CN108785274A - Nano combined preparation of a kind of rope phosphorus cloth Wei and preparation method thereof - Google Patents
Nano combined preparation of a kind of rope phosphorus cloth Wei and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
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- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
Nano combined preparation of a kind of rope phosphorus cloth Wei and preparation method thereof belongs to rope phosphorus cloth Wei technical field of medicine.It is characterized in that：Include the component of following parts by weight：3 ~ 6 parts of rope phosphorus cloth Wei, 3 ~ 4 parts of poly- (fumaric acid-decanedioic acid), phosphatidase 3 ~ 11 part, 1 ~ 3 part of cholesterol, 0.2 ~ 2 part of cholic acid, 0.2 ~ 2 part of bile salt, 0.5 ~ 4 part of vitamin E, 1 ~ 6 part of trehalose, the parts by weight such as 2 ~ 11 parts of beta cyclodextrin, wherein cholic acid and bile salt use are added.The preparation method of the present invention is used is made into organic solution by rope phosphorus cloth Wei, beta cyclodextrin, cholesterol, cholic acid, bile salt and vitamin E addition ethyl alcohol, and phosphatide is made into phospholipid solution using phosphate buffer, and both the above solution is mixed.Rope phosphorus cloth Wei is made nano combined preparation dissolution rate and increases, and then improves the degree of being absorbed and utilized of insoluble drug.
Description
Technical field
Nano combined preparation of a kind of rope phosphorus cloth Wei and preparation method thereof belongs to rope phosphorus cloth Wei technical field of medicine.
Background technology
This product main ingredient is rope fluorine cloth Wei, chemical name：(S)-isopropyl -2- ((S)-(((2R, 3R, 4R, 5R) -5-
(2,4- dioxygens 3,4- dihydro-pyrimidins -1 (2H) base) fluoro- 3- hydroxy-4-methyls tetrahydrofuran bases of -4-) methoxyl group)-(phenyl) phosphorus
Amide) propionic ester.Rope fluorine cloth Wei（Sofosbuvir）It is a kind of oral nucleoside analogue polymerase inhibitor once a day, energy
The required species-specific proteins of hepatitis c viral replication are enough blocked, are developed by Gilead, chronic hepatitis C is used for
Virus（HCV）Infection.
On December 6th, 2013, Food and Drug Adminstration of the US（FDA）Approval rope fluorine cloth Wei piece is for treating chronic hepatitis liver
Scorching virus（HCV）Infection.On January 19th, 2014, hepatitis new drug Sovaldi（Sofosbuvir, 400mg piece）European Union's approval is obtained,
As a part for antiviral therapy scheme, it to be used for chronic hepatitis C（HCV）The treatment of adult the infected.
Chemical structural formula：
Molecular formula：C22H29FN3O9P
Molecular weight：529.45
Basic physical and chemical：Rope phosphorus cloth Wei piece is Film coated tablets, removes whitening color or off-white color after coating.Rope phosphorus cloth Wei is white
Or off-white color crystalline powder, this product is readily soluble in ethyl alcohol, methanol, the slightly soluble in isopropanol, almost insoluble in water, specific rotation
It is+34 ° to+38 °.
But oral rope phosphorus cloth Wei drug has that bioavilability is bad.Rope phosphorus cloth Wei enters Digestive by oral
It is easy to be destroyed by the digestive juice in human body after system so that the blood concentration of rope phosphorus cloth Wei is relatively low, can not obtain preferable treatment
Effect.Although being related in the prior art using carrier carrying-hauling rope phosphorus cloth Wei to the design of intestinal absorption, in the prior art institute
The carrier of selection is poor to the package effect of rope phosphorus cloth Wei, causes the utilization rate of rope phosphorus cloth Wei relatively low, and adverse reaction and stomach and intestine
Road irritation increases.And the grain size of composite particles that carrier is formed with rope phosphorus cloth Wei in the prior art is larger, and it can not be preferable
Film is crossed by body cell to absorb.That there are sizes is uneven for the nano combined micelle of existing rope phosphorus cloth Wei, particle diameter distribution is wider, and rope phosphorus cloth Wei
Nano combined micelle particle diameter distribution is wider, and it is unstable to easily cause rope phosphorus cloth Wei object infiltration rate, and drug effect is difficult to control.
Invention content
The technical problem to be solved by the present invention is to：Overcome the deficiencies of the prior art and provide a kind of size is small, particle diameter distribution compared with
It is narrow, have higher bioavilability, preparation method is easy to operate, the high nano combined preparation of rope phosphorus cloth Wei of production efficiency and its
Preparation method.
The technical solution adopted by the present invention to solve the technical problems is：The nano combined preparation of rope phosphorus cloth Wei, feature
It is, includes the component of following parts by weight：3 ~ 6 parts of rope phosphorus cloth Wei, 3 ~ 4 parts of poly- (fumaric acid-decanedioic acid), phosphatidase 3 ~ 11 part, courage
1 ~ 3 part of sterol, 0.2 ~ 2 part of cholic acid, 0.2 ~ 2 part of bile salt, 0.5 ~ 4 part of vitamin E, 1 ~ 6 part of trehalose, beta cyclodextrin 3 ~ 11
Part, wherein the mass ratio of cholic acid and bile salt is 1:1.
