CN108938607A - A kind of vitamin K composition and preparation method thereof, preparation and purposes - Google Patents
A kind of vitamin K composition and preparation method thereof, preparation and purposes 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
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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Abstract
A kind of vitamin K composition and preparation method thereof, preparation and purposes, it is characterized in that, the vitamin K composition contains the solid adjuvant material other than carrier material and carrier material, and the carrier material is adsorbed with vitamin K, Cholic acids compound, phosphatide, cosurfactant and the oil being optionally present.The vitamin K composition in aqueous solution in the range of pH1.0-8.0 can self-emulsifying form stable nanoemulsions, can significantly increase the In Vitro Dissolution and vivo biodistribution availability of vitamin K；The vitamin K composition is in solid-state, and liquid preparation can be overcome in stability and defect in terms of taking；The vitamin K composition is suitable for biliary obstruction patient.
Description
Technical field
The present invention relates to a kind of vitamin K composition and preparation method thereof, preparation and purposes.
Background technique
Vitamin K is one group of liposoluble vitamin, mainly includes vitamin K1, farnoquinone, Vitamin K3 and vitamin
K4 etc., wherein vitamin K1 and farnoquinone are present in nature, and Vitamin K3 and Vitamin K4 are synthetic.Vitamin K exists
It is played an important role in a variety of important physiological functions of body.Vitamin K participates in liver synthesis as the coenzyme of carboxylase and coagulates
Blood factor II, VII, Ⅸ and Ⅹ is clinically usually used in bleeding caused by treating vitamin K deficiency or prothrombin deficiency and new
Raw youngster's bleeding etc., it can also be used to the rescue of anti-coagulants (such as anticoagulation class raticide) poisoning.Vitamin K also takes part in human body bone generation
It thanks, can be used for treating osteoporosis.Furthermore vitamin it is antitumor, analgesia, in terms of also have application.
But Agua-Mephyton 1 and K2 be it is fat-soluble, solubility is extremely low in water.Clinic should be injected at present with vitamin K
Based on liquid.However adverse reaction rate is higher in domestic vitamin K injection clinical application.Even if the plant first of FDA approval
The emulsion of naphthoquinones injectable is due to containing Emulsifier EL-60, and there is also the risks for leading to serious hypersensitivity.Vitamin K
Oral preparation is safer, and adverse reaction is less.But the fat-soluble dissolution for making drug of vitamin K becomes the rate-limiting step absorbed
Suddenly, cause usual vitamin K piece bioavilability low.And the absorption of vitamin K depends on normal pancreas and biliary tract function of patients,
Biliary obstruction person should not be administered orally.The vitamin K1 of U.S. FDA approval takes orally mixed micelleMM is low in stomach
Micella can be assembled under pH environment, influence absorption (the Van Hasselt PM.Vitamin K of vitamin K1
prophylaxis revisited:focus on risk factors.2009).There is also stabilizations for another aspect liquid preparation
The problems such as property and patient take convenience.
Summary of the invention
The present invention provides a kind of vitamin K composition, on the one hand aqueous solution of the vitamin K composition in different pH value
In can self-emulsifying form stable nanoemulsions, can significantly increase the In Vitro Dissolution and vivo biodistribution availability of vitamin K；
On the other hand the vitamin K composition uses liquid to consolidate compress technique makes it in solid-state with carrier material absorption liquid emulsion, can
To overcome liquid preparation in stability and defect in terms of taking；The vitamin K composition is hindered suitable for biliary tract
Fill in patient.
In order to achieve the goal above, the present invention the following technical schemes are provided:
The present invention provides a kind of vitamin K composition, which is characterized in that the vitamin K composition contains carrier material
With the solid adjuvant material other than carrier material, the carrier material is adsorbed with vitamin K, Cholic acids compound, phosphatide, helps surface living
Property agent and the oil being optionally present.
Preferably, above-mentioned vitamin K composition, it is characterised in that: the vitamin K is selected from vitamin K1 and Wei Sheng
Plain K2.
Preferably, the vitamin K is vitamin K1.
