CN109381447A - A kind of load astaxanthin phosphatide nanoparticle and the preparation method and application thereof - Google Patents
A kind of load astaxanthin phosphatide nanoparticle and the preparation method and application thereof Download PDFInfo
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- CN109381447A CN109381447A CN201811506480.3A CN201811506480A CN109381447A CN 109381447 A CN109381447 A CN 109381447A CN 201811506480 A CN201811506480 A CN 201811506480A CN 109381447 A CN109381447 A CN 109381447A
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 66
- JEBFVOLFMLUKLF-IFPLVEIFSA-N Astaxanthin Natural products CC(=C/C=C/C(=C/C=C/C1=C(C)C(=O)C(O)CC1(C)C)/C)C=CC=C(/C)C=CC=C(/C)C=CC2=C(C)C(=O)C(O)CC2(C)C JEBFVOLFMLUKLF-IFPLVEIFSA-N 0.000 title claims abstract description 60
- 235000013793 astaxanthin Nutrition 0.000 title claims abstract description 60
- 229940022405 astaxanthin Drugs 0.000 title claims abstract description 60
- 239000001168 astaxanthin Substances 0.000 title claims abstract description 60
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 25
- 229940079593 drug Drugs 0.000 claims abstract description 24
- 239000012074 organic phase Substances 0.000 claims abstract description 18
- 239000012071 phase Substances 0.000 claims abstract description 13
- 229920000642 polymer Polymers 0.000 claims abstract description 11
- 238000000935 solvent evaporation Methods 0.000 claims abstract description 10
- 238000004090 dissolution Methods 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 210000003027 ear inner Anatomy 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000005538 encapsulation Methods 0.000 claims description 7
- 238000004945 emulsification Methods 0.000 claims description 6
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 230000001804 emulsifying effect Effects 0.000 claims description 2
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 claims description 2
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical group COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims 4
- 241000209094 Oryza Species 0.000 claims 2
- 235000007164 Oryza sativa Nutrition 0.000 claims 2
- 235000013339 cereals Nutrition 0.000 claims 2
- 235000009566 rice Nutrition 0.000 claims 2
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 238000006116 polymerization reaction Methods 0.000 claims 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 abstract description 19
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 abstract description 19
- -1 polyethylene Polymers 0.000 abstract description 9
- 230000008859 change Effects 0.000 abstract description 5
- 230000004048 modification Effects 0.000 abstract description 4
- 238000012986 modification Methods 0.000 abstract description 4
- 239000004698 Polyethylene Substances 0.000 abstract description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 2
- 229920000747 poly(lactic acid) Polymers 0.000 abstract description 2
- 229920000573 polyethylene Polymers 0.000 abstract description 2
- 239000004626 polylactic acid Substances 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 13
- 229960004316 cisplatin Drugs 0.000 description 13
- 210000002751 lymph Anatomy 0.000 description 13
- 239000012528 membrane Substances 0.000 description 13
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 13
- 229910052697 platinum Inorganic materials 0.000 description 12
- 206010033109 Ototoxicity Diseases 0.000 description 9
- 231100000262 ototoxicity Toxicity 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 230000001681 protective effect Effects 0.000 description 7
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 208000016354 hearing loss disease Diseases 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 206010011878 Deafness Diseases 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 231100000895 deafness Toxicity 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000007928 intraperitoneal injection Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000003064 anti-oxidating effect Effects 0.000 description 3
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- 230000002459 sustained effect Effects 0.000 description 3
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- 230000002588 toxic effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
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- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
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- 238000003756 stirring Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 208000022306 Cerebral injury Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
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- 239000008346 aqueous phase Substances 0.000 description 1
- 238000012076 audiometry Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000003477 cochlea Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 208000032625 disorder of ear Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000002388 eustachian tube Anatomy 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000011554 guinea pig model Methods 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
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- 229920002521 macromolecule Polymers 0.000 description 1
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- 231100001083 no cytotoxicity Toxicity 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
- 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
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of load astaxanthin (AST) phosphatide nanoparticles and preparation method thereof, the phosphatide nanoparticle is to mix the organic phase dissolved with high molecular polymer and astaxanthin with the water phase dissolved with phosphatide, it is obtained by emulsion-solvent evaporation method, wherein high molecular polymer is mono methoxy polyethylene glycol-polylactic acid (MPEG-PLA), and phosphatide is dimyristoyl phosphatidyl choline (DMPC).The present invention contains modification by carrying out phosphatide nanoparticle to astaxanthin, change the dissolution characteristics and size of astaxanthin, greatly improve the water solubility of fat-soluble medicine astaxanthin, phosphatide nanoparticle assigns astaxanthin slow release characteristic simultaneously, i.e. drug continues slow release after entering diseased region cell, dosage rate can be reduced, therapeutic effect is enhanced.