Rope phosphorus cloth Wei is almost insoluble in water, and the present invention is made nano combined preparation dissolution rate and increases, and then improves indissoluble
The degree of being absorbed and utilized of property drug.The nano combined micelle size of rope phosphorus cloth Wei in the nano combined preparation of rope phosphorus cloth Wei is small, grain size point
Cloth is relatively narrow, has higher bioavilability.
Preferably, include the component of following parts by weight：3.8 ~ 4.3 parts of rope phosphorus cloth Wei, poly- (fumaric acid-decanedioic acid) 3 ~ 4
Part, phosphatidase 4 ~ 10 part, 2 ~ 2.5 parts of cholesterol, 0.5 ~ 0.6 part of cholic acid, 0.5 ~ 0.6 part of bile salt, 1.8 ~ 2.2 parts of vitamin E,
1.8 ~ 2.2 parts of trehalose, 4 ~ 6 parts of beta cyclodextrin.
Preferably, the molar ratio of fumaric acid group and decanedioic acid group is 20 in poly- (fumaric acid-decanedioic acid):
80.Described poly- (fumaric acid-decanedioic acid) [P (FA.SA)] (FA：SA=20：80) the characteristics of is that hydrophily is stronger, degrades and releases
Medicine speed is fast, has very strong adhesive force to gastrointestinal mucosa, is mainly used as the controlled-release material of the nano combined preparation of rope phosphorus cloth Wei.Make
Rope phosphorus cloth Wei is more effectively carried to absorption site.
Preferably, the cholic acid is chenodeoxycholic acid；The bile salt is Taurodeoxycholate sodium, ox sulphur deoxidation courage
One or both of sour potassium, NaTDC, deoxycholic acid potassium.
Preferably, the phosphatide is soybean lecithin, egg yolk lecithin, hydrogenated soy phosphatidyl choline, two palmityl phosphatide
Phatidylcholine, Distearoyl Phosphatidylcholine or Dioleoyl Phosphatidylcholine.
Preferably, further include following parts by weight of component：0.5 ~ 4 part of adhesive, 0.6 ~ 5 part of disintegrant, lubricant 0.5 ~ 3
Part, 0.5 ~ 6 part of filler.
Preferably, the disintegrant is sodium carboxymethyl starch, crospovidone, croscarmellose sodium, crosslinking
One or both of polyvinylpyrrolidone, sodium alginate.
It is furthermore preferred that the disintegrant be croscarmellose sodium and crosslinked polyvinylpyrrolidone in mass ratio
17~26:The compound disintegrant of 12 ~ 22 mixing.Rope phosphorus cloth Wei can be made more to imitate and be carried to absorption site.
Preferably, the filler be methylcellulose, light third cellulose, sodium carboxymethylcellulose, ethyl cellulose,
One or both of lactose, calcium sulphate dihydrate, calcium monohydrogen phosphate, mannitol, sorbierite, microcrystalline cellulose.
It is furthermore preferred that the filler is light third cellulose, lactose and mannitol in mass ratio 3 ~ 7:3~5:1 ~ 6 mixing
Composite filler.Rope phosphorus cloth Wei can be made more to imitate and be carried to absorption site.
Preferably, the adhesive be starch, sucrose, dextrin, gelatin, polyethylene glycol, one kind in polyvinyl alcohol or
Two kinds.
Preferably, the lubricant is magnesium stearate, calcium stearate, superfine silica gel powder, talcum powder, lauryl sodium sulfate
One or both of.
The preparation method of the nano combined preparation of a kind of above-mentioned rope phosphorus cloth Wei, which is characterized in that comprise the technical steps that：
1）Rope phosphorus cloth Wei, poly- (fumaric acid-decanedioic acid), cholesterol, cholic acid, bile salt and vitamin E are mixed and obtain total mixing
Total mixture is added in ethanol solution by object, and water bath sonicator makes it dissolve, and forms organic solution A；Organic solution A is used
CO2Supercritical extracting equipment dissolves, and forms organic solution B；Wherein the mixed proportion of ethanol solution and total mixture is per 1L second
70 ~ 100g total mixtures are added in alcoholic solution；
2）Phosphatide is added to stir 10 ~ 20 minutes in 60 ~ 70 DEG C of phosphate buffer and is made into phospholipid solution, wherein phosphate
A concentration of 0.01mol/L, pH of buffer solution are 7.4 ~ 7.6；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 60 ~ 70 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 1 ~ 2 time, then in high pressure homogenizer pressure 1000bar by 1 ~ 2 time, obtains secondary nano-complex suspension；
5）Trehalose, beta cyclodextrin are added into obtained secondary nano-complex suspension, it is dry using spray drying or freezing
It is dry to get.