Preferably, above-mentioned vitamin K composition, it is characterised in that:
The Cholic acids compound is selected from cholic acid, deoxycholic acid, glycocholic acid, tauroursodeoxycholic acid, goose deoxidation gallbladder
One of acid, glycochenodeoxycholate, Irish moss (chondrux) or more than one mixture；
The phosphatide is selected from selected from soybean lecithin (SPC), hydrogenated soya phosphatide (HSPC), egg yolk lecithin
(EPC), glycerophosphatide, phosphatidyl choline, phosphatidyl-ethanolamine, serinephosphatide, lipositol, phosphatidic acid, dioleoyl phospholipid
Phatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoylphosphatidylethanolamine-polyethylene glycol (DOPE-mPEG),
Dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), the poly- second of dipalmitoylphosphatidylethanolamine-
Glycol (DPPE-mPEG), Distearoyl Phosphatidylcholine (DSPC), Distearoyl Phosphatidylethanolamine (DSPE), distearyl
Phosphatidyl-ethanolamine-polyethylene glycol (DSPE-mPEG), distearoylphosphatidylglycerol (DSPG), two myristoyl phosphatidyl gallbladders
Alkali (DMPC) dimyristoylphosphatidylethanolamine (DMPE), dimyristoylphosphatidylethanolamine-polyethylene glycol (DMPE-
MPEG), Dilauroyl Phosphatidylcholine (DLPC), two lauroyl phosphatidyl-ethanolamines (DLPE), two lauroyl phosphatidyl ethanols
One of amine-polyethylene glycol (DLPE-mPEG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or
More than one mixture；Preferably, the phosphatide is selected from soybean lecithin (SPC), egg yolk lecithin (EPC), two hard
One of acyl phosphatidyl-ethanolamine (DSPE), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG) are a kind of
Above mixture；
The cosurfactant is selected from polyethylene glycol, ethyl alcohol, propylene glycol, glycerine, lauryl sodium sulfate, gathers
Sorb ester 20, polyoxyethylene sorbitan monoleate, Sefsol 218, propylene glycol glyceryl monolaurate, diethylene glycol monoethyl ether and poly-
One of glyceryl oleate or more than one mixture；
The carrier material be selected from microcrystalline cellulose, lactose, starch, aluminum magnesium silicate, kaolin, mesoporous silicate,
One of silica, calcium phosphate dibasic anhydrous, calcium phosphate, magnesium carbonate, superfine silica gel powder or more than one mixture；
The solid adjuvant material is selected from microcrystalline cellulose, lactose, amylum pregelatinisatum, crospovidone, polyvinyl pyrrole
Alkanone, hydroxypropyl methylcellulose, polyethylene glycol, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, superfine silica gel powder,
One of magnesium stearate or more than one mixture；
The solid adjuvant material can also be for selected from cholic acid, deoxycholic acid, glycocholic acid, tauroursodeoxycholic acid, goose deoxidation gallbladder
One of acid, glycochenodeoxycholate, Irish moss (chondrux) and their sodium salt or more than one mixture；
The oil is in soybean oil, corn oil, olive oil, MCT Oil, ethyl oleate, oleic acid
One or more kinds of mixtures.
Preferably, above-mentioned vitamin K composition, which is characterized in that with the total weight of vitamin K composition:
The vitamin K mass percent range is 0.5%~8%, preferably 1.5%~4%；
The oil quality percentage range is 0%~10%, preferably 0%~3%；
The mass percent range of the Cholic acids compound of the carrier material absorption is 0.1%~5%, preferably 1%
~3%；
The phosphatide quality percentage range is 0.5%~10%, preferably 1.5%~5%；
The cosurfactant mass percent range is 0.5%~15%, preferably 2%~6%；
Carrier material mass percent (unadsorbed other materials) range be 8%~30%, preferably 13%~
20%；
The solid adjuvant material mass percent range is 50%~90%, preferably 60%~80%.
Preferably, above-mentioned vitamin K composition, it is characterised in that: the vitamin K composition contain carrier material and
Solid adjuvant material other than carrier material, the carrier material are adsorbed with vitamin K1, Cholic acids compound, phosphatide, help surface living
Property agent, with the total weight of vitamin K1, Cholic acids compound, phosphatide and cosurfactant, vitamin K1 mass percent
Range is 20%~25%, and the ratio range of the quality of the gross mass and cosurfactant of phosphatide and Cholic acids compound is
(1.6~2.5): 1, the phosphatide is selected from soybean lecithin (SPC), egg yolk lecithin (EPC), distearoylphosphatidyl ethyl alcohol
One of amine (DSPE) or distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG) or more than one mixture.
Preferably, above-mentioned vitamin K composition, which is characterized in that exist when by vitamin K composition described in 400mg
In 25ml water, under 37 DEG C of constant temperatures, 5min is stirred with the revolving speed of 50rpm, stands 30min, take supernatant liquid filtering laggard
When row emulsion droplet size measures, emulsion droplet average grain diameter < 100nm.
The present invention also provides the methods for preparing above-mentioned vitamin K composition, comprising the following steps: optionally to vitamin
Oil is added in K, phosphatide, cosurfactant, Cholic acids compound, carrier material is added, liquid is made and consolidates compressing powder, is added solid
The mixing of body auxiliary material, is made the vitamin K composition.
Preferably, above-mentioned method, which comprises the following steps:
A) vitamin K is directly used as oily phase, or is dissolved in vitamin K in oil；
B) phosphatide and cosurfactant is added, stirring is allowed to dissolve；
C) Cholic acids compound, stirring to uniform system is added；
D) carrier material is added into step (c) acquired solution, ground and mixed obtains liquid and consolidates compressing powder；
E) powder obtained by step (d) is mixed with solid adjuvant material, the vitamin K composition is made.
The present invention also provides a kind of pharmaceutical preparations, which is characterized in that the pharmaceutical preparation includes that above-mentioned vitamin K combines
Object and optional pharmaceutically acceptable carrier.
Preferably, the pharmaceutical preparation is tablet, hard capsule or dry suspensoid agent.
Preferably, capsule shells include above-mentioned vitamin K composition and optional pharmacy and can connect in the hard capsule
The carrier received.
The present invention also provides above-mentioned vitamin K compositions to lead in preparation treatment vitamin K deficiency or prothrombin deficiency
The bleeding of cause and hemorrhage of newborn, the rescue of poisoning by anticoagulant, treatment osteoporosis, antitumor, analgesia, in antibacterial drug
Purposes.
