CN108478550A - A kind of pharmaceutical carrier and preparation method and application based on alkyl glycosides lysotropic liquid crystal - Google Patents
A kind of pharmaceutical carrier and preparation method and application based on alkyl glycosides lysotropic liquid crystal Download PDFInfo
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- CN108478550A CN108478550A CN201810236053.1A CN201810236053A CN108478550A CN 108478550 A CN108478550 A CN 108478550A CN 201810236053 A CN201810236053 A CN 201810236053A CN 108478550 A CN108478550 A CN 108478550A
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- pharmaceutical carrier
- curcumin
- chitosan
- water
- liquid crystal
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- 239000004973 liquid crystal related substance Substances 0.000 title claims abstract description 50
- 239000003937 drug carrier Substances 0.000 title claims abstract description 43
- 229930182470 glycoside Natural products 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- -1 alkyl glycosides Chemical class 0.000 title claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229920001661 Chitosan Polymers 0.000 claims abstract description 44
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims abstract description 27
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims abstract description 27
- 229940093471 ethyl oleate Drugs 0.000 claims abstract description 27
- 239000004094 surface-active agent Substances 0.000 claims abstract description 27
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000002156 mixing Methods 0.000 claims abstract description 23
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 22
- 229930182478 glucoside Natural products 0.000 claims abstract description 21
- 150000008131 glucosides Chemical class 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 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 claims description 130
- 239000003814 drug Substances 0.000 claims description 71
- 235000012754 curcumin Nutrition 0.000 claims description 66
- 239000004148 curcumin Substances 0.000 claims description 65
- 229940109262 curcumin Drugs 0.000 claims description 65
- 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 claims description 65
- 238000003756 stirring Methods 0.000 claims description 11
- 238000005119 centrifugation Methods 0.000 claims description 4
- 230000006196 deacetylation Effects 0.000 claims description 3
- 238000003381 deacetylation reaction Methods 0.000 claims description 3
- 150000002338 glycosides Chemical class 0.000 claims description 2
- 230000004044 response Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 241000234314 Zingiber Species 0.000 abstract description 5
- 235000006886 Zingiber officinale Nutrition 0.000 abstract description 5
- 235000008397 ginger Nutrition 0.000 abstract description 5
- 239000000523 sample Substances 0.000 description 60
- 229940079593 drug Drugs 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000012153 distilled water Substances 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- 230000003578 releasing effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000000235 small-angle X-ray scattering Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- KKAJSJJFBSOMGS-UHFFFAOYSA-N 3,6-diamino-10-methylacridinium chloride Chemical compound [Cl-].C1=C(N)C=C2[N+](C)=C(C=C(N)C=C3)C3=CC2=C1 KKAJSJJFBSOMGS-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 244000163122 Curcuma domestica Species 0.000 description 2
- 235000003392 Curcuma domestica Nutrition 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000003373 curcuma longa Nutrition 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 235000013976 turmeric Nutrition 0.000 description 2
- 240000002791 Brassica napus Species 0.000 description 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- JYTVKRNTTALBBZ-UHFFFAOYSA-N bis demethoxycurcumin Natural products C1=CC(O)=CC=C1C=CC(=O)CC(=O)C=CC1=CC=CC(O)=C1 JYTVKRNTTALBBZ-UHFFFAOYSA-N 0.000 description 1
- PREBVFJICNPEKM-YDWXAUTNSA-N bisdemethoxycurcumin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)CC(=O)\C=C\C1=CC=C(O)C=C1 PREBVFJICNPEKM-YDWXAUTNSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- YXAKCQIIROBKOP-UHFFFAOYSA-N di-p-hydroxycinnamoylmethane Natural products C=1C=C(O)C=CC=1C=CC(=O)C=C(O)C=CC1=CC=C(O)C=C1 YXAKCQIIROBKOP-UHFFFAOYSA-N 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- GEAWFZNTIFJMHR-UHFFFAOYSA-N hepta-1,6-diene Chemical compound C=CCCCC=C GEAWFZNTIFJMHR-UHFFFAOYSA-N 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000002535 lyotropic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Toxicology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Inorganic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of pharmaceutical carrier and preparation method and application based on alkyl glycosides lysotropic liquid crystal, pharmaceutical carrier are mixed to form layered liquid crystal by surfactant, ethyl oleate and water, and the mass percent of surfactant, ethyl oleate and water is 40~81:5.7~21.4:0~49.5, wherein surfactant is the mixture of dodecyl mixing glucosides and chitosan, and the mass ratio of the dodecyl mixing glucosides and chitosan is 9:1~7:3, which has preferable slow release effect to ginger color, and has pH responses.