Main drug is rope phosphorus cloth Wei, and membrane material includes poly- (fumaric acid-decanedioic acid), phosphatide, cholesterol and waits weight
The cholic acid and bile salt that part is added, the design not only make rope phosphorus cloth Wei be entered after digestive system from gastric juice, bile etc. by oral
Destruction, and be effectively carried to absorption site so that the blood concentration of rope phosphorus cloth Wei increases.Inventor makes in the present invention
With cholesterol, effect is to form about 4 nanometer thickness of stable bilayer with rope phosphorus cloth Wei, poly- (fumaric acid-decanedioic acid), phosphatide
Cell biological film, form the spherical vesicles body of the double-deck fat molecule after agitation, drug encapsulation formed in class bilayer
Miniature vesicular body, micro-bubbles capsule diameters ranging from 25 ~ 1000nm.Suitable beta cyclodextrin in invention, can enhance mixed-powder
Stability, poly- (fumaric acid decanedioic acid) [P (FA.SA)] (FA：SA=20：80) the characteristics of is that hydrophily is stronger, degrades and releases
Medicine speed is fast, has very strong adhesive force to gastrointestinal mucosa, is used as the controlled-release material of the nano combined preparation of rope phosphorus cloth Wei, can improve
Rope phosphorus cloth Wei dissolution rate.
It the cholic acid and bile salt that parts by weight are added such as is used in the present invention, and limits cholic acid as chenodeoxycholic acid；It is described
Bile salt be selected as Taurodeoxycholate sodium, taurodeoxycholic acid potassium, NaTDC, one kind in deoxycholic acid potassium or two
Kind；According to a certain percentage stable nano-microcapsule system is mixed with rope phosphorus cloth Wei, phosphatide.
Step 1）It is middle that rope phosphorus cloth Wei, poly- (fumaric acid-decanedioic acid), phosphatide, cholesterol, courage are disperseed using ethanol solution mixing
Acid, bile salt and vitamin E, and by water bath sonicator accelerate rope phosphorus cloth Wei, poly- (fumaric acid-decanedioic acid), phosphatide, cholesterol,
The dissolving of cholic acid, bile salt and vitamin E in ethanol solution obtains organic solution A, to further increase each component in ethyl alcohol
Dispersion effect in solution, applicant use CO2Supercritical extracting equipment makes rope phosphorus cloth Wei, poly- (fumaric acid-in organic solution A
Decanedioic acid), phosphatide, cholesterol, cholic acid, bile salt and vitamin E be dispersed to nanometer particle size, in order in step 3）In to rope phosphorus
Bu Wei is fully wrapped up.Ethanol solution used is the ethanol water that volume fraction is 98.00 ~ 99.99% in the present invention.
Wherein step 2）In phosphate buffer pH7.4 ~ 7.6, ingredient be potassium dihydrogen phosphate and make solvent water and
The micro sodium hydroxide for adjusting phosphate buffer pH.In the composition for the nano combined preparation of rope phosphorus cloth Wei that the present invention obtains
In, parts by weight shared by phosphate are small, can be ignored.
Wherein step 3）Effect be：By the way of injecting while stirring, and limit holding rope phosphorus cloth in injection process
60 ~ 70 DEG C of Wei solution degree can play the role of primary emulsifying, acquisition colostric fluid.
Wherein step 4）The middle effect using high pressure homogenizer whole grain is：Colostric fluid makes its grain through the arrangement of multiple high pressure mixing
Degree distribution reaches 200nm hereinafter, making dispersion of medicine, and forms stable nanometer suspension system.
Wherein step 5）Middle addition trehalose as protective agent, in spray drying or freezing dry process, to rope phosphorus cloth
The nano combined micelle of Wei is protected, prevent in drying process destroy the nano combined micelle of rope phosphorus cloth Wei outside by rope phosphorus cloth Wei,
The protective film that phosphatide, cholesterol, cholic acid, bile salt and vitamin E are formed.Beta cyclodextrin is added, is to preferably enhance mixing
The stability of powder.
Compared with prior art, have possessed by nano combined preparation of a kind of rope phosphorus cloth Wei of the invention and preparation method thereof
Beneficial effect is：
1, after the present invention to rope phosphorus cloth Wei by carrying out nano-complex encapsulating, rope phosphorus cloth Wei is not only made to enter Digestive by oral
From gastric juice, the destruction of bile etc. after system, and effectively it is carried to absorption site so that the blood concentration of rope phosphorus cloth Wei increases；
Compared with giving the rope phosphorus cloth Wei for not being encapsulated as nano-complex, the former blood concentration increases, and bioavilability improves.Application
People it has been investigated that：The cholic acid and bile salt of human endocrine（Weight part ratio 1:1）It can group with rope phosphorus cloth Wei, phosphatide, cholesterol
At cholic acid and bile salt（Weight part ratio 1:1）There is particle delivery lipid component to be diffused into mucosa cells, sorbefacient work(
Energy.Based on this function, the research to nano-complex oral administration system, in addition to using traditional membrane material, such as poly- (fumaric acid-last of the ten Heavenly stems
Diacid), phosphatide and cholesterol, add cholic acid and bile salt（Weight part ratio 1:1）This special membrane material, the rope phosphorus prepared
The nano combined micelle of cloth Wei not only has the advantages of Conventional nano compound, is also act against the digestion of digestive system and will be wrapped
The drug carrier of envelope solves the problems, such as that oral rope phosphorus cloth Wei bioavilability is bad, reduces adverse reaction and stomach to absorption site
Enteron aisle irritation.
