CN116549430B - Linoleic acid preparation and application thereof in preparation of acute lung injury treatment drugs - Google Patents
Linoleic acid preparation and application thereof in preparation of acute lung injury treatment drugs Download PDFInfo
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- CN116549430B CN116549430B CN202310650494.7A CN202310650494A CN116549430B CN 116549430 B CN116549430 B CN 116549430B CN 202310650494 A CN202310650494 A CN 202310650494A CN 116549430 B CN116549430 B CN 116549430B
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- linoleic acid
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- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 title claims abstract description 147
- 235000020778 linoleic acid Nutrition 0.000 title claims abstract description 146
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 title claims abstract description 146
- 238000002360 preparation method Methods 0.000 title claims abstract description 99
- 206010069351 acute lung injury Diseases 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title claims abstract description 7
- 238000011282 treatment Methods 0.000 title description 27
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000008157 edible vegetable oil Substances 0.000 claims abstract description 18
- 235000011187 glycerol Nutrition 0.000 claims abstract description 16
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 16
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 16
- 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 12
- 235000010445 lecithin Nutrition 0.000 claims abstract description 12
- 239000000787 lecithin Substances 0.000 claims abstract description 12
- 229940067606 lecithin Drugs 0.000 claims abstract description 12
- 239000002245 particle Substances 0.000 claims description 22
- 239000003921 oil Substances 0.000 claims description 17
- 235000019198 oils Nutrition 0.000 claims description 17
- 239000003813 safflower oil Substances 0.000 claims description 12
- 235000019498 Walnut oil Nutrition 0.000 claims description 11
- 239000008170 walnut oil Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 8
- 229920002301 cellulose acetate Polymers 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000000265 homogenisation Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 230000001954 sterilising effect Effects 0.000 claims description 6
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 4
- 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 description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229940083466 soybean lecithin Drugs 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims 8
- 239000012071 phase Substances 0.000 claims 6
- 239000004615 ingredient Substances 0.000 claims 1
- 238000003260 vortexing Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 24
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
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- 210000004072 lung Anatomy 0.000 description 28
- 241000699670 Mus sp. Species 0.000 description 22
- 239000000203 mixture Substances 0.000 description 17
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- 238000009472 formulation Methods 0.000 description 14
- 210000000440 neutrophil Anatomy 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 239000007928 intraperitoneal injection Substances 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
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- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
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- 239000012530 fluid Substances 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 210000003437 trachea Anatomy 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 3
- 206010037423 Pulmonary oedema Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000003149 assay kit Methods 0.000 description 3
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- 210000003022 colostrum Anatomy 0.000 description 3
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- 238000010790 dilution Methods 0.000 description 3
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- 230000007954 hypoxia Effects 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 210000001147 pulmonary artery Anatomy 0.000 description 3
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- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 238000011725 BALB/c mouse Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
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- 231100000915 pathological change Toxicity 0.000 description 2
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- 208000005333 pulmonary edema Diseases 0.000 description 2
- 210000004879 pulmonary tissue Anatomy 0.000 description 2
- 201000004193 respiratory failure Diseases 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
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- 235000021122 unsaturated fatty acids Nutrition 0.000 description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000009447 Cardiac Edema Diseases 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001043 capillary endothelial cell Anatomy 0.000 description 1
- 238000011976 chest X-ray Methods 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 235000020665 omega-6 fatty acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 230000003519 ventilatory effect 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- 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
- 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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Public Health (AREA)
- Veterinary Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
The invention relates to the technical field of medicines, and in particular discloses an application of a linoleic acid preparation in preparing a medicine for treating acute lung injury. The linoleic acid or edible oil containing the linoleic acid, lecithin, tween-80, glycerin and water are homogenized at high speed and high pressure to prepare the linoleic acid preparation, the effect of the linoleic acid preparation in preparing the medicine for treating acute lung injury is expanded, the obvious effect is achieved in the experimental process, the curative effect is definite, no obvious toxic or side effect is caused, the preparation method is easy to implement and effective in oral administration, the certainty of the linoleic acid is enhanced, the pungent smell is covered, and the application prospect is wide.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a linoleic acid preparation and application thereof in preparing a medicine for treating acute lung injury.