Description
Technical field
The present invention relates to a kind of pharmaceutical carrier and preparation method and application based on alkyl glycosides lysotropic liquid crystal.
Background technology
Curcumin is a kind of draft polyphenol compound, is that extraction extraction obtains from famous spice turmeric.Have
Various biological characteristic pharmacological activity：Anti-oxidant, anti-inflammatory, immunological regulation is antimicrobial, anticancer etc..But since curcumin exists
Under light and heat condition, pH is unstable, solubility in water it is low it is fast with accretion rate etc. cause the availability of curcumin low, limit
It is applied.In order to overcome these disadvantages of curcumin, frequently with there are two ways to：First, being changed to curcumin by chemical reaction
Property, wherein common method has 1. pairs of phenyl ring to modify：Phenolic hydroxyl group is at ester or at ether etc.；2. pair 1,6 heptadiene, 3,5 diketone connects
Double bond present in structure is modified as restored double bond, modified methylene, the condensation etc. for ketone group in the modification of chain link
Method, but this method operating process of chemical modification is complicated, limits its application；Second is that constructing pharmaceutical carrier, drug is carried out
Encapsulating can not only improve the solubility of drug, moreover it is possible to play certain sustained release to the release of drug due to encapsulating this means
Effect protects drug not corroded by complicated external environment.And the original structure of drug can also be kept not to be destroyed, closely
Nian Lai, a variety of encapsulating methods are widely used, including：Lysotropic liquid crystal, microemulsion, liposome etc..
Wherein lysotropic liquid crystal is that transparent, Thermodynamically stable is formed by when surfactant reaches a certain concentration, no
The system of flowing, a kind of structure unordered in microcosmic upper long-range order short distance.According to the difference of its microstructure, lysotropic liquid crystal
Lamellar phase, cubic phase, hexagonal phase can be divided into.Layered liquid crystal is due to the bilayer structure similar to cell membrane, as medicine
Object carrier has preferable application prospect, and compound soluble easily in water can be dissolved in its hydrophilic area, hydrophobic region can be with
Hydrophobic compound is dissolved, therefore lysotropic liquid crystal can both contain hydrophobic drug, hydrophilic drug can also be contained,
Increase the solubility of drug, realizes the slow release to drug.So while its outstanding load medicine and Release Performance and obtain wide
General concern.
Alkyl glycosides is that have the hydroxyl after the generation aldol condensation of glucose to occur under the conditions of acid catalyzed with fatty alcohol
Chemical reaction, sloughs the mix products after a molecular water.It is degradable with preferable biocompatibility, for skin irritatin
Property it is low, to temperature no dependence and for synthesize raw material (such as：Starch and rapeseed) it is also natural reproducible, it is one
The good biocompatible surfactants of kind.Its bio-compatible will generally be considered as pharmaceutical carrier by constructing lysotropic liquid crystal
Property, it is expected that the green low toxicity pharmaceutical carrier harmless to organism is constructed, so the selected amphiphilic constructed selected by lysotropic liquid crystal
Molecule will have the characteristics that：Biodegradable, biocompatibility and nontoxicity etc., so the amphiphilic of this green of alkyl glycosides
Molecule is a kind of good raw material for constructing pharmaceutical carrier.However, so far, pharmaceutical carrier is constructed about using alkyl glycosides
Relevant report it is few.
Invention content
In order to solve the deficiencies in the prior art, an object of the present invention is to provide a kind of based on alkyl glycosides lysotropic liquid crystal
Pharmaceutical carrier, the pharmaceutical carrier to ginger color have preferable slow release effect, and have pH responses.