Description
Technical field
The present invention relates to a kind of phosphatide nanoparticle for carrying high anti-oxidation object active medicine more particularly to a kind of carry astaxanthin
Phosphatide nanoparticle preparation method and applications.
Background technique
The common pathogenetic mechanism of the disease of inner ear such as noise, drug-induced deafness is related to inner ear microenvironment active oxygen (ROS) liter
Height, anti-oxidation stress reduce.A large amount of small molecule compounds with antioxidant activity are proved have in experimental study in vivo and in vitro
Ototoxicity caused by having prevention, antagonism ROS to increase, some drugs have entered clinical experimental stage.However, due to the special knot of inner ear
Structure, often the small molecule compound through systemic administration cannot be introduced into diseased region and clinical test caused to fail.
Astaxanthin has extremely strong antioxidant activity, has been found hepatic injury caused by can be used for anoxic, cerebral injury and more devices
Official's damage etc..However, astaxanthin is for the research of the ototoxicities such as hearing impairment caused by inner ear oxidative stress, there is not been reported.Study carefully
Its reason may have following two points: 1) astaxanthin belongs to fat-soluble, in water slightly soluble, is unfavorable for patent medicine；2) inner ear belongs to semiclosed knot
Structure, there is blood-brain and the lost double barrier protection of blood-, and systemic medication is difficult to reach diseased region.And part inner ear medication is usual
It can be lost by Eustachian tube, need repeatedly medication repeatedly, easily increase artificial wound and infection probability of happening.
Therefore, those skilled in the art are dedicated to improving the physicochemical property of astaxanthin, can be used for it in prevention or treatment
Ear disease.
Summary of the invention
The present invention is directed to improve astaxanthin (ASTxanthin, AST) physicochemical property by pharmacy means, that is, prepare building
It carries astaxanthin phosphatide nanoparticle (lipid-polymer hybrid nanoparticles, LPN), it is water-soluble to improve astaxanthin
Property, while its slow release characteristic is assigned, to realize the purpose for being administered for preventing or treat disease of inner ear in the tympanum of inner ear part.
To achieve the above object, present invention firstly provides a kind of preparations for carrying astaxanthin phosphatide nanoparticle (AST-LPN)
Method, the phosphatide nanoparticle are to use organic phase solvent of the methylene chloride as astaxanthin, will by emulsion-solvent evaporation method
It is obtained after organic phase volatilization；Specifically by the organic phase dissolved with high molecular polymer and astaxanthin and being dissolved with phosphatide
Water phase mixing ultrasonic emulsification after, obtained after organic phase is volatilized.
Wherein, the high molecular polymer is preferably methoxy polyethylene glycol-polylactic acid (MPEG-PLA), and the phosphatide is excellent
It is selected as dimyristoyl phosphatidyl choline (DMPC).
Preferably, the aqueous phase solvent is methanol aqueous solution.
Preferably, the mass ratio for being used to prepare the DMPC and MPEG-PLA of the phosphatide nanoparticle for carrying astaxanthin is 1:1-
20, more preferably 1:9-10.
Further, it is described carry astaxanthin phosphatide nanoparticle preparation method the following steps are included:
1) MPEG-PLA and AST are dissolved in methylene chloride, as organic phase；
2) DMPC is dissolved in methanol aqueous solution, as water phase；
3) organic phase is added dropwise in water phase, and uses ultrasonic emulsification；
4) lotion is poured into cholic acid sodium water solution after emulsifying；
5) certain time is stirred, organic solvent is made to volatilize completely.
Preferably, the concentration of ordinary dissolution of MPEG-PLA in methylene chloride is 20-40g/L, most preferably 30g/L in step 1)；
The concentration of ordinary dissolution of AST in methylene chloride is 1-10g/L, more preferably 2-5g/L.