The present invention also provides above-mentioned pharmaceutical preparations to go out caused by preparation treatment vitamin K deficiency or prothrombin deficiency
Blood and hemorrhage of newborn, the rescue of poisoning by anticoagulant, treatment osteoporosis, antitumor, analgesia, the use in antibacterial drug
On the way.
Beneficial effects of the present invention:
Vitamin K composition of the invention in water can be from cream using phosphatide and Cholic acids compound as surfactant
Change and form the stable nanoemulsions that partial size is less than 100nm, can spontaneously form o/w micro emulsion or nano-emulsion in gastrointestinal tract, one
Aspect is distributed drug uniformly quickly in gastrointestinal tract by increasing specific surface area and drug solubility, improves permeability and absorption
Efficiency increases the solubility and dissolution rate of vitamin K, improves the bioavilability of vitamin K；On the other hand drug sheet can be reduced
Body or due to local drug concentration it is excessively high caused by gastrointestinal side effect.The vitamin K composition is in solid-state, and drug can be improved
Stability and the convenience taken, overcome the shortcomings of liquid preparation in stability and in terms of take.The dimension life
Plain K composition applies also for biliary obstruction patient.
With the total weight of vitamin K1, Cholic acids compound, phosphatide and cosurfactant, vitamin K1 quality percentage
It is 20%~25% than range, the ratio range of the quality of the gross mass and cosurfactant of phosphatide and Cholic acids compound is
(1.6~2.5): 1, the phosphatide is selected from soybean lecithin (SPC), egg yolk lecithin (EPC), distearoylphosphatidyl ethyl alcohol
One of amine (DSPE) or distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG) or more than one mixture
When, vitamin K composition nanoemulsions formed in the aqueous solution within the scope of pH value 1.0-8.0 all have preferably
Stability, and the dissolution in vitro of vitamin K and vivo biodistribution availability are higher.
The various terms and phrase that the present invention uses are with well known to a person skilled in the art general significances.The term referred to
With phrase if any meaning inconsistent with common art-recognized meanings, that the present invention of being subject to is stated.
As described in the present invention, term " oil " refer to can be used as it is that pharmaceutic adjuvant uses or pharmaceutically acceptable
Oil.Its example is as described above in the present invention.
As described in the present invention, term " carrier material " refer to it is in solid form, have high-specific surface area, pharmaceutically may be used
The auxiliary material of receiving.Its example is as described above in the present invention.
As described in the present invention, term " solid adjuvant material " refers in solid form, pharmaceutically acceptable auxiliary material.Including
Adhesive, disintegrating agent used in solid pharmaceutical preparation, retarding agent and glidant, such as, but not limited to microcrystalline cellulose, can press at lactose
Property starch, crospovidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyethylene glycol, sodium carboxymethyl starch, carboxymethyl it is fine
Tie up one of plain sodium, hydroxypropyl cellulose, superfine silica gel powder, magnesium stearate or more than one mixture.As described herein
, solid adjuvant material is further selected from cholic acid, deoxycholic acid, glycocholic acid, tauroursodeoxycholic acid, chenodesoxycholic acid, sweet ammonia goose deoxidation
Cholic acid and one of Irish moss (chondrux) and its sodium salt or more than one mixture
Detailed description of the invention
Fig. 1 is the self-emulsifying nanometer cream grain-size graph that vitamin K composition self-emulsifying rebuilds test result in test example 1,
Middle abscissa partial size, ordinate are relative intensity.
Fig. 2 is the self-emulsifying nanometer cream transmission electron microscope that vitamin K composition self-emulsifying rebuilds test result in test example 1
Figure.
Fig. 3 is Dissolution profiles of the vitamin K composition in 0.5%SDS solution in test example 3, in which: ■ is this hair
Bright vitamin K composition, ● it is vitamin K ordinary tablet；Ordinate is dissolution rate, and abscissa is the time.
Fig. 4 is Dissolution profiles of the vitamin K composition in pH1.0 hydrochloric acid solution in test example 3, in which: ■ is this
The vitamin K composition of invention, ● it is vitamin K ordinary tablet；Ordinate is dissolution rate, and abscissa is the time.
Fig. 5 is the Dissolution profiles of vitamin K composition in water in test example 3, in which: ■ is the embodiment of the present invention 1
Vitamin K composition, ● be the embodiment of the present invention 3 vitamin K composition, ▲ be the embodiment of the present invention 4 vitamin K group
Close object；Ordinate is dissolution rate, and abscissa is the time.
Fig. 6 is vitamin K1 blood plasma medicine after beasle dog oral vitamin K composition in test example 4 and commercially available vitamin K1 piece
Object concentration time curve.
Fig. 7 be test example 5 in bile duct ligation rat oral gavage vitamin K composition andVitamin K1 blood after MM
Starch pharmaceutical concentration-time curve.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Illustrate the present invention to understanding, the following example and being given for example only property of experimental example, and should not be taken as limiting the scope of the invention.It is real
Apply the person that is not specified actual conditions in example and test example, carry out according to conventional conditions or manufacturer's recommended conditions, agents useful for same or
Production firm person is not specified in instrument, and being can be with conventional products that are commercially available.
