CN108785682A - A kind of lipid carrier and preparation method thereof, application to low aqueous solubility Polyphenols drug with slow releasing function - Google Patents
A kind of lipid carrier and preparation method thereof, application to low aqueous solubility Polyphenols drug with slow releasing function Download PDFInfo
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- CN108785682A CN108785682A CN201810697381.1A CN201810697381A CN108785682A CN 108785682 A CN108785682 A CN 108785682A CN 201810697381 A CN201810697381 A CN 201810697381A CN 108785682 A CN108785682 A CN 108785682A
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- Prior art keywords
- drug
- water
- parts
- lecithin
- dihydromyricetin
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- 239000003814 drug Substances 0.000 title claims abstract description 59
- 229940079593 drug Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 235000013824 polyphenols Nutrition 0.000 title claims abstract description 19
- 230000003578 releasing effect Effects 0.000 title claims abstract description 18
- 150000008442 polyphenolic compounds Chemical class 0.000 title claims abstract description 17
- 150000002632 lipids Chemical class 0.000 title claims abstract description 16
- KJXSIXMJHKAJOD-LSDHHAIUSA-N (+)-dihydromyricetin Chemical compound C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC(O)=C(O)C(O)=C1 KJXSIXMJHKAJOD-LSDHHAIUSA-N 0.000 claims abstract description 124
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 claims abstract description 71
- KQILIWXGGKGKNX-UHFFFAOYSA-N dihydromyricetin Natural products OC1C(=C(Oc2cc(O)cc(O)c12)c3cc(O)c(O)c(O)c3)O KQILIWXGGKGKNX-UHFFFAOYSA-N 0.000 claims abstract description 62
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims abstract description 39
- 229940117955 isoamyl acetate Drugs 0.000 claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000000787 lecithin Substances 0.000 claims abstract description 26
- 229940067606 lecithin Drugs 0.000 claims abstract description 26
- 235000010445 lecithin Nutrition 0.000 claims abstract description 26
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 25
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims abstract description 25
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 21
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- 238000002156 mixing Methods 0.000 claims abstract description 5
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- 238000000034 method Methods 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 3
- 239000004973 liquid crystal related substance Substances 0.000 abstract description 23
- 239000003937 drug carrier Substances 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 4
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- UBLAMKHIFZBBSS-UHFFFAOYSA-N 3-Methylbutyl pentanoate Chemical compound CCCCC(=O)OCCC(C)C UBLAMKHIFZBBSS-UHFFFAOYSA-N 0.000 description 2
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
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- 150000002215 flavonoids Chemical class 0.000 description 2
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- 125000003128 glycerophosphate group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 102000010637 Aquaporins Human genes 0.000 description 1
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- 229920002955 Art silk Polymers 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
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- 239000004064 cosurfactant Substances 0.000 description 1
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- 229940109262 curcumin Drugs 0.000 description 1
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- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
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- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
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Classifications
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
Abstract
The present invention is a kind of lipid carrier and preparation method thereof, application to low aqueous solubility Polyphenols drug with slow releasing function, and the lysotropic liquid crystal (lamellar phase and reversed hexagonal) being mixed to form by soybean lecithin, isoamyl acetate, PEG400, water is as the pharmaceutical carrier for loading dihydromyricetin.Wherein, isoamyl acetate and PEG400 are as mixing oil phase.The lecithin, oil phase, water mass ratio be 60:5~35:5~35, the mass ratio of oil phase isoamyl acetate and PEG400 are 2.9~6.2:A concentration of 0.7mg/g~9mg/g of 1 dihydromyricetin in the liquid crystal.The pharmaceutical carrier has preferable slow release effect and higher preparation to drugs of low aqueous solubility dihydromyricetin.
Description
Technical field
It is the invention belongs to low aqueous solubility Polyphenols pharmaceutical carrier field, more particularly to a kind of to low aqueous solubility Polyphenols drug
Lipid carrier with slow releasing function and preparation method thereof, application.