2, production method of the invention is easy to operate, and production efficiency is fast, and the nano combined system of rope phosphorus cloth Wei obtained
Rope phosphorus cloth Wei nano combined micelle can reach nanometer particle size in agent, be significantly improved in bioavilability；And rope phosphorus
The grain size of the nano combined micelle of cloth Wei is more uniform, and particle diameter distribution is narrow, convenient for controlling bioavilability.The present invention obtains
The rope nano combined preparation of phosphorus cloth Wei obtained is made of the nano combined micelle of many rope phosphorus cloth Weis, and the nano combined micelle of rope phosphorus cloth Wei can
Reach nanometer particle size.And the particle diameter distribution for the nano combined micelle of rope phosphorus cloth Wei that the present invention obtains is relatively narrow, wherein quantity account for 73 ~
For the 88% nano combined micelle particle diameter distribution of rope phosphorus cloth Wei between 90 ~ 130nm, the size of the nano combined micelle of rope phosphorus cloth Wei is small
And it is more uniform, when portion is absorbed and utilized in vivo, infiltration rate is fast and stablizes, convenient for control, has slow release and targeting
The advantages of.
Description of the drawings
Stripping curve of the nano combined preparation of rope phosphorus cloth Wei of Fig. 1 embodiments 5 in 6.8 phosphate buffers.
Stripping curve of the nano combined preparation of rope phosphorus cloth Wei of Fig. 2 embodiments 2 in 0.1M hydrochloric acid.
Stripping curve of the nano combined preparation of rope phosphorus cloth Wei of Fig. 3 embodiments 4 in pH4.5 acetate buffer solutions.
The stripping curve of the nano combined preparation of rope phosphorus cloth Wei of Fig. 4 embodiments 4 in water.
The dissolution situation of data is it is found that the nano combined preparation of rope phosphorus cloth Wei produced by the present invention dissolves out in each medium in figure
Comparatively fast, reached 85% or more at 15 minutes.
Specific implementation mode
Embodiment 1 ~ 8 is the specific implementation mode of the present invention, and wherein embodiment 1 is most preferred embodiment.
Embodiment 1
1）By weight will：4.1 parts of rope phosphorus cloth Wei, 3.5 parts of poly- (fumaric acid-decanedioic acid), 2.25 parts of cholesterol, cholic acid 0.55
Part, 0.55 part of bile salt, 2 parts of mixing of vitamin E obtain total mixture, wherein fumaric acid group in poly- (fumaric acid-decanedioic acid)
Molar ratio with decanedioic acid group is 20:80；Total mixture is added in ethanol solution, water bath sonicator makes it dissolve, and is formed
Organic solution A；Organic solution A is used into CO2Supercritical extracting equipment dissolves, and forms organic solution B；Wherein ethanol solution with it is total
The mixed proportion of mixture is per addition 85g total mixtures in 1L ethanol solutions；
2）By weight by 7 parts of soybean lecithins, egg yolk lecithin, hydrogenated soy phosphatidyl choline, dipalmitoylphosphatidylcholine, two
Stearoylphosphatidylcholine or Dioleoyl Phosphatidylcholine, which are added to stir 15 minutes in 65 DEG C of phosphate buffer, is made into phosphorus
Lipoprotein solution, wherein a concentration of 0.01mol/L, pH 7.5 of phosphate buffer；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 65 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 1 time, then in high pressure homogenizer pressure 1000bar by 2 times, obtains secondary nano-complex suspension；
5）2 parts of trehalose, 5 parts of beta cyclodextrin, using spraying is added by weight into obtained secondary nano-complex suspension
Dry or freeze-drying, dried object and 2 parts of dextrin, croscarmellose sodium and crosslinked polyvinylpyrrolidone are in mass ratio
22:3 parts of compound disintegrant, 1.8 parts of superfine silica gel powder, light third cellulose, lactose and the mannitol in mass ratio 6 of 16 mixing:4:3 is mixed
Tablet or capsule is made in 4 parts of the composite filler of conjunction after mixing to obtain the final product.