To achieve the goals above, the technical scheme is that：
A kind of pharmaceutical carrier based on alkyl glycosides lysotropic liquid crystal, is mixed to form by surfactant, ethyl oleate and water
The mass percent of layered liquid crystal, surfactant, ethyl oleate and water is 40~81:5.7~21.4:0~49.5, wherein
Water is not 0, and surfactant is the mixture of dodecyl mixing glucosides and chitosan, the dodecyl mixing glucosides and shell
The mass ratio of glycan is 9:1~7:3.
Ethyl oleate is added using dodecyl mixing glucosides as surfactant first by the present invention and water is prepared for stratiform
Liquid crystal, however, with the layered liquid crystal to curcumin carry out drug release when discovery, only using dodecyl mixing glucosides as
The drug release rate for the layered liquid crystal that surfactant obtains is too fast, and does not have pH responses.It is thus of the invention to dodecane
Base mixing glucosides is added to chitosan, reduces the drug release rate of curcumin, and the drug release tool of curcumin in fact
There are pH responses.
The second object of the present invention is to provide a kind of preparation method of said medicine carrier, by dodecyl mixing glucosides,
Chitosan, ethyl oleate and water are placed in 60~70 DEG C after mixing, and bubble removing is gone to can be obtained pharmaceutical carrier.
The third object of the present invention is to provide a kind of said medicine carrier answering in load curcumin prepares carrier medicament
With.
The fourth object of the present invention is to provide a kind of carrier medicament, the carrier loaded curcumin of said medicine.
The fifth object of the present invention is to provide a kind of preparation method of above-mentioned carrier medicament, and curcumin is added to above-mentioned medicine
Stirring removes bubble removing, stands 6~8 days and can be obtained carrier medicine until curcumin is completely dissolved in 37 ± 0.5 DEG C in object carrier
Object.
Beneficial effects of the present invention are：
1. the present invention is prepared for layered liquid crystal using dodecyl mixing glucosides, ethyl oleate, water, and by adding shell
Layered liquid crystal prepared by glycan rear surface has preferable slow release effect to curcumin.
2. pharmaceutical carrier prepared by the present invention has pH responses to the releasing effect of curcumin.
3. pharmaceutical carrier prepared by the present invention has response to the burst size of curcumin to temperature, when the temperature increases ginger
The cumulative release amount of flavine increases.
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 three-phase diagram, and (a) is APG/EtOL/H2O systems (b) are APG/WCS (9:1)/EtOL/H2O systems；
Fig. 2 is BL0And BL1SAXS spectrograms；
Fig. 3 is BL0And BL1Temperature scanning figure；
Fig. 4 is BL0And BL1Shear viscosity with shear rate variation relation figure；
Fig. 5 is BL0And BL1The relationship of storage modulus loss modulus and compound viscosity and frequency；
Fig. 6 is curcumin in ethanol solution, sample L0, sample L1In In-vitro release curves；
Fig. 7 be different pH under curcumin different samples In-vitro release curves；
Fig. 8 is curcumin under different temperatures in L1In In-vitro release curves；
Fig. 9 is In-vitro release curves of the curcumin in different samples, wherein a is the molten cause layer that different oil contents are constructed
Shape liquid crystalline sample, b are the lyotropic lamellar phase sample that different water contents are constructed.
Specific implementation mode
It is noted that described further below be all exemplary, 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.
It should be noted that term used herein above is merely to describe specific implementation mode, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singulative
It is also intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or combination thereof.
Dodecyl mixing glucosides described herein is the mixture of dodecyl list glycosides and dodecyl polyglucosides, can be with
It is abbreviated as C12Gn(n is the non-integer more than 1), is abbreviated as APG in this application.
As background technology is introduced, does not utilize alkyl glycosides to construct the record of pharmaceutical carrier in the prior art, be
Solution technical problem as above, present applicant proposes a kind of pharmaceutical carrier and preparation method based on alkyl glycosides lysotropic liquid crystal
And application.