Background technology
Dihydromyricetin (DMY), a kind of low aqueous solubility flavonoids drug can be extracted from the cauline leaf of vine tea plant.It should
Drug has been proved to possess multiple biological activities and pharmacological action.Such as, anti-oxidant, antibacterial, anticancer, protect liver, anti-diabetic are lived
Property etc..However, dihydromyricetin leads to its oral bioavailability due to its lower solubility (0.2mg/g) in aqueous solution
Spend it is low and in enteron aisle lower permeability (Peff=(1.84 ± 0.37) × 10-6Cm/s) the defects of.Therefore, dihydromyricetin
Element is listed in the IVth class drug of Biopharmaceutics Classification system.In order to improve such defect, some formulation method quilts in recent years
For improving such compound solubility problem.Wherein, include mainly solid dispersions (ASD), lysotropic liquid crystal, microemulsion, ring
Dextrin, cocrystallization, the methods of hydrogel.Wherein, the lysotropic liquid crystal formed by lecithin due to its good biocompatibility and
Biodegradability is widely present in the cell membrane of human organ.Therefore, lecithin self assembly lysotropic liquid crystal formula is based on to make
Extensive concern is caused for drug delivery system.
Lecithin also known as phosphatidyl choline are a kind of natural phospholipids being present in most of organisms.It accounts for biomembrane
50% or more of lipidic matrix.Since lecithin is a kind of complete biocompatible substance, made extensively as surfactant
Used in human and animal's food, medicine, cosmetics, in the industries such as pharmacy.By lecithin, oil, the lysotropic liquid crystal that water is constituted is in recent years
To be widely studied.
Isoamyl acetate also known as isoamyl acetate, are used as solvent, and for seasoning, process hides, artificial silk, film and textile
Equal processing industry.It can be used in the daily chemical essences such as perfumed soap, synthetic detergent formula, but be mainly used in flavor formulation, it can
Allocate a variety of Fruity type essence such as banana, apple, strawberry.
PEG400 is nontoxic, nonirritant, has good water solubility, and have good mix with many organic constituents
Property, it can be used as solvent, cosolvent, O/W types emulsifier and stabilizer, for making cement suspension, emulsion, injection etc., also use
Make water-soluble ointment base and suppository base, the high solid waxy polyethylene glycol of relative molecular weight is usually used in increasing low molecular weight liquid
The viscosity of body PEG and at solidity.For the drug not readily dissolved in water, it can also make the carrier of solid dispersion, to reach solid
Disperse purpose.
Patent CN107582515A discloses a kind of pharmaceutical carrier and preparation method of lecithin aliphatic radical load dihydromyricetin.
The pharmaceutical carrier is a kind of reversed hexagonal liquid crystal, including lecithin, polyethylene glycol and water.The pharmaceutical carrier can be to dihydromyricetin
Element has preferable sustained release performance.But the structure of its liquid crystal is single, poor controllability, accumulative release rate are only 80% or so (80h).
Therefore, it is adjustable to be badly in need of a kind of structure of research and development, the high novel liquid crystal of release rate is added up to low aqueous solubility flavonoids drug
Carrier.
Invention content
In order to overcome above-mentioned deficiency, the present invention to provide a kind of lipid to low aqueous solubility Polyphenols drug with slow releasing function
The preparation of carrier and performance.Surfactant, a kind of food additives second are used as using the soybean lecithin (SL) of bio-compatible
Isoamyl valerate (IAAC) is used as oil phase, and introduces PEG400 (solubilized dihydromyricetin) thereto and constructed SL/IAAC-
PEG400/H2O pseudoternary phase diagrams.And it is brilliant to select the point of different oil contents to be used for constructing load liquid in phase region.It is aobvious with polarisation
Micro mirror, small angle X ray scattering (SAXS) means are to liquid crystalline sample oil content, physical chemistry caused by the variation of liquid crystal phase
Matter change is studied.Also, further study release in vitro performance of the dihydromyricetin in simulated intestinal fluid.This
Outside, the liquid crystalline sample for studying different structure is fitted to drug release row to release profiles with a variety of kinetic models
For influence, and then have evaluated release dynamics of the dihydromyricetin in liquid crystalline sample.