Preferably, the concentration of methanol aqueous solution described in step 2) is 1%-8% with the volume basis of methanol and water, most preferably
It is 4%；Concentration of ordinary dissolution of the DMPC in water phase is 0.5-1.5g/L, most preferably 1g/L.
Preferably, the mass ratio in step 3) for DMPC and MPEG-PLA in the mixed liquor of emulsification is 1:8-12, more preferably
For 1:9-10.
Further, the time for organic phase being added dropwise in step 3) is preferably no more than 5 minutes, more preferably less than 3 minutes；
Preferably, ultrasonic procedure carries out under ice bath environment, and ultrasonic duration is preferably 50-70 seconds, and most preferably 60 seconds.
Preferably, the concentration of cholic acid sodium water solution described in step 4) is calculated as with contained sodium taurocholate grams in every 100mL water
0.3%-0.7%, most preferably 0.5%.
Preferably, mixing time is 6-12 hours in step 5).
Further, the organic solvent in step 5) further comprises the steps of: centrifugation after volatilizing completely, collects precipitating；Wherein it is centrifuged
Revolving speed is preferably 11000-13000rpm, and centrifuging temperature is preferably 0-5 DEG C, and centrifugation time is preferably 25-40 minutes.
Further, the present invention provides the load astaxanthin phosphatide nanoparticles prepared using the above method；The phosphatide
The encapsulation rate of nanoparticle is 20%-80%, preferably 40%-60%, more preferably 50%-55%；The phosphatide nanoparticle
Drugloading rate is 1%-5%, preferably 2%-4%, more preferably 2%-3%；The partial size of the phosphatide nanoparticle is less than 200nm,
Preferably 100-180nm, more preferably 140-160nm；Phosphatide nanoparticle surface is negatively charged.
Further, the solubility of astaxanthin phosphatide nanoparticle in water provided by the invention that carries is at least more than 1g/L.
Further, slow-release time is greater than 5 to load astaxanthin phosphatide nanoparticle provided by the invention in artificial lymph in vitro
It, preferably greater than 7 days, more preferably higher than 10 days；Slow-release time is small greater than 6 in vivo for the load astaxanthin phosphatide nanoparticle
When, preferably greater than 10 hours.
Further, the present invention also provides above-mentioned load astaxanthin phosphatide nanoparticles prevents and treats drug system in disease of inner ear
Application in disease caused by application in standby, especially inner ear microenvironment active oxygen increase, such as noise deafness, Drug ear
It is deaf.
Further, the prevention and treatment drug includes load astaxanthin phosphatide nanoparticle provided by the invention, additionally may be used
Including pharmaceutically acceptable carrier or excipient, the drug is also possible to pharmaceutical composition.
Preferably, the administration mode provided by the invention for carrying astaxanthin phosphatide nanoparticle is administration in the tympanum of inner ear part.
It is demonstrated experimentally that load astaxanthin phosphatide nanoparticle (AST-LPN) of the invention can smoothly enter into after round window membrane is administered
Inner ear lymph, and in inner ear lymph AST-LPN can slow release drug, maintain its concentration can to for 24 hours, sent out for AST
It waves Hearing caused by resisting ROS raising and creates necessary condition.Finally, AST-LPN is after round window membrane is administered, in 2.8-
Significant inhibiting effect, average inhibition about 20dB are shown to the raising of Hearing Threshold caused by cis-platinum within the scope of 22kHz.
The present invention selects phosphatide DMPC and macromolecule polymer material MPEG-PLA, to AST by emulsion-solvent evaporation method
It carries out lipid nano particle and contains modification, and optimize preparation method, obtain and carry astaxanthin phosphatide nanoparticle, change drug
Dissolution characteristics and particle size greatly improve the water solubility (improving about 24 times) of fat-soluble medicine astaxanthin.Phosphatide nanometer
Grain has the phospholipid bilayer similar with cell membrane, improves the biological compatibility of carrier system, while phosphatide nanoparticle assigns
Astaxanthin slow release characteristic, i.e. drug continue slow release after entering diseased region cell, can reduce dosage rate, enhancing treatment effect
Fruit.
