CN110339169A - Coat nano vesicle preparations and its application of vitamin D and vitamin K - Google Patents
Coat nano vesicle preparations and its application of vitamin D and vitamin K Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
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Abstract
The present invention provides a kind of nano vesicle preparations and its application for coating vitamin D and vitamin K, in terms of mass fraction, including 1~3 part of vitamin D, 3~7 parts of vitamin K, 30~100 parts of vesica auxiliary material.The nano vesicle preparations preparation process: vesica auxiliary material, vitamin D and vitamin K are dissolved in after solvent through being uniformly dispersed to obtain vesicle solution.Vitamin D and vitamin K cladding are prepared nano vesicle preparations, it can be achieved that vitamin D and vitamin K are delivered directly in blood by using vesica technique for packing by the present invention, can at least improve tens times of drug effects compared to conventional oral formulation.New method is provided for osteoarthritis research, provides a kind of innovative means to treat, preventing osteoarthritis.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of nano vesicle for coating vitamin D and vitamin K
Preparation and its application；More particularly, to the nano vesicle preparations and the nano vesicle preparations system of cladding vitamin D and vitamin K
It is ready for use on the purposes of the drug for the treatment of osteoarthritis.
Background technique
Osteoarthritis is most commonly seen arthritis, is most commonly in knee joint.It can lead to pain and deformity, seriously affect
The ability to work and quality of life of people.Estimate according to the World Health Organization, the symptomatic bone of 60 years old or more crowd closes in global range
The scorching illness rate male of section is 9.6%, and women 18%.For the whole world in 2010 there are about 2.51 hundred million people of Patients with Knee Osteoarthritis, Zhan is total
The 3.6% of population.Due to the increase of average human life and increasing for obese people, the disease incidence of osteoarthritis will be further
Increase.Osteoarthritis financial burden is huge, and expense accounts for about the developed countries such as the U.S., Britain, France, Canada, Australia
The 1-2.5% of gross national product.However there has been no the treatment methods and drug that can improve osteoarthritic condition at present.
Vitamin D and vitamin K can significantly play osteoarthritis protective effect when being used in combination.It is well known that vitamin D
Absorption with calcium has close relationship.The most important effect of vitamin D is to maintain the dynamic equilibrium of calcium in blood.Vitamin D
It can be complexed with calcium ion after being converted into activated vitamin D in vivo, to increase the absorption of calcium, improve the concentration of calcium in blood.
And vitamin K can then activate a kind of vitamin K dependent protein for being known as osteocalcin.Osteocalcin can combine calcium into bone matrix
In, while preventing doped calcium in arterial blood tube wall.The synergistic effect of vitamin D and K are exactly that vitamin D can promote in alimentary canal
Calcium uptake enters blood circulation, and calcium then can be oriented effectively and import and be fixed in bone rather than precipitate by vitamin K
In on vascular wall.
Vitamin D and vitamin K can significantly play osteoarthritis protective effect when being used in combination.It is well known that vitamin D
Absorption with calcium has close relationship.The most important effect of vitamin D is to maintain the dynamic equilibrium of calcium in blood.Vitamin D
It can be complexed with calcium ion after being converted into activated vitamin D in vivo, to increase the absorption of calcium, improve the concentration of calcium in blood.
And vitamin K can then activate a kind of vitamin K dependent protein for being known as osteocalcin.Osteocalcin can combine calcium into bone matrix
In, while preventing doped calcium in arterial blood tube wall.The synergistic effect of vitamin D and K are exactly that vitamin D can promote in alimentary canal
Calcium uptake enters blood circulation, and calcium then can be oriented effectively and import and be fixed in bone rather than precipitate by vitamin K
In on vascular wall.