To achieve the goals above, the present invention adopts the following technical scheme that：
A kind of lipid carrier to low aqueous solubility Polyphenols drug with slow releasing function, by the raw material group of following parts by weight
At：60~65 parts of lecithin, 5-35 parts of oil phases, 5~35 parts of water；Wherein, oil phase is isoamyl acetate IAAC and polyethylene glycol
The molar ratio of PEG400, the two are 9~19：1.
The application research is found：In soybean lecithin, isoamyl acetate, PEG400 and water mixed process, it may appear that two
The translucent immobilising liquid crystalline phase (lamellar phase and reversed hexagonal) of kind and a kind of micellar solution of viscous flow.Wherein, it prepares
Lamellar phase liquid crystalline when carrying out drug release to dihydromyricetin, there is the slow release effect up to 60h, and in 60h, drug
Preparation be up to 95% or more.In contrast, although the reversed hexagonal liquid crystal and micellar solution of preparation also have compared with
Good releasing effect, but do not reach this preparation within the corresponding time.Therefore, the lamellar phase liquid crystalline that selected system is constructed is more
It is suitable as containing the pharmaceutical carrier of dihydromyricetin.
Preferably, it is composed of the following raw materials in parts by weight：62.5~65 parts of lecithin, 20-35 parts of oil phases, 20~35 parts
Water；Wherein, oil phase is isoamyl acetate IAAC and polyethylene glycol PEG400, and the molar ratio of the two is 9~19：1.
Preferably, it is composed of the following raw materials in parts by weight：60~62.5 parts of lecithin, 5-20 parts of oil phases, 5~20 parts of water；
Wherein, oil phase is isoamyl acetate (IAAC) and polyethylene glycol PEG400, and the molar ratio of the two is 9~19：1.
Preferably, the lecithin is soybean lecithin.
There is provided a kind of lipid loads to low aqueous solubility Polyphenols drug with slow releasing function for the second purpose of the application
The preparation method of body, including：
1) isoamyl acetate is uniformly mixed with PEG 400, as oil phase；
2) lecithin will be added in above-mentioned oil phase, is placed in water-bath I, after mixing, water is added, finally, in perseverance
Be balanced in tepidarium II to get.
Preferably, the temperature of the water-bath I is 60~70 DEG C.
Preferably, the temperature of the water-bath II is 37~40 DEG C
The present invention also provides a kind of carrier medicaments, including：Low aqueous solubility Polyphenols drug, any above-mentioned lipid carry
Body.
Preferably, the low aqueous solubility Polyphenols drug is dihydromyricetin, and content is 0.7mg/g~9mg/g, to carry
Body drug gross mass meter.
Low aqueous solubility Polyphenols drug can also be curcumin or apiolin in addition to dihydromyricetin in the application.
There is provided isoamyl acetates to prepare to low aqueous solubility Polyphenols drug with sustained release for the third object of the present invention
Application in the lipid carrier of effect.
Beneficial effects of the present invention
(1) present invention is prepared for the medicine with sustained release dihydromyricetin using soybean lecithin, isoamyl acetate, PEG400
Object carrier, the pharmaceutical carrier are a kind of lamellar phase liquid crystallines, belong to a kind of lysotropic liquid crystal.Double properties with solid and liquid,
It has good stability, dihydromyricetin can be made to stablize sustained release.
(2) pharmaceutical carrier prepared by the present invention can reach the release time of dihydromyricetin from the point of view of releasing effect
60h or more has slowly releasing effect.Drug dihydromyricetin can be reduced takes number.And prepared lamellar phase liquid crystalline exists
The preparation of 60h can reach 95% or more.
(3) preparation that pharmaceutical carrier prepared by the present invention passes through the structure control drug of regulation and control carrier.(such as：
Prepared reversed hexagonal liquid crystal in 60h or more to the preparation of dihydromyricetin 60% or so, lamellar phase liquid crystalline pair
The preparation of dihydromyricetin can be controlled in 90% or more).