(1) preparation of vitamin K composition of the present invention
" solid adjuvant material " described in following embodiments is vitamin K in formula, phosphatide, Cholic acids compound, helps surface living
Auxiliary material other than property agent, carrier material.
Embodiment 1: the preparation of vitamin K composition
Preparation method: it by egg yolk lecithin, propylene glycol and vitamin K1 stirring and dissolving under the conditions of 50 DEG C of waters bath with thermostatic control, mixes
It closes uniform.Deoxycholic acid is added and continues stirring until being completely dissolved, forms homogeneous and transparent yellow solution.It is added dropwise to superfine silica gel powder
In, ground and mixed forms liquid and consolidates compressing powder.Solid adjuvant material mixing is added to get vitamin K composition.Gained vitamin K group
Close object can directly pressed powder or be sub-packed in hard capsule or direct packaging in packaging bag be in dry suspensoid agent drug system of the present invention
Agent.
Embodiment 2: the preparation of vitamin K composition
Preparation method: by DSPE-mPEG, egg yolk lecithin, diethylene glycol monoethyl ether under the conditions of 50 DEG C of waters bath with thermostatic control
With vitamin K1 stirring and dissolving, it is uniformly mixed.Glycocholic acid is added and continues stirring until being completely dissolved, forms homogeneous and transparent Huang
Color solution.It is added dropwise in anhydrous calcium phosphate, ground and mixed forms liquid and consolidates compressing powder.Solid adjuvant material mixing is added to get dimension life
Plain K composition.Gained vitamin K composition directly pressed powder or can be sub-packed in hard capsule or direct packaging in packaging bag
In the pharmaceutical preparation of the present invention of dry suspensoid agent.
Embodiment 3: the preparation of vitamin K composition
Preparation method: by soybean lecithin, diethylene glycol monoethyl ether and vitamin K1 under the conditions of 50 DEG C of waters bath with thermostatic control
Stirring and dissolving is uniformly mixed.Glycocholic acid is added and continues stirring until being completely dissolved, forms homogeneous and transparent yellow solution.Drop
It is added in anhydrous calcium phosphate, ground and mixed forms liquid and consolidates compressing powder.Solid adjuvant material mixing is added to get vitamin K composition.
Gained vitamin K composition directly pressed powder or can be sub-packed in hard capsule or direct packaging in packaging bag in dry suspensoid agent
Pharmaceutical preparation of the present invention.
Embodiment 4: the preparation of vitamin K composition
Preparation method: by DSPG, Sefsol 218 and vitamin K1 stirring and dissolving under the conditions of 50 DEG C of waters bath with thermostatic control,
It is uniformly mixed.Cholic acid is added and continues stirring until being completely dissolved, forms homogeneous and transparent yellow solution.It is added dropwise in lactose, grinds
Mill is mixed to form liquid and consolidates compressing powder.Solid adjuvant material mixing is added to get vitamin K composition.Gained vitamin K composition can
Direct pressed powder is sub-packed in hard capsule.
Embodiment 5: the preparation of vitamin K composition
Preparation method: by DSPE-mPEG, egg yolk lecithin, diethylene glycol monoethyl ether under the conditions of 50 DEG C of waters bath with thermostatic control
With vitamin K1 stirring and dissolving, it is uniformly mixed.Glycocholic acid is added and continues stirring until being completely dissolved, forms homogeneous and transparent Huang
Color solution.It is added dropwise in anhydrous calcium phosphate, ground and mixed forms liquid and consolidates compressing powder.Solid adjuvant material mixing is added to get dimension life
Plain K composition.Gained vitamin K composition directly pressed powder or can be sub-packed in hard capsule or direct packaging in packaging bag
In the pharmaceutical preparation of the present invention of dry suspensoid agent.
Embodiment 6: the preparation of vitamin K composition
Preparation method: farnoquinone, DSPE are added in MCT Oil under the conditions of 50 DEG C of waters bath with thermostatic control
Stirring and dissolving is uniformly mixed.Tauroursodeoxycholic acid is added and continues stirring until being completely dissolved, forms homogeneous and transparent solution.Drop
It is added in silica, ground and mixed forms liquid and consolidates compressing powder.Solid adjuvant material mixing is added to get vitamin K composition.Institute
Vitamin K composition directly pressed powder or can be sub-packed in hard capsule or direct packaging in packaging bag in dry suspensoid agent
Pharmaceutical preparation of the present invention.
Embodiment 7: the preparation of vitamin K composition
Preparation method: being added stirring and dissolving in oleic acid for farnoquinone, HSPC under the conditions of 50 DEG C of waters bath with thermostatic control, and mixing is equal
It is even.Glycochenodeoxycholate is added and continues stirring until being completely dissolved, forms homogeneous and transparent solution.It is added dropwise to aluminum magnesium silicate
In, ground and mixed forms liquid and consolidates compressing powder.Solid adjuvant material mixing is added to get vitamin K composition.Gained vitamin K group
Close object can directly pressed powder or be sub-packed in hard capsule or direct packaging in packaging bag be in dry suspensoid agent drug system of the present invention
Agent.