The compound preparation of vitamin D and vitamin K is mainly formed into conventional capsule and tablet, however due to vitamin D and
Vitamin K be it is fat-soluble, be difficult to enter blood circulation, therefore bioavilability is lower.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provide it is a kind of cladding vitamin D and vitamin K nano vesicle preparations and
It is applied, and vitamin D and vitamin K cladding are prepared nano vesicle preparations, it can be achieved that will dimension by using vesica technique for packing
Raw element D and vitamin K are delivered directly in blood, can at least improve tens times of drug effects compared to conventional oral formulation.
To solve the above problems, on the one hand, the invention reside in provide a kind of nanocapsule for coating vitamin D and vitamin K
Brewed dose, in terms of mass fraction, including 1~3 part of vitamin D, 3~7 parts of vitamin K, 30~100 parts of vesica auxiliary material.
Further, the vitamin D includes vitamin D2And vitamin D3.Preferred vitamin D3。
Further, the vitamin K can be vitamin K1And vitamin K2In menaquinone-4, menaquinone-7, first naphthalene
Quinone -8, menadione -9 and menadione -10, preferably menaquinone-7.
It is further preferred that the combination of vitamin D and vitamin K may is that vitamin D in the nano vesicle preparations3
It is by 2 parts of vitamin D with menaquinone-7 composition3Menaquinone-7 with 5 parts forms；Vitamin D2It is combined with menaquinone-7
Object is by 3 parts of vitamin D3Menaquinone-7 with 5 parts forms；Vitamin D3It is by 1 part with menaquinone-4 composition
Vitamin D3Menaquinone-4 with 4 parts forms.
Further, the vesica auxiliary material includes lecithin lipoid plastid, and the lecithin lipoid plastid is from plant or moves
It is extracted in object.
It is further preferred that the plant is mainly soybean, cottonseed, peanut and sunflower etc.；The animal is primarily referred to as
Yolk and various brain tissues etc..Preferably lecithin lipoid plastid is extracted from soybean and egg yolk lecithin.
It is further preferred that the main component of the lecithin lipoid plastid includes phosphatide acetylcholine (PC), phosphatidyl
Ethanol amine (PE) and phosphatidylinositols (PI), wherein the percentage composition of PC is 40~95%.Preferably, the percentage composition of PC is
80%, further preferably 90%.Preferred PC is amphipathic compound, and solubility in organic solvent is very high, but in water
In solubility it is very low.PC is easy water suction and deliquesces, but can under the action of in the presence of a large amount of water in high-speed stirred or ultrasonic wave
Enough it is dispersed in water to form Bilayer vesicle.
On the other hand, the present invention provides a kind of preparation method of nano vesicle preparations for coating vitamin D and vitamin K,
Detailed process is as follows: vesica auxiliary material, vitamin D and vitamin K are dissolved in after solvent through being uniformly dispersed to obtain vesicle solution；
Wherein, the solvent include non-aqueous solvent and polarity can aqueous solvent,
1) solvent is removed when the solvent is water-insoluble solvent, after dissolution and obtains organic matter dry film, adds water solution
It is dispersed and uniformly obtains vesicle solution；
2) when the solvent be polarity can hydrotropic solvent when, aqueous solution is added after dissolution and is dispersed uniformly that obtain vesica molten
Liquid.
Further, the aqueous solution is ion buffer, such as NaAc_HAc buffer solution, phosphoric acid-sodium phosphate delay
Rush solution etc..Preferably, after the ion buffer is added, the pH of reaction system is controlled between 5~8.Preferably, it is being added
When aqueous solution, by the way of being slowly added dropwise, the speed stirred during being added dropwise is 800~1500rpm, is continued after being added dropwise to complete
Stir 30~60min.Ion buffer is added, can inhibit the hydrolysis of lecithin lipoid plastid, also can control and maintain vesica ring
The pH value in border.
Further, in 1), before being uniformly dispersed, being passed through high pure nitrogen is in reaction system in nitrogen atmosphere.
Further, in 2), before aqueous solution is added, being passed through high pure nitrogen is in reaction system in nitrogen atmosphere.