Embodiment 2
1）By weight will：3.8 parts of rope phosphorus cloth Wei, 4 parts of poly- (fumaric acid-decanedioic acid), 2 parts of cholesterol, 0.6 part of cholic acid, bile
0.6 part of salt, 1.8 parts of mixing of vitamin E obtain total mixture, wherein fumaric acid group and the last of the ten Heavenly stems two in poly- (fumaric acid-decanedioic acid)
The molar ratio of acid groups is 20:80；Total mixture is added in ethanol solution, water bath sonicator makes it dissolve, and is formed organic molten
Liquid A；Organic solution A is used into CO2Supercritical extracting equipment dissolves, and forms organic solution B；Wherein ethanol solution and total mixture
Mixed proportion be per 1L ethanol solutions in 80g total mixtures are added；
2）By weight by 10 parts of soybean lecithins, egg yolk lecithin, hydrogenated soy phosphatidyl choline, dipalmitoylphosphatidylcholine,
Distearoyl Phosphatidylcholine or Dioleoyl Phosphatidylcholine are added to stir 18 minutes in 62 DEG C of phosphate buffer and be made into
Phospholipid solution, wherein a concentration of 0.01mol/L, pH 7.4 of phosphate buffer；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 62 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 1 time, then in high pressure homogenizer pressure 1000bar by 2 times, obtains secondary nano-complex suspension；
5）2.2 parts of trehalose, 4 parts of beta cyclodextrin, using spray is added by weight into obtained secondary nano-complex suspension
Mist is dry or freeze-drying, dried object press quality with 4 parts of croscarmellose sodiums of sucrose and crosslinked polyvinylpyrrolidone
Than 17:5 parts of compound disintegrant, 0.5 part of lauryl sodium sulfate, light third cellulose, lactose and the mannitol of 22 mixing press quality
Than 3: 5:Tablet or capsule is made in 6 parts of the composite filler of 1 mixing after mixing to obtain the final product.
Embodiment 3
1）By weight will：4.3 parts of rope phosphorus cloth Wei, 3 parts of poly- (fumaric acid-decanedioic acid), 2.5 parts of cholesterol, 0.5 part of cholic acid, courage
0.5 part of juice salt, 2.2 parts of mixing of vitamin E obtain total mixture, wherein fumaric acid group and the last of the ten Heavenly stems in poly- (fumaric acid-decanedioic acid)
The molar ratio of diacid group is 20:80；Total mixture is added in ethanol solution, water bath sonicator makes it dissolve, and is formed organic
Solution A；Organic solution A is used into CO2Supercritical extracting equipment dissolves, and forms organic solution B；Wherein ethanol solution with always mix
The mixed proportion of object is per addition 90g total mixtures in 1L ethanol solutions；
2）By weight by 4 parts of soybean lecithins, egg yolk lecithin, hydrogenated soy phosphatidyl choline, dipalmitoylphosphatidylcholine, two
Stearoylphosphatidylcholine or Dioleoyl Phosphatidylcholine, which are added to stir 13 minutes in 67 DEG C of phosphate buffer, is made into phosphorus
Lipoprotein solution, wherein a concentration of 0.01mol/L, pH 7.5 of phosphate buffer；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 67 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 2 times, then in high pressure homogenizer pressure 1000bar by 1 time, obtains secondary nano-complex suspension；
5）1.8 parts of trehalose, 6 parts of beta cyclodextrin, using spray is added by weight into obtained secondary nano-complex suspension
Mist is dry or freeze-drying, dried object press matter with 0.5 part of gelatin, croscarmellose sodium and crosslinked polyvinylpyrrolidone
Measure ratio 26:0.6 part of compound disintegrant, 3 parts of magnesium stearate, light third cellulose, lactose and the mannitol in mass ratio 7 of 12 mixing:
3:Tablet or capsule is made in 0.5 part of the composite filler of 6 mixing after mixing to obtain the final product.
Embodiment 4
1）By weight will：3 parts of rope phosphorus cloth Wei, 4 parts of poly- (fumaric acid-decanedioic acid), 1 part of cholesterol, 2 parts of chenodeoxycholic acid, ox
Sulphur deoxysodium cholate, taurodeoxycholic acid potassium, NaTDC, 2 parts of deoxycholic acid potassium, 0.5 part of mixing of vitamin E obtain total
Mixture, wherein the molar ratio of fumaric acid group and decanedioic acid group is 20 in poly- (fumaric acid-decanedioic acid):80；It will always mix
Object is added in ethanol solution, and water bath sonicator makes it dissolve, and forms organic solution A；Organic solution A is used into CO2Overcritical extraction
Taking equipment dissolves, and forms organic solution B；Wherein the mixed proportion of ethanol solution and total mixture is to be added per in 1L ethanol solutions
70g total mixtures；
2）By weight by 3 parts of soybean lecithins, egg yolk lecithin, hydrogenated soy phosphatidyl choline, dipalmitoylphosphatidylcholine, two
Stearoylphosphatidylcholine or Dioleoyl Phosphatidylcholine, which are added to stir 10 minutes in 70 DEG C of phosphate buffer, is made into phosphorus
Lipoprotein solution, wherein a concentration of 0.01mol/L, pH 7.4 of phosphate buffer；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 70 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 1 time, then in high pressure homogenizer pressure 1000bar by 1 time, obtains secondary nano-complex suspension；
5）1 part of trehalose, 11 parts of beta cyclodextrin, using spray is added by weight into obtained secondary nano-complex suspension
Mist is dry or is freeze-dried, 2 parts of dried object and polyethylene glycol, 3 parts of sodium carboxymethyl starch, 2 parts of talcum powder, 3 parts of light third cellulose
Tablet or capsule are made after mixing to obtain the final product.