A kind of exemplary embodiment of the application provides a kind of pharmaceutical carrier based on alkyl glycosides lysotropic liquid crystal, by
Surfactant, ethyl oleate and water are mixed to form layered liquid crystal, and the mass percent of surfactant, ethyl oleate and water is
40~81:5.7~21.4:0~49.5, wherein water is not 0, and surfactant is dodecyl mixing glucosides and chitosan
The mass ratio of mixture, the dodecyl mixing glucosides and chitosan is 9:1~7:3.
Ethyl oleate is added using dodecyl mixing glucosides as surfactant first by the application and water is prepared for stratiform
Liquid crystal, however, with the layered liquid crystal to curcumin carry out drug release when discovery, only using dodecyl mixing glucosides as
The drug release rate for the layered liquid crystal that surfactant obtains is too fast, and does not have pH responses.Thus the application is to dodecane
Base mixing glucosides is added to chitosan, reduces the drug release rate of curcumin, and the drug release tool of curcumin in fact
There are pH responses.
Preferably, the mass ratio of dodecyl mixing glucosides and chitosan is 9:1.
Preferably, the mass ratio of surfactant, ethyl oleate and water is 63:7:30.
Preferably, the chitosan is water soluble chitosan, and deacetylation is more than 85%.The size of the chitosan is 60
Mesh.
The another embodiment of the application provides a kind of preparation method of said medicine carrier, dodecyl is mixed
It closes glucosides, chitosan, ethyl oleate and water and is placed in 60~70 DEG C after mixing, bubble removing is gone to can be obtained pharmaceutical carrier.
Preferably, bubble removing is removed by the way of centrifugation.
The application the third embodiment there is provided a kind of said medicine carrier load curcumin prepare carrier medicament
In application.
Embodiment there is provided a kind of carrier medicament, the carrier loaded curcumins of said medicine for the 4th kind of the application.
Preferably, curcumin is the 1 × 10 of pharmaceutical carrier quality-3%~2 × 10-3%.
Curcumin is added embodiment there is provided a kind of preparation method of above-mentioned carrier medicament for the 5th kind of the application
To stirring removes bubble removing, standing 6~8 days can obtain until curcumin is completely dissolved in 37 ± 0.5 DEG C in above-mentioned pharmaceutical carrier
Obtain carrier medicament.
Preferably, bubble removing is removed by the way of centrifugation.
Preferably, include the preparation method of said medicine carrier.
In order to enable those skilled in the art can clearly understand the technical solution of the application, below with reference to tool
The technical solution of the application is described in detail in the embodiment of body.
Material：Dodecyl mixing glucosides (APG) is provided by Chinese detergents and cosmetic institute, ethyl oleate, curcumin, ethyl alcohol,
Disodium hydrogen phosphate, sodium dihydrogen phosphate are bought from Sinopharm Chemical Reagent Co., Ltd., water soluble chitosan (WCS, 60 mesh,
Deacetylation>85%) it is purchased from Jinan Haidebei Marine Organism Engineering Co., Ltd., all drugs are not further processed using preceding,
Water is redistilled water.
Phasor is drawn
According to surfactant (APG, APG:WCS=9:1) with the mass ratio of oil phase 10:0 changes to 0:10 accurately weigh
Secondly surfactant sequentially adds oil phase ethyl oleate, by sample with colorimetric cylinder according in the accurate colorimetric cylinder of its ratio
It is placed in 60-70 DEG C of water-bath and stirs and evenly mixs, redistilled water is then added dropwise dropwise into colorimetric cylinder, control rate of addition
Each dripping quantity (2% interval increases), stirs and evenly mixs, bubble is driven in centrifugation away, is finally placed in 37 DEG C of water-bath and is balanced, and is observed
Phenomenon needs the equilibration time for extending aggregation when close to phase boundray.The phasor of acquisition is as shown in Figure 1.
Following embodiment, which is carried out, according to phasor prepares sample.
