is 76.2%.
Embodiment 7
Every bottle of 10mg Han vitamin K1, consisting of of 1000 bottles of vitamin K1 micelle injection:
Specific operation process is as follows:
(1) weigh each component according to described proportioning, vitamin K1, NaGC, soybean lecithin are added in 2-methyl-2-propanol, stirring, it is dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying.
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration with salt acid for adjusting pH value, obtain supernatant liquid.
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
Detection: NaGC dissolves slowly, and operating difficulties, vitamin K1 micelle injection mean diameter is 5.8nm, and envelop rate is 80.1%.
Claims (6)
1. a vitamin K1 micelle injection, it is characterised in that include following component: vitamin K1, cholate, phospholipid, pH adjusting agent and water for injection.
2. according to the vitamin K1 micelle injection described in claim 1, it is characterised in that the weight percentage of each component is: vitamin K1 0.5～5%, cholate 2～15%, phosphatidase 3～20%, pH adjusting agent trace, surplus is water for injection.
3., according to the vitamin K1 micelle injection described in claim 2, it is characterised in that the weight percentage of each component is: vitamin K1 0.9%, cholate 5.1%, phosphatidase 6 .6%, pH adjusting agent trace, surplus is water for injection.
4. according to the vitamin K1 micelle injection described in claims 1 to 3 any one; it is characterized in that: described cholate be in NaGC, Bile Salts, Glycodeoxrycholic acid, Calculus Bovis NaTDC, glycochenodeoxycholate sodium, Calculus Bovis chenodeoxy cholic acid sodium any one or any two kinds according to arbitrary proportion composition mixture, preferably NaGC；Described phospholipid be soybean lecithin, Ovum Gallus domesticus Flavus lecithin any one or two kinds according to the mixture of arbitrary proportion composition, preferably soya lecithin.
5. the preparation method of vitamin K1 micelle injection described in a Claims 1-4 any one, it is characterised in that comprise the following steps:
(1) weigh each component according to described proportioning, vitamin K1, cholate, phospholipid are added in organic solvent, stirring, it is dissolved to clarification；
(2) solution in step (1) is put in freeze dryer, it is cooled to-40 DEG C ± 2 DEG C, insulation 2h～4h, then it is evacuated to freeze drying box pressure and is less than 10Pa, then with ramp extremely-25 DEG C ± 2 DEG C sublimation dryings of 4 DEG C/h, be incubated 10h, it is warming up to 30 DEG C～35 DEG C, insulation 2h, lyophilization terminates, and obtains loose drying；
(3) powder is added recipe quantity purified water, be stirred at room temperature, to sample clear, be 5.5～6.5 with pH adjusting agent regulation pH value, add 0.05% activated carbon of (W/V), de-charcoal 30min, sucking filtration, obtain supernatant liquid；
(4) by supernatant liquid fill to ampoule bottle, sealing by fusing.To sterilizing cabinet, 121 DEG C, sterilizing 15min.