Detailed description of the invention
Fig. 1 is that phosphatide in embodiment 1-high molecular polymer different quality ratio using acetonitrile as organic solvent uses nanoprecipitation
The change of size of method preparation gained lipid nano particle；
Fig. 2 is that phosphatide in embodiment 1-high molecular polymer different quality ratio using acetonitrile as organic solvent uses nanoprecipitation
The potential change of method preparation gained lipid nano particle；
Fig. 3 is that phosphatide in embodiment 1-high molecular polymer different quality ratio using acetonitrile as organic solvent uses nanoprecipitation
Method preparation gained lipid nano particle coefficient of dispersion variation；
Fig. 4 is that influence of two kinds of different preparation methods to astaxanthin encapsulation rate is compared in embodiment 1 and embodiment 2；
Fig. 5 is that influence of two kinds of different preparation methods to astaxanthin drugloading rate is compared in embodiment 1 and embodiment 2；
Fig. 6 is that emulsion-solvent evaporation method preparation carries astaxanthin and the partial size without astaxanthin lipid nano particle compares；
Fig. 7 is that emulsion-solvent evaporation method preparation carries astaxanthin and the surface potential without astaxanthin lipid nano particle compares；
Fig. 8 is the transmission electron microscope picture that emulsion-solvent evaporation method preparation carries astaxanthin lipid nano particle, Bar:100nm；
Fig. 9 is AST-LPN release profiles in artificial lymph in vitro；
Figure 10 is release profiles in lymph in AST-LPN cavy body；
Figure 11 is the toxic effect result that blank does not carry medicine phosphatide nanoparticle to HEI-OC1 cell；
Figure 12 is toxic effect result of the various concentration cis-platinum (CDDP) to HEI-OC1 cell；
Figure 13 is the protective effect result that AST-LPN and AST cause cytotoxicity to CDDP；
Figure 14 is the intracellular ROS active fluoro statistic analysis of strength of HEI-OC1 after different dosing is handled；
Figure 15 is the picture of the intracellular ROS activity change of HEI-OC1 after different dosing is handled；
Figure 16 be low dosage repeatedly (4mg/kg/ days, for three days on end) intraperitoneal injection CDDP, respectively at be injected intraperitoneally first 1 day with
The result of ABR detection is carried out within 3 days afterwards；
Figure 17 was high dose single (12mg/kg, 1 time) intraperitoneal injection cis-platinum, respectively at intraperitoneal injection first 1 day and latter 3 days
Carry out the result of ABR detection；
Figure 18 is that AST-LPN 1h before Intraperitoneal Cisplatin is administered before administration and gives through the exposure round window membrane administration of ear posterior approach
3 days record ABR after medicine, the ABR value that administration front and back measures, compared with before administration, p < 0.001 * p < 0.05, * * p < 0.01, * * *；
Numerical value=mean+SD, N=4；
Figure 19 is that AST-LPN 1h before Intraperitoneal Cisplatin is administered before administration and gives through the exposure round window membrane administration of ear posterior approach
3 days record ABR after medicine, the administration front and back domain ABR is moved, compared with cis-platinum group, p < 0.001 * p < 0.05, * * p < 0.01, * * *；Numerical value
=mean+SD, N=4.
Specific embodiment
It is described further below with reference to technical effect of the attached drawing to design of the invention, specific structure and generation, with
It is fully understood from the purpose of the present invention, feature and effect, but the present invention is not intended to be limited thereto.
Embodiment one: nanoprecipitation method prepares astaxanthin phosphatide nanoparticle (AST-LPN)
30mg MPEG-PLA (high molecular polymer) and 2-5mg AST are dissolved in 1mL acetonitrile solution, as organic phase；
3mg DMPC (phosphatide) is dissolved in 4% ethanol solution of 10mL, as water phase.Water phase is preheated to 65 DEG C, and 900rpm is stirred,
It is completely dissolved to DMPC.The organic phase containing drug is added dropwise dropwise, is dripped off in 3min, continues to stir 2min, mixing speed is adjusted
To 300rpm, gentle agitation is volatilized completely to organic phase overnight.With Millipore 10kDa centrifugal concentrating pipe in 4000g, 4 DEG C
It is centrifuged 40min, removes non-entrapped drug and organic solvent etc., it is continuous centrifugal 2 times, final to obtain about 500 μ L nanoparticle concentrates.
DMPC and MPEG-PLA mass ratio are respectively 1:0,1:1,1:5,1:10,1:20,0:1, prepare AST-LPN partial size within this range
Range is 90.2-138.4nm (Fig. 1), current potential -9.8--15.3mV (Fig. 2).