Embodiment 5
1）By weight will：6 parts of rope phosphorus cloth Wei, 3 parts of poly- (fumaric acid-decanedioic acid), 3 parts of cholesterol, 0.2 part of chenodeoxycholic acid,
Taurodeoxycholate sodium, taurodeoxycholic acid potassium, NaTDC, 0.2 part of deoxycholic acid potassium, 4 parts of mixing of vitamin E obtain
Total mixture, wherein the molar ratio of fumaric acid group and decanedioic acid group is 20 in poly- (fumaric acid-decanedioic acid):80；It will always mix
It closes object to be added in ethanol solution, water bath sonicator makes it dissolve, and forms organic solution A；Organic solution A is used into CO2It is overcritical
Extraction equipment dissolves, and forms organic solution B；Wherein the mixed proportion of ethanol solution and total mixture is to add per in 1L ethanol solutions
Enter 100g total mixtures；
2）By weight by 11 parts of soybean lecithins, egg yolk lecithin, hydrogenated soy phosphatidyl choline, dipalmitoylphosphatidylcholine,
Distearoyl Phosphatidylcholine or Dioleoyl Phosphatidylcholine are added to stir 20 minutes in 60 DEG C of phosphate buffer and be made into
Phospholipid solution, wherein a concentration of 0.01mol/L, pH 7.6 of phosphate buffer；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 60 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 2 times, then in high pressure homogenizer pressure 1000bar by 2 times, obtains secondary nano-complex suspension；
5）6 parts of trehalose, 3 parts of beta cyclodextrin, using spraying is added by weight into obtained secondary nano-complex suspension
0.5 part of dry or freeze-drying, dried object and starch, 4 parts of croscarmellose sodium, 1.5 parts of superfine silica gel powder, 6 parts of lactose
Tablet or capsule are made after mixing to obtain the final product.
Comparative example 1
1）By weight will：4.1 parts of rope phosphorus cloth Wei, 2.25 parts of cholesterol, 0.55 part of cholic acid, 0.55 part of bile salt, vitamin E 2
Part mixing obtains total mixture；Total mixture is added in ethanol solution, water bath sonicator makes it dissolve, and forms organic solution A；
Organic solution A is used into CO2Supercritical extracting equipment dissolves, and forms organic solution B；Wherein ethanol solution and total mixture is mixed
Composition and division in a proportion example is per addition 85g total mixtures in 1L ethanol solutions；
2）By weight by 7 parts of soybean lecithins, egg yolk lecithin, hydrogenated soy phosphatidyl choline, dipalmitoylphosphatidylcholine, two
Stearoylphosphatidylcholine or Dioleoyl Phosphatidylcholine, which are added to stir 15 minutes in 65 DEG C of phosphate buffer, is made into phosphorus
Lipoprotein solution, wherein a concentration of 0.01mol/L, pH 7.5 of phosphate buffer；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 65 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 1 time, then in high pressure homogenizer pressure 1000bar by 2 times, obtains secondary nano-complex suspension；
5）2 parts of trehalose, 5 parts of beta cyclodextrin, using spraying is added by weight into obtained secondary nano-complex suspension
Dry or freeze-drying, with 2 parts of dextrin, croscarmellose sodium and crosslinked polyvinylpyrrolidone in mass ratio 22:16
3 parts of compound disintegrant, 1.8 parts of superfine silica gel powder, light third cellulose, lactose and the mannitol in mass ratio 6 of mixing:4:3 mixing
Tablet or capsule is made in 4 parts of composite filler after mixing to obtain the final product.
Comparative example 2
1）By weight will：4.1 parts of rope phosphorus cloth Wei, 3.5 parts of poly- (fumaric acid-decanedioic acid), 2.25 parts of cholesterol, cholic acid 0.55
Part, 0.55 part of bile salt, 2 parts of mixing of vitamin E obtain total mixture, wherein fumaric acid group in poly- (fumaric acid-decanedioic acid)
Molar ratio with decanedioic acid group is 20:80；Total mixture is added in ethanol solution, water bath sonicator makes it dissolve, and is formed
Organic solution A；Organic solution A is used into CO2Supercritical extracting equipment dissolves, and forms organic solution B；Wherein ethanol solution with it is total
The mixed proportion of mixture is per addition 85g total mixtures in 1L ethanol solutions；
2）By weight by 7 parts of soybean lecithins, egg yolk lecithin, hydrogenated soy phosphatidyl choline, dipalmitoylphosphatidylcholine, two
Stearoylphosphatidylcholine or Dioleoyl Phosphatidylcholine, which are added to stir 15 minutes in 65 DEG C of phosphate buffer, is made into phosphorus
Lipoprotein solution, wherein a concentration of 0.01mol/L, pH 7.5 of phosphate buffer；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 65 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 1 time, then in high pressure homogenizer pressure 1000bar by 2 times, obtains secondary nano-complex suspension；
5）2 parts of trehalose is added by weight into obtained secondary nano-complex suspension, using spray drying or freezing
It is dry, with 2 parts of dextrin, croscarmellose sodium and crosslinked polyvinylpyrrolidone in mass ratio 22:16 mixing it is compound
3 parts of disintegrant, 1.8 parts of superfine silica gel powder, light third cellulose, lactose and mannitol in mass ratio 6:4:The composite filler 4 of 3 mixing
Tablet or capsule is made in part after mixing to obtain the final product.