Embodiment 1
Alkyl glycosides 1.26g is weighed respectively, and ethyl oleate 0.14g is placed in clean colorimetric cylinder, is put into magneton, is then added
Distilled water 0.6g use magnetic stirrer, control 60~70 DEG C of bath temperature, be uniformly mixed.Using centrifuge,
The bubble removed in sample is denoted as BL to obtain the blank pharmaceutical carrier of chitosan-containing0。
Embodiment 2
Alkyl glycosides 1.134g, chitosan 0.126g are weighed respectively, and ethyl oleate 0.14g is placed in clean colorimetric cylinder, puts
Enter magneton, the distilled water 0.6g being then added uses magnetic stirrer, controls 60~70 DEG C of bath temperature, is uniformly mixed.
Using centrifuge, the bubble removed in sample is denoted as BL to obtain the blank pharmaceutical carrier of chitosan-containing1。
Embodiment 3
Alkyl glycosides 1.26g is weighed respectively, and ethyl oleate 0.14g is placed in clean colorimetric cylinder, is put into magneton, is then added
Distilled water 0.6g use magnetic stirrer, control 60~70 DEG C of bath temperature, be uniformly mixed.Using centrifuge,
The bubble in sample is removed, to obtain the blank pharmaceutical carrier of chitosan-containing, bisdemethoxycurcumin .4mg is weighed and blank liquid crystal is added
In, constant temperature stirring is carried out at 37 DEG C until complete drug dissolution, is centrifuged off bubble.Prepared sample is balanced at room temperature
One week, that is, stable carrier medicament sample is obtained, L is denoted as0。
Embodiment 4
Alkyl glycosides 1.134g, chitosan 0.126g are weighed respectively, and ethyl oleate 0.14g is placed in clean colorimetric cylinder, puts
Enter magneton, the distilled water 0.6g being then added uses magnetic stirrer, controls 60~70 DEG C of bath temperature, is uniformly mixed.
Using centrifuge, the bubble removed in sample weighs curcumin to obtain the blank pharmaceutical carrier of chitosan-containing
3.4mg is added in blank liquid crystal, and constant temperature stirring is carried out at 37 DEG C until complete drug dissolution, is centrifuged off bubble.It will be made
Standby sample balances one week at room temperature, that is, obtains stable carrier medicament sample, be denoted as L1。
Embodiment 5
Alkyl glycosides 1.008g, chitosan 0.112g are weighed respectively, and ethyl oleate 0.28g is placed in clean colorimetric cylinder, puts
Enter magneton, the distilled water 0.6g being then added uses magnetic stirrer, controls 60~70 DEG C of bath temperature, is uniformly mixed.
Using centrifuge, the bubble removed in sample weighs curcumin to obtain the blank pharmaceutical carrier of chitosan-containing
3.4mg is added in blank liquid crystal, and constant temperature stirring is carried out at 37 DEG C until complete drug dissolution, is centrifuged off bubble.It will be made
Standby sample balances one week at room temperature, that is, obtains stable carrier medicament sample, be denoted as L2。
Embodiment 6
Alkyl glycosides 0.882g, chitosan 0.098g are weighed respectively, and ethyl oleate 0.42g is placed in clean colorimetric cylinder, puts
Enter magneton, the distilled water 0.6g being then added uses magnetic stirrer, controls 60~70 DEG C of bath temperature, is uniformly mixed.
Using centrifuge, the bubble removed in sample weighs curcumin to obtain the blank pharmaceutical carrier of chitosan-containing
3.4mg is added in blank liquid crystal, and constant temperature stirring is carried out at 37 DEG C until complete drug dissolution, is centrifuged off bubble.It will be made
Standby sample balances one week at room temperature, that is, obtains stable carrier medicament sample, be denoted as L3。
Embodiment 7
Alkyl glycosides 1.053g, chitosan 0.117g are weighed respectively, and ethyl oleate 0.13g is placed in clean colorimetric cylinder, puts
Enter magneton, the distilled water 0.7g being then added uses magnetic stirrer, controls 60~70 DEG C of bath temperature, is uniformly mixed.