Background
Acute lung injury (acutelunginjury, ALI) is defined as: acute onset, with severe hypoxia, bilateral infiltration of the chest X-ray, and no cardiac edema, pulmonary Artery Wedge Pressure (PAWP) 18 or no left atrial hypertension, a lighter syndrome with PaO 2/FiO2 between 200-300 mmHg. Is acute hypoxia respiratory insufficiency or failure caused by diffuse pulmonary interstitial and alveolar edema due to injury of pulmonary capillary endothelial cells and alveolar epithelial cells in the non-cardiac disease process of infection, shock, wound, burn and the like. Pulmonary imaging is characterized by reduced lung volume, reduced lung compliance, severe ventilatory dysfunction, and deregulation of blood flow proportions, clinically manifested as progressive hypoxia and respiratory distress, and non-uniform exudative lesions.
The edible oil sold in the market contains various unsaturated fatty acids, oleic acid and linoleic acid are main unsaturated fatty acids, and the highest linoleic acid content in safflower seed oil can reach 79%. Linoleic acid belongs to polyunsaturated fatty acid, CH 3(CH2)4CH＝CHCH2CH＝CH(CH2)7 COOH, is one of fatty acids necessary for human body, and is an important precursor of omega-6 PUFA, and can be metabolized by various enzymes to produce important eicosanoid hormone, and has the effects of reducing serum cholesterol, inhibiting arterial thrombosis, preventing atherosclerosis and osteoporosis, etc. The prior art does not show its effect in the treatment of acute lung injury.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a linoleic acid preparation and application thereof in preparing medicines for treating acute lung injury. The linoleic acid preparation prepared by the invention has obvious effect in treating acute lung injury, definite curative effect and no obvious toxic or side effect. The oral administration is effective, the certainty of linoleic acid is enhanced, the pungent smell is covered, and the application prospect is wide.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
An application of linoleic acid preparation in preparing medicine for preventing and treating acute lung injury is provided.
Further, the linoleic acid preparation is an oil-in-water preparation taking linoleic acid as an active ingredient, and is prepared by homogenizing linoleic acid or edible oil containing the linoleic acid, lecithin, tween-80, glycerol and water at high speed and high pressure; or homogenizing edible oil containing linoleic acid, tween-80, glycerol and water under high pressure. When applied, the linoleic acid formulation was diluted with PBS. The content of linoleic acid in the diluted linoleic acid preparation is 5-20 mu L/mL; preferably, the content of linoleic acid in the diluted linoleic acid preparation is 10-20 mu L/mL; more preferably, the content of linoleic acid in the diluted linoleic acid preparation is 15-20 mu L/mL; most preferably, the linoleic acid content of the diluted linoleic acid preparation is 18.8. Mu.L/mL. The dosage of the linoleic acid preparation after dilution is recommended to be 10-15 mu L/g.
The content of linoleic acid in the edible oil containing linoleic acid is more than 60%; preferably, the edible oil containing linoleic acid is safflower seed oil or walnut oil.
Further, the lecithin may be one selected from egg yolk lecithin and soybean lecithin.
The particle size of the linoleic acid preparation is 180-220 nm, and the Zeta potential is-50 to-20 mV; preferably, the particle size of the linoleic acid preparation is 200-220 nm, and the Zeta potential is-35 mV to-25 mV; more preferably, the particle size of the linoleic acid preparation is 210nm and the Zeta potential is-28.4 mV.
Further, the preparation method of the linoleic acid preparation comprises the following steps: dissolving lecithin in linoleic acid or edible oil containing linoleic acid to prepare an oil phase, wherein the volume ratio of the oil phase to the water phase is 1: and 4, dripping the oil phase into a water phase prepared by dissolving glycerol and tween-80 in pure water, stirring, homogenizing at a high speed, and homogenizing at a high pressure to obtain the linoleic acid preparation.
Further, the preparation method of the linoleic acid preparation comprises the following steps: adding lecithin into linoleic acid or edible oil containing the linoleic acid, and heating to 55-65 ℃ to enable the lecithin to be fully dissolved in the linoleic acid to prepare an oil phase, wherein the final concentration of the lecithin is 3w/v%, and w/v=g/mL; adding glycerin and tween-80 into pure water, uniformly mixing to prepare a water phase, wherein the final concentration of the glycerin is 2.81v/v%, and the final concentration of the tween-80 is 1.25v/v%, and preheating to 55-65 ℃; then adding the preheated molten oil phase into the water phase, wherein the volume ratio of the oil phase to the water phase is 1: and 4, dropwise adding vortex at the same time, continuously heating and stirring for 5-15 min after all the components are uniformly mixed, homogenizing at high speed, homogenizing at high pressure, cooling to room temperature, filtering by a cellulose acetate filter with the particle size of 0.45 mu m, and sterilizing to obtain the linoleic acid preparation with uniform particle size.