Embodiment 8-16
Vitamin K1
Phosphatide (egg yolk lecithin)
Cholic acids compound (glycocholic acid)
Cosurfactant (diethylene glycol monoethyl ether)
Preparation method: the gross mass for fixing vitamin K1, phosphatide, Cholic acids compound and cosurfactant is 40g, is pressed
The following table 1 vitamin K1 mass percent and phosphatide+Cholic acids compound/cosurfactant mass values calculate supplementary material and use
Amount.By phosphatide, cosurfactant and vitamin K1 stirring and dissolving under the conditions of 50 DEG C of waters bath with thermostatic control, it is uniformly mixed.Gallbladder is added
Acid compounds continue stirring until being completely dissolved.It is added dropwise in calcium phosphate dibasic anhydrous, ground and mixed forms liquid and consolidates compressing powder.
Solid adjuvant material mixing is added to get vitamin K composition.
Table 1
Comparative example 1:
Preparation method: directly by vitamin K1 with carrier material anhydrous calcium phosphate adsorb, then with solid adjuvant material mixed pressuring plate,
Vitamin K ordinary tablet is made.
(2) the effect test research of vitamin K composition of the present invention
Test example 1: vitamin K composition self-emulsifying rebuilds test
1, it test method: takes above-described embodiment 2 to prepare vitamin K composition 400mg, is placed in 25ml distilled water, in 37
Under DEG C constant temperature, 5min is stirred with the revolving speed of 50rpm, 30min is stood and takes filtrate in laser grain with 0.45 μm of membrane filtration
It spends instrument and measures partial size, transmission electron microscope observing is carried out with phosphotungstic acid negative staining.
Test result: the results are shown in attached figure 1 for particle size determination；Transmission electron microscope is shown in attached drawing 2.
Nano-emulsion can be formed with self-emulsifying after being disintegrated in water by the visible vitamin K composition of attached Fig. 1 and 2, emulsion droplet is average
Partial size is 47.74nm, is evenly distributed, and polydispersity coefficient (PDI) is 0.248.
2, the vitamin K composition 400mg for taking above-described embodiment 8-16 to prepare, is placed in 25ml distilled water, in 37 DEG C of perseverances
Under the conditions of temperature, 5min is stirred with the revolving speed of 50rpm, 30min is stood and takes filtrate in laser particle analyzer with 0.45 μm of membrane filtration
Partial size is measured, the results are shown in Table 2.
By 2 result of table as it can be seen that vitamin K composition can form nano-emulsion after being disintegrated in water with self-emulsifying.Embodiment 8
The nano-emulsion emulsion droplet size that vitamin K composition is formed is 50.16nm, the vitamin K composition shape of embodiment 9-11 and 13-16
At nano-emulsion emulsion droplet size it is larger.
Table 2
Test example 2: the stability test of vitamin K composition at low ph conditions
It is in cloudy state when being dispersed in water due to carrier material and solid adjuvant material, influences to observe, therefore, this test is not to
Vitamin K lotion when carrier material and solid adjuvant material is added carries out stability study.
Test method: 2 method of above-described embodiment is pressed, by DSPE-mPEG, yolk lecithin under the conditions of 50 DEG C of waters bath with thermostatic control
Rouge, diethylene glycol monoethyl ether and vitamin K1 stirring and dissolving are uniformly mixed.Glycocholic acid is added and continues stirring until completely molten
Solution, forms homogeneous and transparent yellow solution.Take appropriate (containing about vitamin K1 10mg), be respectively placed in 10ml distilled water,
In 0.1mol/L hydrochloric acid solution and pH6.8 phosphate buffer, gently shake.10min is stood, appearance character is observed and measures grain
Diameter.Separately takeAppropriate MM is diluted to respectively with distilled water, 0.1mol/L hydrochloric acid solution and pH6.8 phosphate buffer
Vitamin K1 1mg/ml stands 10min, observes appearance character and measures partial size.
Test result: appearance character and particle size determination the results are shown in Table 3.
By 3 result of table as it can be seen that vitamin K composition is in distilled water, 0.1mol/L hydrochloric acid solution and pH6.8 phosphate buffer
In to spontaneously form appearance character and partial size after nano-emulsion stable；And0.1mol/L hydrochloric acid solution of the MM in low pH
In due to assembling, cause micellar particle size to become larger, solution turbid.
Table 3: low pH stability test result
Test example 3: vitamin K composition dissolution determination test
1, vitamin K composition, direct pressed powder, specification 10mg test method: are prepared by above-described embodiment 2.Separately take
Vitamin K ordinary tablet prepared by comparative example 1.According to 2015 editions two Ⅹ C of annex of the Pharmacopoeia of the People's Republic of China, " dissolution rate is surveyed
Determine the second method of method " carry out dissolution determination, the 0.5%SDS solution or pH1.0 hydrochloric acid solution for using 500ml as dissolution medium, in
100rpm revolving speed measures at 37 DEG C.5min, 10min, 15min and 30min after starting measurement take liquid 5ml, are filtered with 0.45 μm
Film filtering, reject primary filtrate take subsequent filtrate to measure absorbance in 273nm on ultraviolet specrophotometer, calculate dissolution rate.
Test result: dissolution test result is shown in attached drawing 3 and attached drawing 4.