Performance test
Using laser particle analyzer（U.S. PSS Nicomp 380DLS）Obtained in the embodiment 1 ~ 5 and comparative example 1,2 of detection
The particle diameter distribution of the nano combined micelle of rope phosphorus cloth Wei in the nano combined preparation of rope phosphorus cloth Wei, and grain size is counted in 90 ~ 120nm
Between the nano combined micelle quantity of rope phosphorus cloth Wei account for the percentage of total nano combined micelle quantity of rope phosphorus cloth Wei, by embodiment 1 ~
5 and comparative example 1,2 testing result typing tables 1.The dissolution rate of the tablet of 1,2 gained of embodiment 1 ~ 5 and comparative example, inspection are detected simultaneously
Survey result typing table 1.
1 embodiment of table, 1 ~ 7 testing result
。
It can be seen from Table 1 that：In the nano combined preparation of rope phosphorus cloth Wei that embodiment 1 ~ 5 is obtained, rope phosphorus cloth Wei is formed
The nano combined micelle particle diameter distribution of rope phosphorus cloth Wei of nano combined preparation is relatively narrow, and wherein grain size is in the compound micro- of 90 ~ 120nm
Group accounts for the 79 ~ 85 of total nano combined micelle quantity of rope phosphorus cloth Wei.The nano combined micelle of rope phosphorus cloth Wei of 90 ~ 120nm taken orally into
Enter digestive system effectively to be penetrated in biological semi-permeable membrane transport to body fluid circulatory system, the higher dissolution rate of the cooperation present invention makes
The blood concentration for obtaining rope phosphorus cloth Wei increases, and improves bioavilability.And due to the grain size of the nano combined micelle of rope phosphorus cloth Wei
The variation of size uniform rope phosphorus cloth Wei infiltration rate is stablized, and the nano combined preparation of rope phosphorus cloth Wei of the invention is when being made oral preparation
Additive amount is more convenient for controlling.
Embodiment test dissolution result is selected below and draws stripping curve.
Dissolution result of the nano combined preparation of rope phosphorus cloth Wei of 2 embodiment 5 of table in 6.8 phosphate buffers
。
It is molten in 6.8 phosphate buffers according to the nano combined preparation of rope phosphorus cloth Wei of embodiment 5 made of the data of table 2
Go out curve and sees Fig. 1.
Dissolution result of the nano combined preparation of rope phosphorus cloth Wei of 3 embodiment 2 of table in 0.1M hydrochloric acid
。
It is bent according to dissolution of the nano combined preparation of rope phosphorus cloth Wei of embodiment 2 made of the data of table 3 in 0.1M hydrochloric acid
Line is shown in Fig. 2.
Dissolution result of the nano combined preparation of rope phosphorus cloth Wei of 4 embodiment 4 of table in pH4.5 acetate buffer solutions
。
According to the nano combined preparation of rope phosphorus cloth Wei of embodiment 4 made of the data of table 4 in pH4.5 acetate buffer solutions
Stripping curve is shown in Fig. 3.
The dissolution result of the nano combined preparation of rope phosphorus cloth Wei of 5 embodiment 4 of table in water
。
See figure according to the stripping curve of the nano combined preparation of rope phosphorus cloth Wei of embodiment 4 made of the data of table 5 in water
4。
Conclusion：The dissolution situations of above-mentioned data it is found that the nano combined preparation of rope phosphorus cloth Wei produced by the present invention in each medium
Middle dissolution is very fast, reaches 85% or more at 15 minutes.
The above described is only a preferred embodiment of the present invention, be not the limitation for making other forms to invention, it is any
Those skilled in the art are changed or are modified as the equivalent of equivalent variations possibly also with the technology contents of the disclosure above
Embodiment.But it is every without departing from technical solution of the present invention content, above example is made according to the technical essence of the invention
Any simple modification, equivalent variations and remodeling, still fall within the protection domain of technical solution of the present invention.
Claims (10)
1. a kind of nano combined preparation of rope phosphorus cloth Wei, which is characterized in that include the component of following parts by weight：3 ~ 6 parts of rope phosphorus cloth Wei,
3 ~ 4 parts of poly- (fumaric acid-decanedioic acid), phosphatidase 3 ~ 11 part, 1 ~ 3 part of cholesterol, 0.2 ~ 2 part of cholic acid, 0.2 ~ 2 part of bile salt, dimension life
0.5 ~ 4 part of plain E, 1 ~ 6 part of trehalose, 3 ~ 11 parts of beta cyclodextrin, the wherein mass ratio of cholic acid and bile salt are 1:1.