Using centrifuge, the bubble removed in sample weighs curcumin to obtain the blank pharmaceutical carrier of chitosan-containing
3.4mg is added in blank liquid crystal, and constant temperature stirring is carried out at 37 DEG C until complete drug dissolution, is centrifuged off bubble.It will be made
Standby sample balances one week at room temperature, that is, obtains stable carrier medicament sample, be denoted as L4。
Embodiment 8
Alkyl glycosides 0.972g, chitosan 0.108g are weighed respectively, and ethyl oleate 0.12g is placed in clean colorimetric cylinder, puts
Enter magneton, the distilled water 0.8g being then added uses magnetic stirrer, controls 60~70 DEG C of bath temperature, is uniformly mixed.
Using centrifuge, the bubble removed in sample weighs curcumin to obtain the blank pharmaceutical carrier of chitosan-containing
3.4mg is added in blank liquid crystal, and constant temperature stirring is carried out at 37 DEG C until complete drug dissolution, is centrifuged off bubble.It will be made
Standby sample balances one week at room temperature, that is, obtains stable carrier medicament sample, be denoted as L5。
Sample composition prepared by Examples 1 to 8 is as shown in table 1
Sample composition prepared by 1 Examples 1 to 8 of table is as shown in table 1
The sample prepared to Examples 1 to 8 is characterized as below：
Small angle X ray scattering (SAXS)
The light source of small angle X ray scattering instrument is copper target, excitation wavelength 0.1542nm, its operating voltage and electric current difference
Distance for 40kV and 50mA, sample to be tested to detector is 264.5nm, and setting measuring temperature is 37 DEG C.What measurement obtained
SAXS spectrograms can be used for analyzing the microstructure of liquid crystalline sample and corresponding structural parameters.
The measurement of the rheological equationm of state
Use the rheological equationm of state of U.S.'s Discovery HR-2 rheometry liquid crystal.Used vertebral plate diameter when measurement
For 20mm, cone angle is 2 °.Sample is slowly added on Peltier board, head is slowly dropped to and measures position, extra sample
Product are scraped off with sample scraper.Temperature is controlled with the water bath with thermostatic control being connect with Peltier board, and worst error control is surveyed in ± 0.1 DEG C of
Sample is kept before amount, and constant temperature 10min. dynamic frequency scannings are passing through the obtained linear viscoelastic region of stress scans in the sensor
It is carried out under interior stress value, scanning range 0.01-600rad/s.Steady-state creep rate measurement range is from 0.01 to 1000S-1.
The release in vitro of curcumin
By the release in vitro behavior of the technique study curcumin of extracorporal dialysis, the medium of release in vitro is that ethanol content is
40% PBS solution weighs the load liquid crystalline substance of about 0.5g in the small intestine semi-permeable membrane handled well, the bag filter for being surrounded by sample is placed
In filling in the beaker of PBS buffer solutions of 60mL, beaker is placed in the thermostat water bath of a certain steady temperature and is stirred,
It is discharged under conditions of constant temperature, per taking-up 5mL dissolution mediums at regular intervals, while adding the fresh dissolution medium of 5mL
The constant volume for ensureing dissolution medium is taken out using ultraviolet specrophotometer in the maximum absorption wave strong point measurement of curcumin
The absorbance of curcumin in dissolution medium.
In the preparation %=sample times of drug in cumulative release amount/carrier of drug drug total amount * 100
Characterization result
Sample BL0And BL1As shown in Fig. 2, sample BL0SAXS spectrograms on show 3 peaks Bragg, the position at the peaks Bragg
The relationship for the ratio set is 1:2:3, this illustrates that sample BL0 belongs to lamellar phase liquid crystalline structure, after introducing WCS, sample BL1The position at peak
Significant change does not occur, is still lamellar phase.
As seen from Figure 3, temperature is from when being changed to 70 DEG C for 10 DEG C.The elasticity modulus of layered liquid crystal and the value of viscous modulus are basic
It is temperature independent, illustrate that layered liquid crystal lamellar phase structure within the temperature range of research keeps stablizing, phase transition hair does not occur
It is raw.The viscous modulus of the sample of chitosan-containing, elasticity modulus are higher than the sample of not chitosan-containing.