Fig. 1 is the results show that when phosphatide/polymer ratio is 1:20, and phosphatide nanoparticle partial size is minimum, about 80nm or so.
When content of phospholipid is raised and lowered, phosphatide nanoparticle partial size is increased.DMPC:MPEG-PLA ratio is that 1:0 prepares nanoparticle grain
Diameter about 120nm, and DMPC:MPEG-PLA ratio prepares liposomal particle size for 0:1 and is up to 1750nm.
Fig. 2 is but negatively charged the results show that phosphatide nanoparticle current potential is improved as DMPC content increases.The largest of about
For -3mV, minimum is about -15mV.Subsequent experimental selects DMPC:MPEG-PLA ratio to prepare for 1:10 and carries astaxanthin phosphatide nanometer
Grain.
Fig. 3 is the results show that DMPC:MPEG-PLA ratio prepares phosphatide nanoparticle partial size point when being 1:0,1:1,1:5,1:10
For scattered coefficient between 0.1-0.2, dispersion degree is preferable.
It is lower that this method prepares AST-LPN encapsulation rate (encapsulation efficiency, EE%), only
3.2-8%；Drugloading rate (Drug Loading, DL%) is relatively low, only about 0.38-0.5%, and as dosage increases encapsulation rate
It decreases with drugloading rate, this may be related with drug overload (Fig. 4 and Fig. 5).
2 emulsion-solvent evaporation method of embodiment prepares astaxanthin phosphatide nanoparticle (AST-LPN)
The main reason for analyzing nanoprecipitation method preparation gained astaxanthin lipid nano particle encapsulation rate and too low drugloading rate, can
It can be caused by AST solubility in acetonitrile is lower.The AST of phase homogenous quantities is dissolved in acetonitrile and methylene chloride, is vortexed after dissolution,
Dichloromethane solution is more clarified bright, thus it is speculated that solubility is higher than acetonitrile solution to AST in methylene chloride.So using dichloromethane
Alkane replaces acetonitrile to dissolve AST and MPEG-PLA, dissolves DMPC, preparation with 4% (volume ratio of methanol and water) methanol aqueous solution
AST-LPN.Detailed step is as follows: 30mg MPEG-PLA and 2-5mg AST are dissolved in 1mL methylene chloride, as organic phase；
3mg DMPC is dissolved in 4% methanol aqueous solution of 3mL, as water phase.Organic phase containing drug is added dropwise to water phase dropwise
It is interior, it is dripped off in 3min, is placed in the emulsification of ultrasonication instrument, power is about 480w, continuous ultrasound 60s.To avoid in ultrasonic procedure
The heat of generation impacts astaxanthin activity, and ultrasonic procedure is placed on ice.Lotion is poured into 26mL after ultrasound
In 0.5% sodium cholate solution, it is placed on Stirring instrument and is stirred overnight (300rpm), residual organic solvents is made to volatilize completely.
Final solution is AST-LPN in 12,000rpm, 4 DEG C of centrifugation 30min, gained precipitating.
As shown in Figures 4 and 5, methylene chloride is replaced into acetonitrile, emulsion-solvent evaporation method replaces nanoprecipitation method, prepares
The EE% and DL% of AST-LPN respectively may be about 51.8% and 2.65%.This method prepares the EE% and DL% of AST-LPN compared with nanometer
The precipitation method improve about 6.48-16.19% and 5.3-7.5%, greatly improve AST drug water solubility, have very strong clinic
Application value.
Emulsion-solvent evaporation method preparation AST-LPN and unloaded lipid nano particle (NP) partial size are about 138.97nm or so, and two
There was no significant difference by person (Fig. 6).The surface AST-LPN and NP is negatively charged, respectively may be about -9.3 and -22.8mV (Fig. 7), and
AST-LPN surface charge is significantly higher than NP, this may be the shielding since fat-soluble high molecular weight AST is covered in nanoparticle surface
Caused by a part of charge.Electronic Speculum is projected the results show that the surface AST-LPN rounding is smooth, particle size is uniform, about 150nm,
It is almost the same (Fig. 8) with particle instrument testing result.