Description of the drawings
The accompanying drawings which form a part of this application are used for providing further understanding of the present application, and the application's shows
Meaning property embodiment and its explanation do not constitute the improper restriction to the application for explaining the application.
Fig. 1 is SL/IAAC-PEG400 (19 at 37 DEG C:1,12:1,9:1)/H2O system pseudoternary phase diagrams.Illustration is phase
The polarisation picture of counter sample point in area.(all pictures balance 5h at 37 DEG C, choose central region and are shot)；
Fig. 2 is (a) SL/IAAC-PEG400 (9 at 37 DEG C:1)/H2O,(b)SL/IAAC-PEG400(12:1)/H2O,(c)
SL/IAAC-PEG400(19:1)/H2The SAXS spectrograms of O system liquid crystalline samples.
Fig. 3 is lecithin (SL), and isoamyl acetate (IAAC), PEG400, DMY carry medicine liquid crystalline sample A3 (DMY-LLC
(A3)) ATR-FTIR spectrograms.
Fig. 4 is the standard curve of dihydromyricetin, and illustration is the absorption spectrum of dihydromyricetin.
Fig. 5 is at 37 DEG C, and dihydromyricetin is in sample (a) A1, A2, A3, (b) B1, B2, B3, (c) C1, C2, releasing in C3
Put curve.Illustration is each polarisation picture for carrying medicine sample.
Specific implementation mode
It is noted that following detailed description is all illustrative, it is intended to provide further instruction to the application.Unless another
It indicates, all technical and scientific terms used herein has usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
Embodiment 1
1. experimental section
1.1 instruments and reagent
The drafting of 1.2 phasors
With the molar ratio of isoamyl acetate and PEG 400 for 9：1,12：1,19：1 mixed liquor is oil phase, by oil phase and ovum
Phosphatide mass ratio is from 10:0 to 0:10 variation, which weighs, to be placed in band plug colorimetric cylinder, and colorimetric cylinder is placed in 60-70 DEG C of water
It is sufficiently stirred in bath, the gradient for then being increased 2w% with water content is added dropwise distilled water and mixed well.Mixing after mixing
Object is placed in 37 DEG C of water bath with thermostatic control and balances, and phenomenon is observed and recorded after balance.Close to when balance being appropriately extended when phase boundray
Between.The color presented by estimating sample, transparency, viscosity, hardness etc. tentatively judge phase boundray.The liquid crystalline sample of configuration is being surveyed
Need at least to balance one week before examination to ensure to be formed complete liquid crystal structure.
1.3 carry the preparation of medicine liquid crystalline sample
It accurately weighs dihydromyricetin 0.1g to be added in the color-comparison tube for filling 400 solution of 1.0g PEG, whirlpool is mixed
Even 10 minutes.It is sealed to be placed in 37 DEG C of water-baths and is protected from light stirring for 24 hours, dihydromyricetin is made fully to dissolve.In SL/IAAC-
PEG400(19:1)/H2O,SL/IAAC-PEG 400(12:1)/H2O,SL/IAAC-PEG 400(9:1)/H2It is chosen in O systems
The sample spot of different oil contents.First, the content of fixation surface activating agent is 60wt%, prepares the different sample of oil/water.Wherein
The mass percent of each component is respectively 60/35/5,60/20/20,60/5/35.All samples mix after 50 DEG C of heating water baths
It is even, it is centrifuged off bubble.7 days are stood in 37 DEG C of water-baths.Load medicine sample is set to reach equilibrium state.All oil phases are using containing
The PEG400 solution of DMY.The title and composition of sample are listed in Table 1 below.
The name of 1. each sample of table and composition
The measurement of 1.4 polarization textures
It takes a small amount of liquid crystalline sample to be coated on glass slide, puts coverslip and carry out tabletting and avoid the remnants of bubble as possible, so
Afterwards sample strip is placed in 37 DEG C of environment to balance is influenced with reducing caused by squeezing sample.Sample after balance is good is aobvious
It is observed on the objective table of micro mirror.Polarisation photo is obtained by CCD camera and corresponding computer software.