2. a kind of nano combined preparation of rope phosphorus cloth Wei according to claim 1, it is characterised in that：Including following parts by weight
Component：3.8 ~ 4.3 parts of rope phosphorus cloth Wei, 3 ~ 4 parts of poly- (fumaric acid-decanedioic acid), phosphatidase 4 ~ 10 part, 2 ~ 2.5 parts of cholesterol, cholic acid
0.5 ~ 0.6 part, 0.5 ~ 0.6 part of bile salt, 1.8 ~ 2.2 parts of vitamin E, 1.8 ~ 2.2 parts of trehalose, 4 ~ 6 parts of beta cyclodextrin.
3. the nano combined preparation of a kind of rope phosphorus cloth Wei according to claim 1 or 2, it is characterised in that：Described is poly- (rich
Horse acid-decanedioic acid) in the molar ratio of fumaric acid group and decanedioic acid group be 20:80.
4. a kind of nano combined preparation of rope phosphorus cloth Wei according to claim 1 or 2, it is characterised in that：The cholic acid is
Chenodeoxycholic acid；The bile salt is Taurodeoxycholate sodium, taurodeoxycholic acid potassium, NaTDC, deoxycholic acid potassium
One or both of.
5. a kind of nano combined preparation of rope phosphorus cloth Wei according to claim 1 or 2, which is characterized in that further include following heavy
Measure part component：0.5 ~ 4 part of adhesive, 0.6 ~ 5 part of disintegrant, 0.5 ~ 3 part of lubricant, 0.5 ~ 6 part of filler.
6. a kind of nano combined preparation of rope phosphorus cloth Wei according to claim 5, it is characterised in that：The disintegrant is carboxylic
One kind in methyl starch sodium, crospovidone, croscarmellose sodium, crosslinked polyvinylpyrrolidone, sodium alginate
Or two kinds.
7. a kind of nano combined preparation of rope phosphorus cloth Wei according to claim 5, it is characterised in that：The disintegrant is to hand over
Join sodium carboxymethylcellulose and crosslinked polyvinylpyrrolidone in mass ratio 17 ~ 26:The compound disintegrant of 12 ~ 22 mixing.
8. a kind of nano combined preparation of rope phosphorus cloth Wei according to claim 5, it is characterised in that：The filler is first
Base cellulose, light third cellulose, sodium carboxymethylcellulose, ethyl cellulose, lactose, calcium sulphate dihydrate, calcium monohydrogen phosphate, sweet dew
One or both of alcohol, sorbierite, microcrystalline cellulose.
9. a kind of nano combined preparation of rope phosphorus cloth Wei according to claim 5, it is characterised in that：The filler is light
Third cellulose, lactose and mannitol in mass ratio 3 ~ 7:3~5:The composite filler of 1 ~ 6 mixing.
10. a kind of preparation method of the nano combined preparation of rope phosphorus cloth Wei of claim 1 ~ 9 any one of them, which is characterized in that
It comprises the technical steps that：
1）Rope phosphorus cloth Wei, poly- (fumaric acid-decanedioic acid), cholesterol, cholic acid, bile salt and vitamin E are mixed and obtain total mixing
Total mixture is added in ethanol solution by object, and water bath sonicator makes it dissolve, and forms organic solution A；Organic solution A is used
CO2Supercritical extracting equipment dissolves, and forms organic solution B；Wherein the mixed proportion of ethanol solution and total mixture is per 1L second
70 ~ 100g total mixtures are added in alcoholic solution；
2）Phosphatide is added to stir 10 ~ 20 minutes in 60 ~ 70 DEG C of phosphate buffer and is made into phospholipid solution, wherein phosphate
A concentration of 0.01mol/L, pH of buffer solution are 7.4 ~ 7.6；
3）By the way of injecting while stirring, organic solution B is injected into step 2）In the phospholipid solution of acquisition, injected
Keep phospholipid solution temperature at 60 ~ 70 DEG C in journey；Stirring makes ethyl alcohol volatilize, and primary nano-complex suspension is made；
4）Primary nano-complex suspension is directly crossed into high pressure homogenizer whole grain, is first led in high pressure homogenizer pressure 500bar
It crosses 1 ~ 2 time, then in high pressure homogenizer pressure 1000bar by 1 ~ 2 time, obtains secondary nano-complex suspension；
5）Trehalose, beta cyclodextrin are added into obtained secondary nano-complex suspension, it is dry using spray drying or freezing
It is dry to get.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130136776A1 (en) * | 2011-11-29 | 2013-05-30 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis c virus |
| CN103908431A (en) * | 2014-04-26 | 2014-07-09 | 山东世博金都药业有限公司 | Entecavir compound nano-preparation and preparation method thereof |
-
2018
- 2018-07-09 CN CN201810744486.8A patent/CN108785274A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130136776A1 (en) * | 2011-11-29 | 2013-05-30 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis c virus |
| CN103908431A (en) * | 2014-04-26 | 2014-07-09 | 山东世博金都药业有限公司 | Entecavir compound nano-preparation and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 姚日生: "《药用高分子材料》", 31 August 2003, 化学工业出版社 * |
| 姜锡瑞: "《生物发酵产业技术》", 31 May 2016, 中国轻工业出版社 * |
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