As seen from Figure 4, with the increase of shear rate, sample BL0And BL1Viscosity number continuously decrease, show as cutting
Cut diluted behavior.It can be construed to be construed to be made of laminated structure from level to level due to layered liquid crystal, Ke Yanshui
Mutually or oil phase slides in any direction.Therefore under shear action, the positioning of the internal microstructure unit of sample with
Shear direction is parallel, and interlayer is made to slide, and viscosity is caused to decline.And BL1Shear viscosity in measurement range be higher than BL0,
This illustrates that WCS's is introduced into the interaction increased in lamellar phase liquid crystalline between molecule, hinders its mobility, reason pushes away
It surveys as water soluble chitosan in the hydrophilic head base and water layer of surfactant, reduces the thickness of water layer, cunning between layers
It is dynamic to become difficult, so sample BL1Viscosity be more than sample BL0.The introducing of chitosan improves the stabilization of lamellar phase liquid crystalline.It carries
There is the lysotropic liquid crystal of drug under the environment (such as live body) for having shearing, the strong liquid crystal of anti-shear ability, which can be stablized the long period, to be deposited
Be conducive to the continuous slow release of drug in carrier.It is discharged with it corresponding.
As can be seen from Figure 5 for sample BL0,BL1, in frequency sweeping ranges, elasticity modulus and viscous modulus are with frequency
The increase of rate slowly rises, and G ' is higher than G " in measured frequency range, and complex viscosity linearly declines with frequency
Gesture, this is the rheological property possessed by typical layered liquid crystal phase, and comparison introduces the springform of lysotropic liquid crystal after chitosan
Amount and viscous modulus value are it can be found that the viscous modulus value for introducing lysotropic liquid crystal after chitosan reduces, and elastic mould value increases, i.e.,
Sample spot BL1With maximum elastic property and minimum adhesion properties, when due to lysotropic liquid crystal as pharmaceutical carrier, elasticity
Matter is higher, slower for rate of release.So after introducing chitosan, slow releasing function of the sample for drug may be increased.
Curcumin ethanol solution rate of release is very fast as seen from Figure 6, has just reached cumulative maximum in 2.5h or so
There is the phenomenon that quick release in release rate, poor to the slow release effect of drug.And lysotropic liquid crystal has preferably curcumin
Slow release effect.And two kinds of lamellar phase lysotropic liquid crystals are different for the slow release effect of drug, are a kind of good pharmaceutical carriers.
We further study the release behavior of drug at different conditions after being not introduced into WCS and introducing WCS.
When Fig. 6 is 37 DEG C, the variation relation of preparation (CR) and time of the curcumin in lamellar phase liquid crystalline.With ginger
Flavine ethanol solution is compared, sample L0And L1All there is slow releasing function to curcumin.Sample L0, before releasing the phase (500min it
Before), curcumin rate of release is very fast, and rate of release has reached 70%, and then rate of release gradually slows down, and finally reaches platform.
Sample L1, phase (preceding 1100min) before releasing, curcumin rate of release is very fast, as release rate of release gradually slows down；Most
Afterwards, preparation is basically unchanged.This will be attributed to：Phase before releasing, the curcumin being partly adhered on lysotropic liquid crystal pass through
Molecular motion, it is easier to effusion so, the rate of release of curcumin is very fast in this stage.Mid-term is discharged, solubilising is in oil phase
Drug be gradually diffused into boundary layer, rate of release slows down gradually.The later stage is discharged, the accumulative release rate of curcumin is kept not substantially
Become, release reaches balance.Further, it is also possible to find out, L1With L0Longer compared to its release release time, this illustrates that it introduces WCS
The release time of drug can be extended.After introducing chitosan, the shear viscosity increase of aggregation is consistent.At the same time,
Sample L for preparation1To be significantly lower than sample L0.This illustrates that the introducing of WCS reduces the cumulative release speed of curcumin
Rate.This result and sample L in frequency scanning1Elastic mould value higher be consistent.