1.5 small angle X ray scatterings (SAXS)
The spacing of lattice of liquid crystalline sample is measured at 37 ± 0.1 DEG C with SAXSess high throughput small angle X ray scattering instrument,
Light source of the copper target as X-ray, wavelength 0.154nm, operation voltage and current are respectively set as 40kV and 50mA, sample to inspection
The distance for surveying device is 264.5mm.Experimentation need to carry out under vacuum.It is determined by the ratio of the relative position of SAXS scattering peaks
The phase type of lysotropic liquid crystal.
1.6 infrared spectrums (ATR-FTIR)
Liquid crystal group is measured using AlphaT types Fourier Transform Infrared Spectrometer (Bruker Optik GmbH, Germany)
The chemical interaction of functional group after dividing variation and introducing.Wave-length coverage is set as 4000cm-1-400cm-1Spectra resolution rate is set
It is set to 4cm-1, frequency is set as 50, is scanned at room temperature to sample.The liquid crystalline sample of soya bean size is equably coated in prism crystalline substance
On body.Every time after test, with ethyl alcohol and distilled water cleaning down crystal.
1.7 extracorporeal releasing experiment
1.7.1 the drafting of dihydromyricetin standard curve
30% ethanol solution of a certain concentration containing dihydromyricetin is prepared, with ultraviolet specrophotometer in 600-220nm models
Interior carry out spectral scan is enclosed, absorbance-wavelength curve is obtained, determines that the maximum absorption band of dihydromyricetin is 290nm.Using dilute
A series of dihydromyricetin ethanol solution of various concentrations is prepared in interpretation of the law, its absorbance is measured at the long 290nm of standing wave, is drawn and is inhaled
Luminosity-concentration standard curve.Dihydromyricetin standard curve is obtained by fitting a straight line.
1.7.2 dihydromyricetin release in vitro research
Extracorporeal releasing experiments of the DMY in liquid crystal is carried out at 37 DEG C of physiological temp using the method for dialysis.With phosphate
Buffer solution (pH=6.8) simulates small intestine condition.It takes 1.0g to carry liquid crystalline substance in bag filter (1000D), bag filter is immersed in Sheng
In the beaker for having 50mL PBS buffer solution, it is stirred at 100 rpm with constant speed using magneton.Every a timing
Between, 3.0mL dissolution mediums are taken out, while the fresh dissolution medium of same volume being added into beaker.Pass through uv-spectrophotometric
Meter (X-3, Shanghai Yuan Xi Instrument Ltd.) measures the absorbance of dihydromyricetin under the wavelength of 292nm and then passes through calculating
It obtains the burst size of drug and then calculates preparation.
Total amount × 100% of drug in drug accumulation release rate=drug Cumulative release amount/carrier
2. results and discussion
2.1. phase behavior
The application is in SL/IAAC/H2Cosurfactant PEG400 is introduced in O systems, has studied SL/ at 37 DEG C
IAAC-PEG400/H2The pseudoternary phase diagram of O systems.As shown in Figure 1.Occur a softness in each system, has
The bright brown color of viscoplasticity leads to immobilising region (II) and the region (I) of sticky oblique flow.It is added with PEG400
Ratio increases, and flow region (I) area becomes larger.It is larger compared with occurring a hardness under low water content in each phasor, it does not glue
Irregular grain is presented in thick yellow-brown solid region (III), this region polarisation.This may under compared with low water content (< 10%)
The hardening of the glycerophosphate chain of lecithin is related.With PEG400 ratios increase, this zones vanishes this may be due to
PEG400 is dissolved in the hydrophilic head base portion position of lecithin, reduces the hardening of glycerophosphate chain, its mobility is caused to enhance.When
When fixation surface active agent content is 60% (Wt), with the reduction of oil/water ratio, mosaic line is presented in polarization texture respectively
Reason, oil stripping texture, random fuzzy texture, no polarization texture.The application is tentatively sentenced by polarization texture and sample appearance state
Disconnected, as oil/water ratio increases, aggregation shows lamellar phase, hexagonal phase and isotropism micellar solution respectively.Oil contains
The increase of amount leads to the transformation of non-laminar phase, this may be since the hydrophobic tail that oil phase isoamyl acetate is filled into lecithin is led
It causes its hydrophobic tail volume to become larger, increase CPP (critical Packing parameter) values thus lecithin/aqueous systems negative cruvature is caused to increase
It is induced to form reverse phase hexagonal phase.The application selects to select the sample spot of different oil contents (5%, 20%, 35%) to make in phasor
Dihydromyricetin, which is contained, for pharmaceutical carrier carries out next step research.