By attached drawing 3 as it can be seen that vitamin K composition of the invention dissolves out rapidly in 0.5%SDS solution, 5min dissolution rate
It can be dissolved out completely of about 90%, 10min or so.And only about 20%, 30min is dissolved out vitamin K ordinary tablet 5min dissolution rate
Degree is less than 40%.
By attached drawing 4 as it can be seen that vitamin K composition of the invention dissolves out rapidly in pH1.0 hydrochloric acid solution, 10min dissolution
Degree can dissolve out completely of about 80%, 15min or so.And vitamin K ordinary tablet is substantially insoluble in pH1.0 hydrochloric acid solution
Out, dissolution rate is lower than 10%.
2, vitamin K composition, direct powder pressure test method: are prepared by above-described embodiment 1, embodiment 3 and embodiment 4
Piece, specification 10mg.It is carried out according to 2015 editions two Ⅹ C of annex " the second method of dissolution method " of the Pharmacopoeia of the People's Republic of China
Dissolution determination uses the water of 500ml as dissolution medium, and 100rpm revolving speed measures at 37 DEG C.In start measurement after 5min,
10min, 15min and 30min take liquid 5ml, and with 0.45 μm of membrane filtration, reject primary filtrate takes subsequent filtrate in uv-spectrophotometric
273nm measures absorbance on meter, calculates dissolution rate.
Test result: dissolution test result is shown in attached drawing 5.
By attached drawing 5 as it can be seen that the vitamin K composition dissolution of embodiment 1, embodiment 3 and embodiment 4 is rapid, 5min dissolution
Degree can be dissolved out up to 85% or more, 10min or so completely.
3, test method: the direct pressed powder of vitamin K composition of Example 8-16 preparation separately takes comparative example 1 to make
Standby vitamin K ordinary tablet, according to 2015 editions two annex Ⅹ C " dissolution methods second of the Pharmacopoeia of the People's Republic of China
Method " carries out dissolution determination, uses 500ml water as dissolution medium, 100rpm revolving speed measures at 37 DEG C.After starting measurement
20min takes liquid 5ml, and with 0.45 μm of membrane filtration, reject primary filtrate takes subsequent filtrate to measure in 273nm on ultraviolet specrophotometer
Absorbance calculates dissolution rate.
Test result: dissolution test result is shown in Table 4.
As shown in Table 4, compared with the vitamin K ordinary tablet of comparative example 1, vitamin K composition of the invention is molten in water
Out-degree greatly improves, wherein dissolution rate is most fast in water for the vitamin K composition of embodiment 8, and 20min dissolution rate is reachable
93.13%,
Table 4
The above result shows that vitamin K composition of the invention is in water-bearing media due to that self-emulsifying formation can receive rapidly
Rice milk, therefore the solubility of vitamin K1 is increased, substantially increase the dissolution rate of vitamin K1.
Test example 4: vitamin K composition beasle dog medicine dynamic test
Test method: with above-described embodiment 2 prepare tablet (10mg) that the direct pressed powder of vitamin K composition obtains with
Commercially available vitamin K1 piece (times special, Chengdu Brilliant Pharmaceutical Co., Ltd.) (10mg) carries out beasle dog pharmacokinetic studies, dosage
10mg/ dog.Healthy beasle dog 6, half male and half female is random to be grouped, and is intersected using binary cycle and is administered, and cleans the phase 7 days.Prohibit before administration
Eat 12h, free water.Respectively at administration before and administration after 1,2,3,4,5,6,8,10,12, for 24 hours, use anticoagulant heparin Guan Yuhou
Limb saphena takes blood 3ml.3000rpm is centrifuged 10min separated plasma, using retinyl acetate as internal standard, HPLC-MS/MS measurement
Plasma vitamin K1 concentration.
Test result: vitamin K1 drug plasma is dense after beasle dog oral vitamin K composition and commercially available vitamin K1 piece
Degree-time graph is shown in attached drawing 6.
Peak drug levels are 65.31 ± 6.78ng/ after taking orally vitamin K composition of the present invention by the visible beasle dog of attached drawing 6
Ml, hence it is evident that higher than 38.22 ± 5.85ng/ml of marketed tablet group.After beasle dog takes orally vitamin K composition of the present invention
AUC0-24hFor 495.64ngml-1H is 1.81 times of marketed tablet group.
The above result shows that vitamin K composition of the invention improves the dissolution rate of vitamin K1, vitamin is promoted
K1 improves bioavilability in the intracorporal absorption of beasle dog.
Test example 5: the big raticide dynamic test of vitamin K composition bile duct ligation
Test method: Wistar rat, male, are randomly divided into 4 groups by 20.Wherein 2 groups of 10 progress bile duct ligation conducts
Bile duct ligation group；Another 10 are performed the operation with method but do not ligature bile duct as a control group.4 groups of rats are buried at away from 10~15mm of pylorus
Plant intubation.With above-described embodiment 5 prepare vitamin K composition powder suspension andMM, extremely through intravasal administration
Duodenum, dosage 1mg.1,2,3,4,5,6,8,10h before administration and after administration, take blood 0.5ml in eye socket.
3000rpm is centrifuged 10min separated plasma, and using retinyl acetate as internal standard, it is dense that HPLC-MS/MS measures plasma vitamin K1
Degree.