Further, the time of the processing that is uniformly dispersed is 5~30min.
Further, the solvent includes organic solvent, such as alcohols, ethers, alkanes, esters and halogenated alkanes are molten
Agent；The non-aqueous solvent includes ethers, alkanes, esters or halogenated alkanes solvent；The polarity can hydrotropic solvent include alcohol
Class, ethers or water.Alcohols can be methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol and the butyl alcohol-tert of short chain；Ether
Class can be water-soluble and water-insoluble, such as ether, propyl ether, tetrahydrofuran and dioxane；Alkanes can be hexane,
Hexamethylene, heptane and octane etc.；Esters can be methyl formate, Ethyl formate, propyl formate, methyl acetate, ethyl acetate, second
Propyl propionate, butyl acetate and tebutate etc..The presence of solvent can quickly dissolve vitamin D and vitamin K, also for
It can sufficiently be mixed with lecithin lipoid plastid.
Further, described be uniformly dispersed can be used but not limited to following equipment: high speed agitator, ultrasonic wave dispersion
Device, vesica extruder or high pressure homogenisers.Using these equipment, can quickly there be effective realize to be uniformly dispersed.
Further, the vesicle solution obtains solid powder through spraying or freeze-drying again.
Further, the process of the freeze-drying is as follows: after the vesicle solution is heated removal solvent, water supplement
After solution to original volume, freeze-drying obtains solid powder.
Further, antioxidant can be added in the vesicle solution.The antioxidant includes but is not limited to dimension life
Plain E, vitamin C, vitamin E sodium salt, vitamin C sodium salt, vitamin E sylvite, vitamin C sylvite, curcumin etc..The antioxygen
Agent dosage can be 1%~20% of the quality of PC in lecithin lipoid plastid, preferably 5~15%.Antioxidant is deposited
The storage stability of vesicle solution can be improved, reducing oxygen or the influence of other free radicals.
On the other hand, the present invention provides a kind of pharmaceutical composition comprising vesicle formation preparation and medicine prepared by the present invention
Acceptable carrier on.
On the other hand, the present invention provide it is a kind of cladding vitamin D and vitamin K vesicle formation preparation treatment, protection
Or the purposes in the drug of prevention osteoarthritis.
Compared with prior art, the invention has the following beneficial effects:
Raw material lecithin lipoid plastid used in vesicle solution prepared by the present invention can be from pure natural product
It extracts, mass production, and cheap；The lecithin lipoid plastid such as lecithin of parents' molecule is dispersed in water can
To be self-assembled into Bilayer vesicle, the cell membrane of structure and human body cell is quite similar, and granular size can be from tens nanometers
To several hundred nanometers.Vitamin D and vitamin K are dispersed in vesicle solution, then substantially existed with molecular forms, it can be achieved that capsule
The effect being delivered directly in blood is steeped, and then greatly improves drug effect.
By the way that vitamin D and vitamin K to be coated on inside phospholipid capsule bubble, greatly the clinical of enhancement Antiarthritic is treated
Effect；In addition, the almost non-toxic side effect of raw material used in this vesicle formation, can provide new side for the treatment of anti-osteoarthritis
To.New method is provided for osteoarthritis research, provides a kind of innovative means to treat, preventing osteoarthritis.
Preparation method of the invention is simple, efficient, can be suitble to industrialized production.
Detailed description of the invention
Fig. 1 is each group mouse knee joint OARSI scoring figure.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated, and however, it is not limited to this.
In following embodiment unless otherwise specified, derived from using raw material commercially available, used method is this field
Conventional practices well known to technical staff.
Embodiment:
Embodiment 1
In 250 milliliters of flasks, by lecithin lipoid plastid (containing 1 gram of PC), 7.5 milligrams of vitamin Ks and 3 milligrams of vitamins
D is dissolved in 5 milliliters of chloroforms, and rotary evaporation removes solvent, and 99 milliliters of Acetic acid-sodium acetate buffer of pH=6 are added, and leads to high pure nitrogen
It is that 300W ultrasonic emulsification instrument is ultrasonically treated 10 minutes that 20 minutes, which are 20KHz power with frequency, obtains lurid stable capsule
Steep liquid.