2.2. the microstructure of liquid crystalline substance is carried
In order to accurately measure the phase of liquid crystalline sample, liquid crystalline sample is characterized using SAXS.Liquid crystalline sample at 37 DEG C
SAXS spectrograms it is as shown in Figure 2.It can be seen that from the scattering curve of Fig. 2.Liquid crystal sample A1, B1, C1 show level-one, two level
Scattering peak.Wherein corresponding Scattering of Vector (q) ratio is q1:Q2=1:2, corresponding Miller indices are 100,200, correspond to layer
Shape phase.This shows that aggregation forms lamellar phase liquid crystalline when oil content is 5% (wt) in system.When oil content is increased to
When 20% (wt), sample C2 shows three scattering peaks.Corresponding Scattering of Vector (q) ratio of these three scattering peaks isCorresponding Miller indices are 100,110,210, this belongs to typical hexagonal phase.Sample A2, B2 are presented
Go out four scattering peaks, except corresponding 100,110,210 three peaks, has also appeared a second-order scattering miscellaneous peak, this table
The bright liquid crystalline sample belongs to mixed phase.There is likely to be other knots in addition to main hexagonal phase structure for sample interior network structure
Structure.As can be seen from the figure gradually becoming as the ratio of isoamyl acetate/PEG400 gradually rises corresponding second-order scattering peak
It obtains obviously.This may be caused by being dissolved in surfactant hydrophobic tail portion due to the isoamyl acetate of a large amount of short chain.Due to
The water content of liquid crystalline sample A2, B2, C2 are only 20wt%.Thus calculated critical Packing parameter (CPP) is more than 1, therefore, this
Application concludes that it is reversed hexagonal to be formed by main phase.When the oil content in system is increased to 35%, sample C1, C2, C3
Only there is a unconspicuous scattering peak, according to the flowing viscous pasty state for the sample observed from system phase diagram before, therefore,
The application infers that aggregation forms vermiculate glues.
2.3 carry the infrared property representation of medicine sample
Fig. 3 is lecithin (SL), and isoamyl acetate (IAAC), PEG400, DMY carry medicine liquid crystalline sample A3 (DMY-LLC
(A3)) ATR-FTIR spectrograms.Dihydromyricetin (DMY), in 3260cm-1(phenolic hydroxyl group O-H stretching vibrations), 1640cm-1(C=
O, C=C stretching vibrations), 1163cm-1(aromatic series C-O stretching vibrations), 1483cm-1It is shown at (alkene C-H bending vibrations)
Characteristic peak.Lecithin is in 2927cm-1、2855cm-1(-CH2Stretching vibration), 1736cm-1(symmetrical C=O stretching vibrations),
1230cm-1(PO4Antisymmetry telescopic band) at show its characteristic peak.PEG400 is in 3450cm-1(- OH stretching vibrations), 2870cm-1(-CH2Be saturated stretching vibration), 1113cm-1(C-O-C stretching vibrations) shows characteristic peak.Isoamyl acetate (IAAC) exists
2960cm-1(-CH2Be saturated stretching vibration), 1736cm-1(symmetrical C=O stretching vibrations), 1239cm-1(C-O stretching vibrations),
1366cm-1(-CH3Deformation vibration) show its characteristic peak.When DMY is encapsulated into liquid crystalline sample, peak position and shape with
Lecithin is in 2927cm-1、2855cm-1、1740cm-1、1230cm-1The peak position at place and shape are similar.Meanwhile DMY-LLC (A3)
Peak position respectively by the 3260cm of DMY-1Red shift is to 3398cm-1, by 1640cm-1Red shift is to 1740cm-1, show drug DMY with
There is interactions between carrier.At the same time, DMY is in 3575cm-1、1163cm-1Place, PEG400 is in 1113cm-1(C-O-C
Stretching vibration) at characteristic peak disappear, show to be interacted between the phenolic hydroxyl group of DMY and phosphatide or PEG400, very may be used
Can pass through interaction of hydrogen bond.Also, the characteristic peaks of DMY weaken, this may be since DMY is encapsulated in LCD vector
Portion, therefore, their characteristic peak is by " hiding ".