6. according to preparation method described in claim 5, it is characterised in that: step (1) described organic solvent selected from 2-methyl-2-propanol, 2-methyl-2-butanol any one or two kinds according to arbitrary proportion or any one mixture with different proportion water composition；The mixture that most preferably 2-methyl-2-propanol and water form according to volume ratio 4:1；
Wherein, step (1) is counted according to g/ml, vitamin K1, cholate, the gross mass of phospholipid: solvent=1:10-30, preferably 1:20；
In step (3) pH adjusting agent selected from hydrochloric acid, acetic acid, citric acid any one or two kinds according to arbitrary proportion, preferably hydrochloric acid.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107854431A (en) * | 2017-09-30 | 2018-03-30 | 四川大学 | It is a kind of targeted to hyaluronic acid nanometer micella of HSCs and its preparation method and application |
| CN108938607A (en) * | 2017-05-18 | 2018-12-07 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of vitamin K composition and preparation method thereof, preparation and purposes |
| CN110742863A (en) * | 2019-11-22 | 2020-02-04 | 青海民族大学 | Quercetin derivative nano micelle and preparation method thereof |
| CN110876719A (en) * | 2018-09-06 | 2020-03-13 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
| CN112870160A (en) * | 2021-02-01 | 2021-06-01 | 江苏华阳制药有限公司 | Novel fat-soluble vitamin mixed micelle injection and preparation method thereof |
| CN115554241A (en) * | 2022-09-14 | 2023-01-03 | 浙江诚意药业股份有限公司 | Micelle type vitamin K1 injection and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04244021A (en) * | 1990-08-17 | 1992-09-01 | F Hoffmann La Roche Ag | Use of mixed micell |
| CN1843327A (en) * | 2006-04-17 | 2006-10-11 | 重庆医药工业研究院有限责任公司 | Stable freeze-dried formulation containing multiple kinds of vitamin and its preparation method |
| CN103536623A (en) * | 2013-10-15 | 2014-01-29 | 海南卫康制药(潜山)有限公司 | Potassium magnesium aspartate composition freeze-dried powder for injection |
| CN104208077A (en) * | 2014-08-27 | 2014-12-17 | 王乐 | Lipid-soluble vitamin drug composition for injection and preparation method thereof |
| CN105287366A (en) * | 2014-06-18 | 2016-02-03 | 张蕊 | Vitamin K1 injection and preparation method thereof |
-
2016
- 2016-06-17 CN CN201610444660.8A patent/CN105997869A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04244021A (en) * | 1990-08-17 | 1992-09-01 | F Hoffmann La Roche Ag | Use of mixed micell |
| CN1843327A (en) * | 2006-04-17 | 2006-10-11 | 重庆医药工业研究院有限责任公司 | Stable freeze-dried formulation containing multiple kinds of vitamin and its preparation method |
| CN103536623A (en) * | 2013-10-15 | 2014-01-29 | 海南卫康制药(潜山)有限公司 | Potassium magnesium aspartate composition freeze-dried powder for injection |
| CN105287366A (en) * | 2014-06-18 | 2016-02-03 | 张蕊 | Vitamin K1 injection and preparation method thereof |
| CN104208077A (en) * | 2014-08-27 | 2014-12-17 | 王乐 | Lipid-soluble vitamin drug composition for injection and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| NAGATA M.,ET AL.: "Solubilization of Vitamin K1 by Bile Salts and Phosphatidylcholine-Bile Salts Mixed Micelles", 《JOURNAL OF PHARMACY & PHARMACOLOGY》 * |
| 王亚男 等: "维生素K1磷脂/胆盐混合胶束的制备及体外评价", 《科学技术与工程》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108938607A (en) * | 2017-05-18 | 2018-12-07 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of vitamin K composition and preparation method thereof, preparation and purposes |
| CN107854431A (en) * | 2017-09-30 | 2018-03-30 | 四川大学 | It is a kind of targeted to hyaluronic acid nanometer micella of HSCs and its preparation method and application |
| CN110876719A (en) * | 2018-09-06 | 2020-03-13 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
| CN110876719B (en) * | 2018-09-06 | 2022-08-09 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
| CN110742863A (en) * | 2019-11-22 | 2020-02-04 | 青海民族大学 | Quercetin derivative nano micelle and preparation method thereof |
| CN110742863B (en) * | 2019-11-22 | 2022-04-12 | 青海民族大学 | Quercetin derivative nano micelle and preparation method thereof |
| CN112870160A (en) * | 2021-02-01 | 2021-06-01 | 江苏华阳制药有限公司 | Novel fat-soluble vitamin mixed micelle injection and preparation method thereof |
| CN115554241A (en) * | 2022-09-14 | 2023-01-03 | 浙江诚意药业股份有限公司 | Micelle type vitamin K1 injection and preparation method and application thereof |
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