Embodiment 2
In 250 milliliters of flasks, by lecithin lipoid plastid (containing 1 gram of PC), 50 milligrams of vitamin Es, 7.5 milligrams of vitamins
K and 3 milligram of vitamin D is dissolved in 5 milliliters of chloroforms, and rotary evaporation removes solvent, and the Acetic acid-sodium acetate buffer 99 of pH=6 is added
Milliliter leads to high pure nitrogen 20 minutes, is that 20KHz power is 300W ultrasonic emulsification instrument ultrasonic treatment 10 minutes with frequency, obtains
Lurid stable vesica liquid.
Embodiment 3
In 250 milliliters of flasks, by lecithin lipoid plastid (containing 1 gram of PC), 50 milligrams of vitamin Es, 7.5 milligrams of vitamins
K and 3 milligram of vitamin D is dissolved in 5 milliliters of chloroforms, and rotary evaporation removes solvent, and the trishydroxymethylaminomethane buffering of pH=8 is added
99 milliliters of liquid, lead to high pure nitrogen 20 minutes, be that 20KHz power is 300W ultrasonic emulsification instrument ultrasonic treatment 10 minutes with frequency,
Obtain lurid stable vesica liquid.
Embodiment 4
In 250 milliliters of flasks, by lecithin lipoid plastid (containing 1 gram of PC), 7.5 milligrams of vitamin Ks and 3 milligrams of vitamins
D is dissolved in 5 milliliters of chloroforms, and rotary evaporation removes solvent, and the Acetic acid-sodium acetate buffer for containing 50 milligrams of ascorbic pH=6 is added
99 milliliters, lead to high pure nitrogen 20 minutes, is that 20KHz power is 300W ultrasonic emulsification instrument ultrasonic treatment 10 minutes with frequency, obtains
To lurid stable vesica liquid.
Embodiment 5
Lecithin lipoid plastid (containing 1 gram of PC), 7.5 milligrams of vitamin Ks and 3 milligrams of vitamin Ds are dissolved in 30 gram 95%
Ethanol solution in.Under a nitrogen, above-mentioned solution is slowly added into the 250 of 70 grams of the Acetic acid-sodium acetate buffer equipped with pH=6
In milliliter flask, the mixing speed during being added dropwise is 1000RPM, after dripping, continues to stir half an hour, is then with frequency
20KHz power is that 300W ultrasonic emulsification instrument is ultrasonically treated 10 minutes, obtains lurid stable vesica liquid.
Embodiment 6
By lecithin lipoid plastid (containing 1 gram of PC), 50 milligrams of vitamin Es, 7.5 milligrams of vitamin Ks and 3 milligrams of vitamin Ds
It is dissolved in 30 gram 95% of ethanol solution.Under a nitrogen, above-mentioned solution is slowly added into the Acetic acid-sodium acetate equipped with pH=6
In 70 grams of buffer of 250 milliliters of flasks, the mixing speed during being added dropwise is 1000RPM, and after dripping, it is small to continue stirring half
When, it is then that 20KHz power is 300W ultrasonic emulsification instrument ultrasonic treatment 10 minutes with frequency, obtains lurid stable capsule
Steep liquid.
Embodiment 7
Lecithin lipoid plastid (containing 1 gram of PC), 7.5 milligrams of vitamin Ks and 3 milligrams of vitamin Ds are dissolved in 30 gram 95%
Ethanol solution in.Under a nitrogen, above-mentioned solution is slowly added into the acetic acid-for containing 50 milligrams of ascorbic pH=6 equipped with 70 grams
In 250 milliliters of flasks of sodium-acetate buffer, the mixing speed during being added dropwise is 1000RPM, after dripping, continues stirring half
Hour, it is then that 20KHz power is 300W ultrasonic emulsification instrument ultrasonic treatment 10 minutes with frequency, obtains lurid stable
Vesica liquid.