Further, the preparation method of the linoleic acid preparation comprises the following steps: adding glycerin and tween-80 into pure water, uniformly mixing to prepare a water phase, wherein the final concentration of the glycerin is 2.81v/v%, and the final concentration of the tween-80 is 1.25v/v%, and preheating to 55-65 ℃; then adding the edible oil containing linoleic acid into the water phase, wherein the volume ratio of the edible oil containing linoleic acid to the water phase is 1:4, dropwise adding and stirring, homogenizing under high pressure, cooling to room temperature, filtering with a 0.45 μm cellulose acetate filter, and sterilizing to obtain linoleic acid preparation with uniform particle size.
Further, the linoleic acid formulation acts on the drug to prevent acute lung injury by alleviating oedema and/or neutrophil aggregation.
Further, the acute lung injury is induced by lipopolysaccharide.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. The certainty of linoleic acid is enhanced, and the pungent smell is covered;
2. Expands the new application of linoleic acid and determines the effect of linoleic acid in preparing the medicine for treating acute lung injury;
3. According to the invention, linoleic acid, safflower seed oil or walnut oil is prepared into a linoleic acid preparation, so that oxidation of the linoleic acid preparation can be effectively slowed down;
4. The linoleic acid, the safflower seed oil or the walnut oil are prepared into the medicine for treating the acute lung injury, has a good treatment effect on the acute lung injury, can obviously improve the survival rate, and is orally taken effectively. The invention is expected to relieve the pain of patients, and can be expected to have better economic and social benefits.
Drawings
FIG. 1 is a graph showing the particle size and Zeta potential of the linoleic acid preparation prepared in example 1.
Fig. 2 is the effect of linoleic acid formulation on LPS-induced ALI mice pulmonary edema in example 2.
FIG. 3 is a graph showing the changes in lung histopathology of mice in each group in example 2.
FIG. 4 shows the effect of linoleic acid formulation on LPS-induced MPO activity in alveolar lavage fluid of ALI mice in example 3.
FIG. 5 is the effect of linoleic acid formulation on LPS-induced leakage of ALI mouse lung tissue protein in example 3.
FIG. 6 is a graph showing the change in lung histopathology of mice in each group in example 3.
Detailed Description
The applicant will now make further details of the technical solution of the present invention with reference to specific examples. It should be understood that the following should not be construed in any way as limiting the scope of the invention as claimed.
The biochemical kit used in the embodiments of the invention is a myeloperoxidase assay kit, and the Nanjing is built into the bioengineering institute, cat No.: a044-1-1; BCA protein concentration assay kit (enhanced), peyun biotechnology limited, cat No.: p0010; the ultraviolet visible spectrophotometry used for measuring the myeloperoxidase is the Simer-Fei NicoletiS; the enzyme-labeled analyzer used for measuring the BCA protein concentration is DG5035A of medical equipment limited liability company of Nanjing Huadong electronic group; FSH-2A adjustable high speed refiner used was purchased from the company of instrument manufacture, inc. In the altar fine da; the ATS high pressure homogenizer used was purchased from AnTuo Nano technology (Suzhou) Co., ltd., model AH-NANO.