Test result: vitamin K1 drug plasma is dense after bile duct ligation rat oral gavage vitamin K composition and Konakion
Degree-time graph is shown in attached drawing 7.
By the visible control rats of attached drawing 7 after intubation gives vitamin K composition or Konakion to duodenum, about
2~3h reaches Cmax, CmaxRespectively 2249.36 and 2768.44ng/ml, AUC0-10hRespectively 10712.50 Hes
10855.99ng·ml-1·h.Vitamin K1 absorbs significant decrease, C after bile duct ligation group gives KonakionmaxOnly about
2.81ng/ml；And the vitamin K1 absorption for giving vitamin K composition group is substantially unaffected, CmaxAnd AUC0-10hRespectively
2044.85ng/ml and 10159.37ngml-1·h。
The above result shows that for bile duct ligation rat, vitamin K1 in vitamin K1 composition of the invention can be with
Successfully absorbed.
In conclusion the present invention provides a kind of new vitamin K composition in solid, compared with prior art, a side
Vitamin K composition described in face in the aqueous solution of different pH value all can self-emulsifying form stable nanoemulsions, can be significant
Increase vitamin K In Vitro Dissolution and vivo biodistribution availability；Another aspect vitamin K composition is in solid-state, can be overcome
Liquid preparation is in stability and defect in terms of taking；Simultaneously for biliary obstruction patient, dimension life of the present invention
Vitamin K in plain K composition can also be successfully absorbed.
It is described the prefered embodiments of the present invention in detail above in conjunction with attached drawing, still, the present invention is not limited to above-mentioned realities
The detail in mode is applied, within the scope of the technical concept of the present invention, a variety of letters can be carried out to technical solution of the present invention
Monotropic type, this simple variant all belong to the scope of protection of the present invention.
Claims (10)
1. a kind of vitamin K composition, which is characterized in that the vitamin K composition contain carrier material and carrier material with
Outer solid adjuvant material, the carrier material are adsorbed with vitamin K, Cholic acids compound, phosphatide, cosurfactant, Yi Jiren
The existing oil of choosing.
2. vitamin K composition according to claim 1, it is characterised in that: the vitamin K be selected from vitamin K1 and
Farnoquinone；Preferably, the vitamin K is vitamin K1.
3. vitamin K composition according to claim 1 or 2, it is characterised in that:
The Cholic acids compound is selected from cholic acid, deoxycholic acid, glycocholic acid, tauroursodeoxycholic acid, chenodesoxycholic acid, sweet
One of ammonia chenodesoxycholic acid, Irish moss (chondrux) or more than one mixture；
The phosphatide is selected from selected from soybean lecithin, hydrogenated soya phosphatide, egg yolk lecithin, glycerophosphatide, phosphatidyl gallbladder
Alkali, phosphatidyl-ethanolamine, serinephosphatide, lipositol, phosphatidic acid, Dioleoyl Phosphatidylcholine, dioleoyl phospholipid acyl ethyl alcohol
Amine, dioleoylphosphatidylethanolamine-polyethylene glycol, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, two palms
Acyl phosphatidyl-ethanolamine-polyethylene glycol, Distearoyl Phosphatidylcholine, Distearoyl Phosphatidylethanolamine, distearyl phosphatide
Acyl ethanol amine-polyethylene glycol, distearoylphosphatidylglycerol, dimyristoyl phosphatidyl choline, two myristoyl phosphatidyl second
Hydramine, dimyristoylphosphatidylethanolamine-polyethylene glycol, Dilauroyl Phosphatidylcholine, two lauroyl phosphatidyl-ethanolamines,
Two lauroyl phosphatidyl-ethanolamines-one of polyethylene glycol and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine or
More than one mixture；Preferably, the phosphatide is selected from soybean lecithin, egg yolk lecithin, distearoylphosphatidyl
One of ethanol amine, distearoylphosphatidylethanolamine-polyethylene glycol or more than one mixture；
The cosurfactant is selected from polyethylene glycol, ethyl alcohol, propylene glycol, glycerine, lauryl sodium sulfate, poly- sorb
Ester 20, polyoxyethylene sorbitan monoleate, Sefsol 218, propylene glycol glyceryl monolaurate, diethylene glycol monoethyl ether and polyglycereol
One of oleate or more than one mixture；
The carrier material is selected from microcrystalline cellulose, lactose, starch, aluminum magnesium silicate, kaolin, mesoporous silicate, dioxy
One of SiClx, calcium phosphate dibasic anhydrous, calcium phosphate, magnesium carbonate, superfine silica gel powder or more than one mixture；
The solid adjuvant material be selected from microcrystalline cellulose, lactose, amylum pregelatinisatum, crospovidone, polyvinylpyrrolidone,
Hydroxypropyl methylcellulose, polyethylene glycol, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, superfine silica gel powder, tristearin
One of sour magnesium or more than one mixture；
The solid adjuvant material can also be for selected from cholic acid, deoxycholic acid, glycocholic acid, tauroursodeoxycholic acid, chenodesoxycholic acid, sweet
One of ammonia chenodesoxycholic acid, Irish moss (chondrux) and their sodium salt or more than one mixture；
The oil is one in soybean oil, corn oil, olive oil, MCT Oil, ethyl oleate, oleic acid
Kind or more than one mixture.