Embodiment 8
By any obtained vesicle solution spray drying of Examples 1 to 7, yellow powder is obtained.
Embodiment 9
By any obtained vesicle solution of embodiment 5~7,80 DEG C are heated to, ethyl alcohol azeotropic distillation is removed, is then mended
Add buffer solution to 100 grams.The non-alcoholic vesicle solution of gained is freeze-dried 24 hours at -55 DEG C, obtains yellow powder.
Embodiment 10
By the vesicle formation of any preparation of the embodiment of the present invention 1~9 to treat osteoarthritis, vitamin can be greatly improved
The bioavilability of D and vitamin K improve curative effect of medication.
Experimental verification:
By this compound (yellow powder and embodiment 9 that seven kinds of modes i.e. in embodiment 8 obtain that each embodiment obtains
In the obtained yellow powder of three kinds of modes, be successively denoted as mode 1 respectively to mode 10) and its same dose of usual vitamin D
With vitamin K (vitamin D: 0.25 μ g/ times；Vitamin K: 0.1 μ g/ times) respectively with the next day primary frequency to the knees of 8 week old
OA model mice (modeling of medial meniscus of knee joint lysis) carries out gastric infusion (drug is scattered in sodium carboxymethylcellulose),
Set up control group mice (sodium carboxymethylcellulose that not drug containing is given in stomach-filling) simultaneously.The 2nd, the 6th and the 10th upon administration
It detects mice serum vitamin D week and vitamin K is horizontal (being after being administered 48 hours last time before gastric infusion).It is administered simultaneously 10 weeks
After take mouse knee joint to carry out safranin O/fast green dyeing to carry out it OARSI scoring to assess knee osteoarthritis severity
(OARSI scoring is higher, and knee osteoarthritis is more serious).
Table 1 is vitamin D level in each time point mice serum, each after the compound administration that mode 1 to mode 10 obtains
The mice serum vitamin D level at a time point is above usual vitamin D and vitamin K is added to be administered.Variance point is carried out to each group
It analyses and is compared two-by-two, the mice serum vitamin D level and usual vitamin D of discovery mode 1 to each time point of mode 10
The difference of vitamin K group is added to all have conspicuousness, P value is respectively less than 0.001.
1 each group mice serum vitamin D concentrations of table
Data indicate with average (standard deviation), unit ng/ml
Table 2 is that vitamin K is horizontal in each time point mice serum, each after the compound administration that mode 1 to mode 10 obtains
The mice serum vitamin K level at a time point is above usual vitamin D and vitamin K is added to be administered.Variance point is carried out to each group
It analyses and is compared two-by-two, the mice serum vitamin K level of discovery mode mode 1 to each time point of mode 10 and common dimension are given birth to
Plain D adds the difference of vitamin K group to all have conspicuousness, and P value is respectively less than 0.001.
2 each group mice serum vitamin K content of table
Data indicate with average (standard deviation), unit ng/ml
In terms of curative effect, vitamin D is wrapped up using lecithin and knee OA model is administered in vitamin K nano vesicle (mode 1-10)
Mouse is compared with usual vitamin D and vitamin K has better curative effect (Fig. 1).Variance analysis is carried out to above-mentioned each group, P value is small
There were significant differences between 0.001, prompt group.The nano vesicle and usual vitamin D Jia Weisheng that further mode 1-10 is obtained
Plain K group is compared two-by-two, it is found that each group difference all has conspicuousness (table 3) substantially.
3 nano vesicle of table and usual vitamin D add vitamin K to knee OA model mice Different therapeutical effect
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of nano vesicle preparations for coating vitamin D and vitamin K, which is characterized in that in terms of mass fraction, including dimension life
Plain D1~3 part, 3~7 parts of vitamin K, 30~100 parts of vesica auxiliary material.