Fig. 7 (a) is at 37 DEG C, and curcumin is in sample L0In release profiles, it can be seen that at various ph values, turmeric
The In-vitro release curves of element do not have significant change, and change pH value influences unobvious for the release behavior of curcumin, as introducing WCS
Afterwards, shown in the release profiles of drug such as Fig. 7 (b), it can be seen that in pH=6.5, the preparation of curcumin reaches
82%, when increasing pH value to 7.5, preparation is changed to 62%, it can be seen that with the increase of pH value, curcumin is in sample
Product L1In release reduce, the reason of leading to this phenomenon is to contain amino in water soluble chitosan, the amino under lower ph
It can protonate, increase the repulsive interaction between molecule in lamellar phase liquid crystalline, become loose so as to cause aggregate structure,
Promote the release of curcumin.Improve the rate of release and preparation of drug.This is because at higher ph values,
WCS forms a close layer, hinders the release of curcumin.
From figure 8, it is seen that the raising of rate of release of the curcumin in layered liquid crystal and preparation with temperature
And increase.Rate of release at 37 DEG C is apparently higher than 25 DEG C, 30 DEG C, this may be since the movement of molecule is affected by temperature,
When increasing the temperature, molecular motion is accelerated, and curcumin is easier to escape from interfacial film, and the rate of release of drug is accelerated, and accumulation is released
Put rate increase.
The ratio of surfactant and oil is shown for influence result such as Fig. 9 (a) of the release behavior of drug, can see
Go out, first, lysotropic liquid crystal has good sustained release performance as the carrier of drug curcumin, and can be found that releasing for curcumin
It lets pass to be influenced by the mass ratio of surfactant and oil, the rate of release and preparation of curcumin are with surfactant
With oil ratio reduction and increase, this is because with the increase of oil content, the structure of lysotropic liquid crystal is swollen, curcumin
It is more easily escaped from interfacial film and reaches water phase, so its rate of release and preparation increase.
It is more excellent in order to find since the component and composition of pharmaceutical carrier have significant impact for the release behavior of drug
The plain carrier of the curcumin of composition, the ratio 9 of fixation surface activating agent and oil:1, select sample (L1,L4,L5) further probe into
Influence of the water content for drug release.The rate of release of curcumin and accumulative release rate are with dampening it can be seen from Fig. 9 (b)
The increase of content and reduce.It may gradually unfold in water due to the increase with water content, polymer chitosan, hinder ginger
Effusion of the flavine molecule from interfacial film.
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 pharmaceutical carrier based on alkyl glycosides lysotropic liquid crystal, characterized in that mixed by surfactant, ethyl oleate and water
Conjunction forms layered liquid crystal, surfactant, the surfactant of ethyl oleate and water, ethyl oleate and water mass percent be
40~81:5.7~21.4:0~49.5, wherein water is not 0, and surfactant is dodecyl mixing glucosides and chitosan
The mass ratio of mixture, the dodecyl mixing glucosides and chitosan is 9:1~7:3.
2. pharmaceutical carrier as shown in claim 1, characterized in that the mass ratio of dodecyl mixing glucosides and chitosan is 9:
1。
3. pharmaceutical carrier as shown in claim 1, characterized in that the mass ratio of surfactant, ethyl oleate and water is 63:
7:30。
4. pharmaceutical carrier as shown in claim 1, characterized in that the chitosan is water soluble chitosan, and deacetylation is big
In 85%.
5. a kind of preparation method of any pharmaceutical carrier of Claims 1 to 4, characterized in that by dodecyl mixed sugar
Glycosides, chitosan, ethyl oleate and water are placed in 60~70 DEG C after mixing, and bubble removing is gone to can be obtained pharmaceutical carrier.
6. preparation method as claimed in claim 5, characterized in that remove bubble removing by the way of centrifugation.
7. a kind of application of any pharmaceutical carrier of Claims 1 to 4 in load curcumin prepares carrier medicament.
8. a kind of carrier medicament, characterized in that any pharmaceutical carrier of Claims 1 to 4 loads curcumin.
9. carrier medicament as claimed in claim 8, characterized in that curcumin is the 1 × 10 of pharmaceutical carrier quality-3%~2 ×
10-3%.
10. the preparation method of the carrier medicament described in a kind of claim 8 or 9, curcumin is added into above-mentioned pharmaceutical carrier
The stirring in 37 ± 0.5 DEG C removes bubble removing, stands 6~8 days and can be obtained carrier medicament until curcumin is completely dissolved.
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