Example 1a method for preparing a linoleic acid formulation for the treatment of acute lung injury, taking 40ml of the linoleic acid formulation as an example, is as follows:
0.24g of egg yolk lecithin is added into 7.52mL of linoleic acid, and then the mixture is placed in a water bath kettle and heated to 60 ℃ to enable the egg yolk lecithin to be fully dissolved in the linoleic acid to form an oil phase;
Dissolving 0.9mL of glycerol and 0.4mL of Tween-80 in 30.7mL of ultrapure water, dissolving thoroughly to form a water phase, and placing in a water bath kettle to preheat to 60 ℃ for standby;
dropwise adding the preheated molten oil phase into the water phase under the condition of a 60 ℃ constant-temperature water bath, dropwise adding vortex, and continuously stirring for 10min after all the molten oil phase and the vortex are uniformly mixed;
Shearing the incompatible two phases at a high speed of 8000rpm for 10min by an FSH-2A adjustable high-speed refiner, and fully and uniformly mixing to obtain colostrum;
And circulating for 6 times under the pressure of 1000bar by an ATS high-pressure homogenizer to form a linoleic acid preparation with uniform particle size, wherein the linoleic acid content in the linoleic acid preparation is 188 mu L/mL. The linoleic acid preparation obtained was cooled to room temperature, filtered through a 0.45 μm cellulose acetate filter, sterilized, and stored at 4℃in a dark place. The administration was diluted to the desired concentration with 0.01mol/LPBS phosphate buffer (pH 7.4).
FIG. 1 is a graph showing the particle size and Zeta potential of the linoleic acid preparation prepared in example 1. The particle size (mean particle size, as in the examples below, not described in detail) of the linoleic acid preparation was 210.3.+ -. 5.4nm and the Zeta potential was-28.4.+ -. 4.3mV.
EXAMPLE 2 use of linoleic acid formulation for treating lipopolysaccharide-induced acute lung injury in mice by intraperitoneal injection
Male BALB/c mice, weighing 20-30g, were divided into 5 groups, blank group (Ctrl.), lipopolysaccharide model group (LPS), high-dose treatment group for intraperitoneal injection of linoleic acid preparation (h-LALNs +LPS), low-dose treatment group for intraperitoneal injection of linoleic acid preparation (l-LALNs +LPS), and control group for intraperitoneal injection of linoleic acid preparation (LALNs), 10 each.
The treatment method comprises the following steps:
the mice in the blank group each had normal diet.
Model mice were instilled with 50. Mu.L of 2mg/mL lipopolysaccharide per trachea, followed by intraperitoneal injection of 300. Mu.L of 0.01mol/LPBS phosphate buffer (pH 7.4).
The linoleic acid preparation-treated group was instilled with 50. Mu.L of 2mg/mL lipopolysaccharide per time through the trachea, and then 300. Mu.L of the linoleic acid preparation prepared in example 1 was injected per one of the high dose treatment groups after 10-fold dilution. The linoleic acid preparation prepared in example 1 was diluted 30-fold and 300. Mu.L of the linoleic acid preparation was injected intraperitoneally into each of the low dose treatment groups.
Linoleic acid preparation control group, 300. Mu.L of linoleic acid preparation was diluted 10-fold per one of the linoleic acid preparation prepared in example 1 by intraperitoneal injection.
The above 5 treatments were repeated every 24h for 3 times, after the last treatment, no water was forbidden, after 12h, blood was taken from the eyeballs, and after animals were sacrificed, the lungs were perfused, and the perfusate was collected and then the lungs were removed.
Animal mortality was recorded: the blank group (ctrl.) and the linoleic acid preparation intraperitoneal injection control group (LALNs) had no animal death, the model group (LPS) had an animal death rate of 9/10, the linoleic acid preparation intraperitoneal injection high dose treatment group (h-LALNs +LPS) had an animal death rate of 3/10, and the linoleic acid preparation intraperitoneal injection low dose treatment group (l-LALNs +LPS) had an animal death rate of 6/10.
The upper left leaf of the removed lung was rinsed briefly with 0.01mol/LPBS phosphate buffer (pH 7.4), and the surface moisture was absorbed by filter paper, accurately weighed by an electronic analytical balance and recorded. The weight obtained at this time was the wet weight of the lung tissue. And (3) putting the lung tissue into a dryer at 65 ℃ for drying treatment, taking out the lung tissue after 48 hours of drying, and accurately weighing again, wherein the obtained weight is the dry weight of the lung tissue. Finally, lung tissue wet to dry weight ratio (W/D) was calculated. The effect of linoleic acid formulation on LPS-induced ALI mice pulmonary edema in example 2 results are shown in fig. 2, with significant increases in W/D in lung tissue in mice in model group compared to the blank group; compared with the model group, the low-dose treatment group of the linoleic acid preparation has a tendency of reducing the W/D of the lung tissue of the mice, and the high-dose treatment group of the linoleic acid preparation can obviously reduce the W/D of the lung tissue of the mice.