2. the nano vesicle preparations of cladding vitamin D and vitamin K according to claim 1, which is characterized in that the dimension
Raw element D includes vitamin D2And vitamin D3；
The vitamin K includes vitamin K1And vitamin K2；
The vesica auxiliary material includes lecithin lipoid plastid, and the lecithin lipoid plastid is extracted from plant or animal.
3. the preparation method of the nano vesicle preparations of a kind of any one of claim 1~2 cladding vitamin D and vitamin K,
It is characterized in that, detailed process is as follows: vesica auxiliary material, vitamin D and vitamin K are dissolved in after solvent through being uniformly dispersed to obtain capsule
Steep solution；
Wherein, the solvent include non-aqueous solvent and polarity can aqueous solvent,
1) solvent is removed when the solvent is water-insoluble solvent, after dissolution and obtains organic matter dry film, adds water solution through dividing
It dissipates and uniformly obtains vesicle solution；
2) when the solvent be polarity can hydrotropic solvent when, aqueous solution be added after dissolution be dispersed and uniformly obtains vesicle solution.
4. the preparation method of the nano vesicle preparations of cladding vitamin D according to claim 3 and vitamin K, feature
It is, the aqueous solution is ion buffer；The ion buffer includes NaAc_HAc buffer solution or phosphoric acid-phosphoric acid
Sodium buffer solution.
5. the preparation method of the nano vesicle preparations of cladding vitamin D according to claim 3 and vitamin K, feature
It is, the non-aqueous solvent includes ethers, alkanes, esters or halogenated alkanes solvent；The polarity can hydrotropic solvent include
Alcohols, ethers or water.
6. the preparation method of the nano vesicle preparations of cladding vitamin D according to claim 3 and vitamin K, feature
It is, the equipment used that is uniformly dispersed includes: high speed agitator, ultrasonic disperser, vesica extruder or high-pressure homogeneous
Device.
7. the preparation method of the nano vesicle preparations of cladding vitamin D according to claim 3 and vitamin K, feature
It is, the vesicle solution obtains solid powder through spraying or freeze-drying again.
8. the preparation method of the nano vesicle preparations of cladding vitamin D according to claim 3 and vitamin K, feature
It is, antioxidant can be added in the vesicle solution.
9. pharmaceutical composition, which is characterized in that including claim 1~the 2 any vesicle formation or claim 3~8
The vesicle formation and pharmaceutically acceptable carrier of any the method preparation.
10. a kind of any described or any the method preparation of claim 3~8 the cladding vitamin D of claim 1~2
With the purposes of the vesicle formation of vitamin K in the drug of preparation treatment, protection or prevention osteoarthritis.
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2018
- 2018-09-06 CN CN201811048974.1A patent/CN109044974A/en active Pending
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2019
- 2019-08-26 CN CN202211149710.1A patent/CN115463092A/en active Pending
- 2019-08-26 CN CN201910791385.0A patent/CN110339169A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101822320A (en) * | 2010-05-22 | 2010-09-08 | 鼎正动物药业（天津）有限公司 | Vitamin water aqua and preparation method thereof |
| CN103705527A (en) * | 2014-01-07 | 2014-04-09 | 昆明云大医药开发有限公司 | Vitamin K2 compound for preventing and treating arthritis |
| CN104337829A (en) * | 2014-05-29 | 2015-02-11 | 西安力邦肇新生物科技有限公司 | Bottled grease micro emulsion freeze-dried preparation with 13 composite vitamins |
| CN104188999A (en) * | 2014-08-13 | 2014-12-10 | 哈药集团制药六厂 | Composition capable of increasing bone density and improving functions of skeletons and joints and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN109044974A (en) | 2018-12-21 |
| CN115463092A (en) | 2022-12-13 |
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