4. vitamin K composition according to any one of claim 1-3, which is characterized in that with vitamin K composition
Total weight:
The vitamin K mass percent range is 0.5%~8%, preferably 1.5%~4%；
The oil quality percentage range is 0%~10%, preferably 0%~3%；
The mass percent range of the Cholic acids compound of carrier material absorption is 0.1%~5%, preferably 1%~
3%；
The phosphatide quality percentage range is 0.5%~10%, preferably 1.5%~5%；
The cosurfactant mass percent range is 0.5%~15%, preferably 2%~6%；
The carrier material mass percent range is 8%~30%, preferably 13%~20%；
The solid adjuvant material mass percent range is 50%~90%, preferably 60%~80%.
5. vitamin K composition described in any one of -4 according to claim 1, it is characterised in that: the vitamin K composition
Containing the solid adjuvant material other than carrier material and carrier material, the carrier material be adsorbed with vitamin K1, Cholic acids compound,
Phosphatide, cosurfactant, with the total weight of vitamin K1, Cholic acids compound, phosphatide and cosurfactant, vitamin
K1 mass percent range is 20%~25%, the quality of the gross mass and cosurfactant of phosphatide and Cholic acids compound
Ratio range is (1.6~2.5): 1, the phosphatide is selected from soybean lecithin, egg yolk lecithin, distearoylphosphatidyl ethyl alcohol
One of amine or distearoylphosphatidylethanolamine-polyethylene glycol or more than one mixture.
6. vitamin K composition according to any one of claims 1-5, which is characterized in that given birth to when will be tieed up described in 400mg
Plain K composition is in 25ml water, under 37 DEG C of constant temperatures, stirs 5min with the revolving speed of 50rpm, stands 30min, take upper liquid
When carrying out emulsion droplet size measurement after body filtering, emulsion droplet average grain diameter < 100nm.
7. the method for preparing vitamin K composition of any of claims 1-6, comprising the following steps: optionally to
Oil is added in vitamin K, phosphatide, cosurfactant, Cholic acids compound, carrier material is added, liquid is made and consolidates compressing powder,
Solid adjuvant material mixing is added, the vitamin K composition is made.
8. the method according to the description of claim 7 is characterized in that the following steps are included:
A) vitamin K is directly used as oily phase, or is dissolved in vitamin K in oil；
B) phosphatide and cosurfactant is added, stirring is allowed to dissolve；
C) Cholic acids compound, stirring to uniform system is added；
D) carrier material is added into step (c) acquired solution, ground and mixed obtains liquid and consolidates compressing powder；
E) powder obtained by step (d) is mixed with solid adjuvant material, the vitamin K composition is made.
9. a kind of pharmaceutical preparation, which is characterized in that the pharmaceutical preparation includes vitamin of any of claims 1-6
K composition and optional pharmaceutically acceptable carrier；Optionally, the pharmaceutical preparation is tablet, hard capsule or dry-mixed outstanding
Agent；Optionally, in the hard capsule capsule shells include vitamin K composition of any of claims 1-6 and
Optional pharmaceutically acceptable carrier.
10. prepared by vitamin K composition of any of claims 1-6 or pharmaceutical preparation as claimed in claim 9
Treat bleeding caused by vitamin K deficiency or prothrombin deficiency and hemorrhage of newborn, the rescue of poisoning by anticoagulant, treatment bone
Matter is loose, antitumor, analgesia, the purposes in antibacterial drug.
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| CN110448534A (en) * | 2019-07-29 | 2019-11-15 | 兰州大学 | A kind of free anthraquinones extracted from rheum self-emulsifying microemulsion piece and preparation method thereof |
| CN111007170A (en) * | 2019-12-13 | 2020-04-14 | 中国农业科学院农产品加工研究所 | Biomarker for intervention treatment of osteoporosis by bone peptide, screening method and application |
| WO2020186392A1 (en) * | 2019-03-15 | 2020-09-24 | 大连大学 | Application of glycocholic acid in preparation of antitumor drugs |
| CN112807277A (en) * | 2019-10-29 | 2021-05-18 | 湖北真奥医药研究院有限公司 | Fat-soluble vitamin self-emulsifying composition and preparation method of preparation thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020186392A1 (en) * | 2019-03-15 | 2020-09-24 | 大连大学 | Application of glycocholic acid in preparation of antitumor drugs |
| CN110448534A (en) * | 2019-07-29 | 2019-11-15 | 兰州大学 | A kind of free anthraquinones extracted from rheum self-emulsifying microemulsion piece and preparation method thereof |
| CN112807277A (en) * | 2019-10-29 | 2021-05-18 | 湖北真奥医药研究院有限公司 | Fat-soluble vitamin self-emulsifying composition and preparation method of preparation thereof |
| CN111007170A (en) * | 2019-12-13 | 2020-04-14 | 中国农业科学院农产品加工研究所 | Biomarker for intervention treatment of osteoporosis by bone peptide, screening method and application |
| CN111007170B (en) * | 2019-12-13 | 2021-06-29 | 中国农业科学院农产品加工研究所 | Biomarker for intervention treatment of osteoporosis by bone peptide, screening method and application |
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Application publication date: 20181207 |