Slow release characteristic is investigated in 3 AST-LPN inner ear lymph of embodiment
As shown in figure 9, AST-LPN is sustained in artificial lymph up to 15 days in vitro.In addition, as shown in Figure 10, inner ear leaching
Bar liquid drug concentration test experience is the results show that AST solution (6 μ g) is after round window membrane is administered, and 30min takes lymph after administration
Liquid is analyzed by mass spectrometry, and AST content is not detected.Result prompt, fat-soluble A ST can not enter inner ear by round window membrane.
Based on this, we determined that AST can not play the protective effect of Cisplatin Ototoxicity after round window membrane medication.Referring to Figure 10, cavy warp
Round window membrane (RWM) is given after AST-LPN (AST concentration: 1.0mg/mL, 6 μ L), and concentration reaches maximum value in lymph after 1 hour
(600.67 ± 247.95ng/mL), sustained drug were sustained to 24 hours；However, AST is administered through abdominal cavity (IP), round window membrane (RWM)
Afterwards, AST content is not detected in inner ear lymph.
The result of study shows that AST substantially increases water solubility, and partial size and surface potential after the modification of phosphatide nanoparticle
It is assigned through round window membrane property, inner ear lymph can be can smoothly enter into, and realizes drug slow release (for 24 hours) in lymph.
Lipid nano particle has widened AST disease treatment application range, improvement deliquescent to AST make its be applied to disease of inner ear prevention or
Treatment is possibly realized, and provides theoretical foundation and experiment basis for the conversion of AST clinic.
Protective effect of 4 AST-LPN of embodiment to cisplatin cytotoxicity
Cisplatin Ototoxicity is common Drug-induced deafness.Cis-platinum is easy to enter inner ear lymph by blood labyrinth barrier, causes
Sense of hearing epithelial cell ROS, which is increased, induces the apoptosis pathway that mitochondria relies on, and hair cell occurs apoptosis and then leads to Hearing very
It is extremely complete deafness.It is that external drug toxicity prevents cell model with auditory cell system HEI-OC1, investigates AST-LPN to cisplatin induced
The protective effect of HEI-OC1 cytotoxicity.The mechanism of cytotoxicity protective effect is further inquired into simultaneously.Experimental result
Show: blank does not carry medicine phosphatide nanoparticle and acts on (Figure 11) to HEI-OC1 no cytotoxicity, and cis-platinum (CDDP) is thin to HEI-OC1
The toxic effect of born of the same parents increases (Figure 12) as cis-platin concentrations increase；AST-LPN significantly inhibits suitable under 1,5,10 μ g/mL concentration
Platinum cytotoxicity (P<0.001), and under same concentrations, AST is without cisplatin cytotoxicity inhibiting effect (P>0.05) (Figure 13).
5 AST-LPN of embodiment leads to the raised antagonism of intracellular ROS to cis-platinum
As shown in FIG. 14 and 15, AST significantly suppresses CDDP (60 μM, for 24 hours) under 1,5,10,15 μ g/mL concentration and draws
The intracellular ROS risen is increased, and embodies strong anti-oxidation characteristic.It is of particular importance that AST-LPN is under 5,10,15 μ g/mL concentration
Inhibit intracellular ROS raising effect caused by CDDP to be significantly stronger than AST effect under same concentrations, and may make intracellular ROS water
It is flat to drop to normal level.
Zoopery of 6 AST-LPN of embodiment to Cisplatin Ototoxicity protective effect
1. Cisplatin Ototoxicity guinea pig model constructs
Different modes of administration is selected to establish cavy Cisplatin Ototoxicity model.As a result as shown in FIG. 16 and 17, low dosage is multiple
(4mg/kg/ days, for three days on end) intraperitoneal injection cis-platinum (cisplatin, CDDP) afterwards third day survey auditory brainstem response
(auditory brainstem response, ABR), Hearing Threshold Shift amplitude is smaller, averagely about 15dB.However, high dose list
ABR is surveyed in third day after cis-platinum is injected intraperitoneally in secondary (12mg/kg, 1 time), and Hearing Threshold Shift amplitude is sufficiently large, especially 4-16kHz frequency
Under range, average hearing threshold shift is about 52dB.Based on this, the subsequent selection high dose single of this test (12mg/kg, 1 time) administration
The cavy ototoxicity model that mode constructs.