The release in vitro research of 2.4 dihydromyricetins
Fig. 4 is the standard curve of dihydromyricetin, and illustration is the absorption spectrum of dihydromyricetin.From the purple of dihydromyricetin
Outer absorption spectrum can be seen that a length of 292nm of maximum absorption wave of dihydromyricetin, and the dihydromyricetin for measuring various concentration exists
The absorbance of maximum absorption wave strong point, the standard absorption curve that dihydromyricetin is obtained by fitting are：
Abs=0.00736+21.1223C (mg/mL) R2=0.9997
Wherein Abs is absorbance of the dihydromyricetin at 292nm, and C is the concentration of dihydromyricetin.
At 2.37 DEG C of table, DMY sample release dynamics mathematical models and fitting parameter are contained.
aN is release index, for indicating different release processes.
Fig. 5 illustrates the In-vitro release curves for carrying medicine sample in simulated intestinal fluid.As shown in Fig. 5 (a), wherein dihydro poplar
Release of the syphilis in ethanol solution is tested as a contrast.By dihydromyricetin it can be seen from release profiles in ethanol solution
Release reach accumulative release platform in 500min.Cumulative maximum release rate reaches 92%.And drug releasing in liquid crystalline sample
It puts rate to be substantially reduced, it is about 4000min to reach the accumulative release platform time.With good slowly releasing effect.It can be seen by Fig. 5
Go out, under the ratio different situations of IAAC/PEG400, when oil content is 5%, the accumulative release rate highest of drug, and release
It is most fast to put rate.Its preparation is respectively 80% (A1), 95% (B1), 99% (C1).For SL/IAAC-PEG400 (9:
1)/H2O systems, release profiles go out apparent difference with the different manifestations of oil content, and as shown in Fig. 5 (a), wherein drug is released
Put rate A1>A3>A2.And preparation is 80%A1,53%A3,41%A2.By sample polarisation photo and small-angle scattering
Data are it is found that A1 forms lamellar phase liquid crystalline, and A3 is reverse phase vermiculate glues, and A2 is mixed phase, wherein mainly reversed hexagonal
Liquid crystal.The difference of preparation and rate of release may be due to caused by internal structure difference.Likewise, for different
The liquid crystal system of I/P, such as Fig. 5 (b), shown in 5 (c), rate of release of the lamellar phase liquid crystalline sample for the drug DMY of poorly water-soluble
It is most fast, and preparation highest.B2 and B3, C2 and C3 are for drug unlike release profiles shown in Fig. 5 (a)
Rate of release and preparation are similar.This may be since reversed hexagonal liquid crystal and anti-vermiform liquid crystal have similar inside
Structure all has cylindrical aquaporin, unlike reversed hexagonal liquid crystal have a well-regulated arrangement, and vermiculate glues be by
The cylindrical aggregation of bending mutually winds and is formed.And the ratio of viscosities lamellar phase of reversed hexagonal and vermiculate glues is big, because
This its structure is not easy to be corroded by extraneous solvent.Therefore, the preparation of drug is relatively low.It is constructed in order to be better understood from
To the release behavior of drug, the application is fitted release profiles using different Dynamic model of release aggregation, quasi-
The results are shown in Table 2 for conjunction, is found by fitting result, compared with other kinetic models, First order dynamic model is to all samples
The degree of fitting highest of product, fitting correlation coefficient (R2>0.99), this illustrates the release in vitro of dihydromyricetin mainly by concentration
Diffusion control.