The results of the changes in the lung histopathology of the mice in example 2 are shown in fig. 3, and the results of the changes in the lung histopathology of the mice in the blank group (ctrl.) are visible under the lung histology of the mice, the bronchus structure is clear, no inflammatory cell infiltrates, the alveolus structure is complete, no neutrophils are in the alveoli, no obvious increase in neutrophils in the alveolus interstitium, no obvious thickening of the alveolus interval, a small amount of flushing blood is caused, and no obvious pathological change is seen; compared with a blank group, the model group mice have almost no normal pulmonary alveolus structure in pulmonary tissue section, neutrophils are in pulmonary alveoli, neutrophils in pulmonary alveolus interstitium are obviously increased, the pulmonary alveolus interstitium thickening condition is serious, and pulmonary vessel pulmonary alveolus part is collapsed and interstitium is thickened; whereas the linoleic acid preparation treatment group significantly attenuated the LPS-induced changes, compared to the model group, the results were shown by relatively intact alveolar structure, substantially no neutrophils present in the alveoli, relatively reduced central granulocytes in the alveolar interstitium, and relatively reduced alveolar space thickening, wherein the high dose treatment group had more pronounced improvement. From the above results, it was found that the intraperitoneal injection of linoleic acid preparation can improve the degree of lung histopathological injury of mice.
Example 3 use of oral linoleic acid formulation for the treatment of lipopolysaccharide induced acute lung injury in mice:
Male BALB/c mice, weighing 20-30g, were divided into 4 groups, blank group (Ctrl.), lipopolysaccharide model group (LPS), linoleic acid preparation lavage treatment group (LALNs +LPS), linoleic acid preparation lavage control group (LALNs), 10 each.
The treatment method comprises the following steps:
the mice in the blank group each had normal diet.
Model mice were instilled with 50. Mu.L of 2mg/mL lipopolysaccharide per trachea followed by gavage with 300. Mu.L of 0.01mol/LPBS phosphate buffer (pH 7.4).
The linoleic acid preparation-treated group was instilled with 50. Mu.L of 2mg/mL lipopolysaccharide through the trachea each time, followed by administration of 300. Mu.L of the linoleic acid preparation prepared in example 1 diluted 10-fold by means of gavage.
Linoleic acid preparation control, 300. Mu.L of linoleic acid preparation prepared in example 1 was administered by gavage after 10-fold dilution.
The above 4 treatments were repeated every 24h for 3 times, after the last treatment, no water was forbidden, after 12h, blood was taken from the eyeballs, and after animals were sacrificed, the lungs were perfused, and the perfusate was collected and then the lungs were removed.
Animal mortality was recorded: the blank group (ctrl.), the linoleic acid preparation lavage control group (LALNs) had no animal death, the model group (LPS) had an animal death rate of 9/10, and the linoleic acid preparation lavage treatment group (LALNs +lps) had an animal death rate of 1/10.
Separating supernatant and precipitate after centrifuging the collected perfusion fluid at 1350rpm at 4 ℃ for 10min, detecting myeloperoxidase activity in the supernatant by using a myeloperoxidase assay kit, wherein the effect of the linoleic acid preparation in example 3 on the MPO activity of the LPS-induced ALI mouse alveolar perfusion fluid is shown in fig. 4, and compared with a blank group, the myeloperoxidase activity in the perfusion fluid of a model group is remarkably increased; compared with the model group, the myeloperoxidase activity of the linoleic acid preparation treatment group tends to be reduced, which indicates that the linoleic acid preparation has better relieving effect on the aggregation of neutrophils of lipopolysaccharide-induced acute lung injury.
The protein content in the perfusate is measured by using a BCA protein concentration measuring kit (enhanced type) for each group of mouse lung perfusate, the effect of the linoleic acid preparation in the embodiment 3 on LPS-induced ALI mouse lung tissue protein leakage is shown in fig. 5, compared with a blank group, the protein content in the perfusate of a model group is obviously improved, compared with the model group, the histone content treated by the linoleic acid preparation is obviously reduced, and the linoleic acid preparation has better effect of relieving edema caused by lipopolysaccharide-induced acute lung injury.