The protective effect that 2.AST-LPN declines Cisplatin Ototoxicity Hearing of Guinea Pigs
AST-LPN selects round window membrane administration, i.e., will draw appropriate AST- through ear posterior approach exposure round window membrane after cavy anesthesia
The gelfoam of LPN solution is placed in round window niche, closes otic capsule, suture.It keeps the position after 1 hour, cis-platinum is injected intraperitoneally
(12mg/kg) waits cavy revival, it is ensured that raising in cage is put back to after state is fine.3 days after being administered first 1 day and being administered
Audiometry force threshold.
Hearing protection result is as shown in Figures 18 and 19.Figure 18 shows that cis-platinum or so ear Hearing Threshold is without conspicuousness before being administered
Difference.Round window membrane is given after AST-LPN protects in advance, and hearing is picked up the ears in administration and non-administration is picked up the ears, and Hearing Threshold has significant difference.
Not give the contralateral ear of AST-LPN solution as cis-platinum control group, AST-LPN is pre-placed 1 hour administration side hearing impairment of cochlea and exists
Hearing Threshold has significant decrease within the scope of 2.8-22kHz, and averagely reduction amplitude is about 20dB (Figure 19).
The preferred embodiment of the present invention has been described in detail above.It should be appreciated that those skilled in the art without
It needs creative work according to the present invention can conceive and makes many modifications and variations.Therefore, all technologies in the art
Personnel are available by logical analysis, reasoning, or a limited experiment on the basis of existing technology under this invention's idea
Technical solution, all should be within the scope of protection determined by the claims.
Claims (10)
1. a kind of preparation method for carrying astaxanthin phosphatide nanoparticle, which is characterized in that the phosphatide nanoparticle is using dichloromethane
Organic phase solvent of the alkane as astaxanthin, obtains after organic phase is volatilized by emulsion-solvent evaporation method.
2. carrying the preparation method of astaxanthin phosphatide nanoparticle as described in claim 1, which is characterized in that the phosphatide nanoparticle
It is after the organic phase dissolved with high molecular polymer and astaxanthin is mixed ultrasonic emulsification with the water phase dissolved with phosphatide, through organic
It is obtained after mutually volatilizing.
3. carrying the preparation method of astaxanthin phosphatide nanoparticle as claimed in claim 2, which is characterized in that the high molecular polymerization
Object is MPEG-PLA, and the phosphatide is DMPC.
4. as claimed in claim 3 carry astaxanthin phosphatide nanoparticle preparation method, which is characterized in that wherein DMPC with
The mass ratio of MPEG-PLA is 1:1-20.
5. a kind of preparation method for carrying astaxanthin phosphatide nanoparticle, which comprises the following steps:
1) MPEG-PLA and AST are dissolved in methylene chloride, as organic phase；
2) DMPC is dissolved in methanol aqueous solution, as water phase；
3) organic phase is added dropwise in water phase, and uses ultrasonic emulsification；
4) lotion is poured into cholic acid sodium water solution after emulsifying；
5) certain time is stirred, organic solvent is made to volatilize completely.
6. carrying the preparation method of astaxanthin phosphatide nanoparticle as claimed in claim 5, which is characterized in that MPEG- in step 1)
The concentration of ordinary dissolution of PLA in methylene chloride is 20-40g/L, and the concentration of ordinary dissolution of AST in methylene chloride is 1-10g/L, step 2)
Concentration of ordinary dissolution of the middle DMPC in methanol aqueous solution is 0.5-1.5g/L.
7. carrying the preparation method of astaxanthin phosphatide nanoparticle as claimed in claim 5, which is characterized in that first described in step 2)
The concentration of alcohol solution is 1%-8% with the volume basis of methanol and water, the concentration of cholic acid sodium water solution described in step 4) with
Contained sodium taurocholate grams is calculated as 0.3%-0.7% in every 100mL water.
8. being received with the load astaxanthin phosphatide of the preparation method preparation as claimed in claim 1 or 5 for carrying astaxanthin phosphatide nanoparticle
The grain of rice, which is characterized in that encapsulation rate 20%-80%, drugloading rate 1%-5%.
9. being received with the load astaxanthin phosphatide of the preparation method preparation as claimed in claim 1 or 5 for carrying astaxanthin phosphatide nanoparticle
The grain of rice prevents and treats the application in medicine preparation in disease of inner ear.
10. a kind of for preventing or treating the drug of disease of inner ear, which is characterized in that including load as claimed in claim 1 or 5
The load astaxanthin phosphatide nanoparticle of the preparation method preparation of astaxanthin phosphatide nanoparticle.
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