3. conclusion
The application uses biocompatibility system SL/IAAC-PEG400/H2O has constructed aggregation, and to contain low aqueous solubility more
Phenols drug dihydromyricetin.Find that constructed its internal structure of aggregation is respectively lamellar phase by polarisation characterization, anti-six
Angle phase, anti-vermiculate glues, this is also confirmed by small angle X ray scattering characterization.To carrying the red of medicine liquid crystalline sample and its constituent
It is outer to show to be likely that there are interaction of hydrogen bond between drug and aggregation, and drug is contained inside aggregation.
The release in vitro of drug shows that carrier has good slow release effect to drug.And constructed lamellar phase liquid crystalline is to drug
With higher preparation.Release in vitro of the dihydromyricetin in constructed aggregation meets first-order release power
It learns, illustrates its release mainly by concentration diffusion control.
The foregoing is merely the preferred embodiments of the application, are not intended to limit this application, for the skill of this field
For art personnel, the application can have various modifications and variations.Within the spirit and principles of this application, any made by repair
Change, equivalent replacement, improvement etc., should be included within the protection domain of the application.
Claims (10)
1. a kind of lipid carrier to low aqueous solubility Polyphenols drug with slow releasing function, which is characterized in that by following parts by weight
Raw material composition：60~65 parts of lecithin, 5-35 parts of oil phases, 5~35 parts of water；Wherein, oil phase is isoamyl acetate IAAC and gathers
The molar ratio of ethylene glycol PEG400, the two are 9~19：1.
2. lipid carrier as described in claim 1, which is characterized in that be composed of the following raw materials in parts by weight：62.5~65 parts
Lecithin, 20-35 part oil phase, 20~35 parts of water；Wherein, oil phase is isoamyl acetate IAAC and polyethylene glycol PEG400, the two
Molar ratio be 9~19：1.
3. lipid carrier as described in claim 1, which is characterized in that be composed of the following raw materials in parts by weight：60~62.5 parts
Lecithin, 5-20 part oil phase, 5~20 parts of water；Wherein, oil phase is isoamyl acetate (IAAC) and polyethylene glycol PEG400, the two
Molar ratio be 9~19：1.
4. lipid carrier as described in any one of claims 1-3, which is characterized in that the lecithin is soybean lecithin.
5. a kind of preparation method to lipid carrier of the low aqueous solubility Polyphenols drug with slow releasing function, which is characterized in that packet
It includes：
1) isoamyl acetate is uniformly mixed with PEG 400, as oil phase；
2) lecithin will be added in above-mentioned oil phase, is placed in water-bath I, after mixing, water is added, finally, in thermostatted water
Bath II in be balanced to get.
6. method as claimed in claim 5, which is characterized in that the temperature of the water-bath I is 60~70 DEG C.
7. method as claimed in claim 5, which is characterized in that the temperature of the water-bath II is 37~40 DEG C.
8. a kind of carrier medicament, which is characterized in that including：Low aqueous solubility Polyphenols drug, claim 1-4 any one of them
Lipid carrier.
9. carrier medicament as claimed in claim 8, which is characterized in that the low aqueous solubility Polyphenols drug is dihydromyricetin
Element, content is 0.7mg/g~9mg/g, in terms of carrier medicament gross mass.
10. application of the isoamyl acetate in preparing the lipid carrier that there is slow releasing function to low aqueous solubility Polyphenols drug.
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| US20090130029A1 (en) * | 2007-11-21 | 2009-05-21 | Foamix Ltd. | Glycerol ethers vehicle and pharmaceutical compositions thereof |
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