The results of the change in lung histopathology of the mice in example 3 are shown in fig. 6, and the results of the change in lung histopathology of the mice in the blank group are shown under the lens of the lung histopathology of the mice in example 3, the bronchus structure is clear, no inflammatory cell infiltrates, the alveolus structure is complete, no neutrophils are in alveoli, no obvious increase of neutrophils in alveolus interstitium, no obvious thickening of alveolus interval, a small amount of blood flushing is carried out, and no obvious pathological change is seen; compared with a blank group, the model group mice have almost no normal pulmonary alveolus structure in pulmonary tissue section, neutrophils are in pulmonary alveoli, neutrophils in pulmonary alveolus interstitium are obviously increased, the pulmonary alveolus interstitium thickening condition is serious, and pulmonary vessel pulmonary alveolus part is collapsed and interstitium is thickened; whereas the linoleic acid preparation treatment group significantly attenuated these LPS-induced changes, compared to the model group, were characterized by a relatively intact alveolar structure, substantially no neutrophils present in the alveoli, a relatively reduced central granulocytes in the alveolar interstitium, and a relatively reduced degree of alveolar space thickening. From the above results, it was found that the gavage linoleic acid preparation was able to improve the degree of lung histopathological damage in mice.
Example 4 a method for preparing a linoleic acid formulation for treating acute lung injury, taking 40mL of the linoleic acid formulation as an example, comprises the following steps:
7.52mL of safflower seed oil (the linoleic acid content is 79%) or walnut oil (the linoleic acid content is 60%) and 0.24g of soybean lecithin are heated to 60 ℃ so that the soybean lecithin is fully dissolved in the safflower seed oil or the walnut oil to form an oil phase;
Dissolving 0.9mL of glycerol and 0.4mL of Tween-80 in 30.7mL of ultrapure water, dissolving thoroughly to form a water phase, and placing in a water bath kettle to preheat to 60 ℃ for standby;
Dropwise adding the preheated molten oil phase into the water phase under the condition of a 60 ℃ constant-temperature water bath, and stirring for 10min continuously after the mixture is uniformly mixed;
Shearing the incompatible two phases at a high speed of 8000rpm for 10min by an FSH-2A adjustable high-speed refiner, and fully and uniformly mixing to obtain colostrum;
and then circulating for 6 times under the pressure of 1000bar by an ATS high-pressure homogenizer to form the linoleic acid preparation with uniform particle size. After cooling to room temperature, filtration was performed with a 0.45 μm cellulose acetate filter, followed by sterilization and storage at 4℃in the absence of light. The particle size of the linoleic acid preparation prepared by taking safflower seed oil as a raw material is 205.4+/-0.17 nm (PDI=0.12), and the Zeta potential is-42.4+/-1.08 mV.
The particle size of the linoleic acid preparation prepared by taking walnut oil as a raw material is 194.5+/-0.98 nm (PDI=0.154), and the Zeta potential is-43.5+/-0.19 mV.
In addition to the high-content linoleic acid, the safflower seed oil and the walnut oil also contain emulsifying agents such as phospholipid, so that the steps of adding phospholipid and high-speed homogenization can be omitted when the edible oil containing linoleic acid such as safflower seed oil or walnut oil is used as a raw material to prepare the linoleic acid preparation.
Example 5a method for preparing a linoleic acid formulation for treating acute lung injury, taking 40mL of the linoleic acid formulation as an example, comprises the following steps:
Dissolving 0.9mL of glycerol and 0.4mL of Tween-80 in 30.7mL of ultrapure water, dissolving thoroughly to form a water phase, and placing in a water bath kettle to preheat to 60 ℃ for standby;
Under the condition of a 60 ℃ constant-temperature water bath, 7.52mL of safflower seed oil or walnut oil is added into the water phase dropwise, and the mixture is stirred dropwise and fully and uniformly mixed to obtain colostrum;
And then circulating for 6 times under the pressure of 1000bar by an ATS high-pressure homogenizer to form the linoleic acid preparation with uniform particle size. After cooling to room temperature, filtration was performed with a 0.45 μm cellulose acetate filter, followed by sterilization and storage at 4℃in the absence of light.
The particle size of the linoleic acid preparation prepared by taking safflower seed oil as a raw material is 211.8+/-0.96 nm (PDI=0.128), and the Zeta potential is-34.5+/-0.49 mV.
The particle size of the linoleic acid preparation prepared by taking walnut oil as a raw material is 211.5+/-1.75 nm (PDI=0.105), and the Zeta potential is-31.9+/-0.69 mV.
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